Pharmacology_Katzung

Pharmacology_Katzung. Flucytosine is currently available in North America only in an oral formulation. The dosage is 100 mg/kg/d in divided doses in patients with normal renal function. It is well absorbed (>90%), with serum concentrations peaking 1–2 hours after an oral dose. It is poorly protein-bound and penetrates well into all body fluid compartments, including the cerebrospinal fluid. It is eliminated by glomerular filtration with a half-life of 3–4 hours and is removed by hemodialysis. Levels rise rapidly with renal impairment and can lead to toxicity. Toxicity is more likely to occur in AIDS patients and those with renal insufficiency. Peak serum concentrations should be measured periodically in patients with renal insufficiency and maintained between 50 and 100 mcg/mL. Mechanisms of Action & Resistance


Pharmacology_Katzung

Pharmacology_Katzung. Mechanisms of Action & Resistance Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively (Figure 48–1). Human cells are unable to convert the parent drug to its active metabolites, resulting in selective toxicity. Synergy with amphotericin B has been demonstrated in vitro and in vivo. It may be related to enhanced penetration of the flu-cytosine through amphotericin-damaged fungal cell membranes. In vitro synergy with azole drugs also has been seen, although the mechanism is unclear. Resistance is thought to be mediated through altered metabolism of flucytosine, and, although uncommon in primary isolates, it develops rapidly in the course of flucytosine monotherapy.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance is thought to be mediated through altered metabolism of flucytosine, and, although uncommon in primary isolates, it develops rapidly in the course of flucytosine monotherapy. The spectrum of activity of flucytosine is restricted to C neoformans, some Candida sp, and the dematiaceous molds that cause chromoblastomycosis. Flucytosine is rarely used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance. At present clinical use is confined to combination therapy with amphotericin B for cryptococcal meningitis, or with itraconazole for chromoblastomycosis. Flucytosine also has limited utility as monotherapy for fluconazole-resistant candidal urinary tract infections.


Pharmacology_Katzung

Pharmacology_Katzung. The adverse effects of flucytosine result from metabolism (possibly by intestinal flora) to the toxic antineoplastic compound fluorouracil. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently. A form of toxic enterocolitis can occur. There seems to be a narrow therapeutic window, with an increased risk of toxicity at higher drug levels and resistance developing rapidly at subtherapeutic concentrations. The use of drug concentration measurements may be helpful in reducing the incidence of toxic reactions, especially when flucytosine is combined with nephrotoxic agents such as amphotericin B. Azoles are synthetic compounds that can be classified as either imidazoles or triazoles according to the number of nitrogen atoms in the five-membered azole ring, as indicated below. The imidazoles consist of ketoconazole, miconazole, and clotrimazole


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 48–2 Structural formulas of some antifungal azoles. (Figure 48–2). The latter two drugs are now used only in topical therapy. The triazoles include itraconazole, fluconazole, voriconazole, isavuconazole, and posaconazole. Other triazoles are currently under investigation. N X X = C, imidazole X = N, triazole N The pharmacology of each of the azoles is unique and accounts for some of the variations in clinical use. Table 48–2 summarizes the differences among six of the azoles. Mechanisms of Action & Resistance The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes (Figure 48–1). The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and adverse effects.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance to azoles occurs via multiple mechanisms. Once rare, increasing numbers of resistant strains are being reported, suggesting that increasing use of these agents for prophylaxis and therapy may be selecting for clinical drug resistance in certain settings. Clinical Uses, Adverse Effects, & Drug Interactions The spectrum of action of azole medications is broad, including many species of Candida, C neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole, posaconazole, isavuconazole, and voriconazole, even Aspergillus infections. They are TABLE 48–2 Pharmacologic properties of six systemic azole drugs. also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 48–2 Pharmacologic properties of six systemic azole drugs. also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii. As a group, the azoles are relatively nontoxic. The most common adverse reaction is relatively minor gastrointestinal upset. All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. Adverse effects specific to individual agents are discussed below. All azole drugs are prone to drug interactions because they affect the mammalian cytochrome P450 enzyme system to some extent. The most significant reactions are indicated below.


Pharmacology_Katzung

Pharmacology_Katzung. All azole drugs are prone to drug interactions because they affect the mammalian cytochrome P450 enzyme system to some extent. The most significant reactions are indicated below. Ketoconazole was the first oral azole introduced into clinical use. It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome P450 enzymes; that is, it is less selective for fungal P450 than are the newer azoles. As a result, systemic ketoconazole has fallen out of clinical use in the USA and is not discussed in any detail here. It is no longer recommended for the treatment of fungal nail or skin infections.


Pharmacology_Katzung

Pharmacology_Katzung. Itraconazole is available in oral and intravenous formulations and is used at a dosage of 100–400 mg/d. Drug absorption from capsules is increased by food and by low gastric pH. Like other lipid-soluble azoles, it interacts with hepatic microsomal enzymes, though to a lesser degree than ketoconazole. An important drug interaction is reduced bioavailability of itraconazole when taken with rifamycins (rifampin, rifabutin, rifapentine). It does not affect mammalian steroid synthesis, and its effects on the metabolism of other hepatically cleared medications are much less than those of ketoconazole. While itraconazole displays potent antifungal activity, effectiveness can be limited by reduced bioavailability. Newer formulations, including an oral liquid and an intravenous preparation, have utilized cyclodextrin as a carrier molecule to enhance solubility and bioavailability. Like ketoconazole, itraconazole penetrates poorly into the cerebrospinal fluid. Itraconazole is the azole of


Pharmacology_Katzung

Pharmacology_Katzung. utilized cyclodextrin as a carrier molecule to enhance solubility and bioavailability. Like ketoconazole, itraconazole penetrates poorly into the cerebrospinal fluid. Itraconazole is the azole of choice for treatment of disease due to the dimorphic fungi Histoplasma, Blastomyces, and Sporothrix. Itraconazole has activity against Aspergillus sp, but it has been replaced by voriconazole as the azole of choice for aspergillosis. Itraconazole is used extensively in the treatment of dermatophytoses and onychomycosis.


Pharmacology_Katzung

Pharmacology_Katzung. Fluconazole displays a high degree of water solubility and good cerebrospinal fluid penetration. Unlike ketoconazole and itraconazole, its oral bioavailability is high. Drug interactions are also less common because fluconazole has the least effect of all the azoles on hepatic microsomal enzymes. Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections. The drug is available in oral and intravenous formulations and is used at a dosage of 100–800 mg/d.


Pharmacology_Katzung

Pharmacology_Katzung. Fluconazole is the azole of choice in the treatment and secondary prophylaxis of cryptococcal meningitis. Intravenous fluconazole has been shown to be equivalent to amphotericin B in treatment of candidemia in ICU patients with normal white blood cell counts, although echinocandins may have superior activity for this indication. Fluconazole is the agent most commonly used for the treatment of mucocutaneous candidiasis. Activity against the dimorphic fungi is mainly limited to coccidioidal disease, and in particular for meningitis, where high doses of fluconazole often obviate the need for intrathecal amphotericin B. Fluconazole displays no activity against Aspergillus or other filamentous fungi. Prophylactic use of fluconazole has been demonstrated to reduce fungal disease in bone marrow transplant recipients and AIDS patients, but the emergence of fluconazole-resistant fungi has raised concerns about this indication.


Pharmacology_Katzung

Pharmacology_Katzung. Voriconazole is available in intravenous and oral formulations. The recommended dosage is 400 mg/d. The drug is well absorbed orally, with a bioavailability exceeding 90%, and it exhibits less protein binding than itraconazole. Metabolism is predominantly hepatic. Voriconazole is a clinically relevant inhibitor of mammalian CYP3A4, and dose reduction of a number of medications is required when voriconazole is started. These include cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. In September 2012, the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta received reports of a number of cases of fungal meningitis in patients who had received injections with the corticosteroid methylprednisolone. An investigation revealed a multistate outbreak of septic arthritis, paraspinal infections, and meningitis due to environmental molds, with the black mold Exserohilum rostratum being the most commonly isolated species. The outbreak was traced to the injection of methylprednisolone that was contaminated during its preparation by a compounding pharmacy facility in New England. Methylprednisolone injections are commonly given to patients with joint or back arthritis, and in the affected cases the patients were not only inadvertently injected with spores of environmental molds, but the normal immune response to this infection was inhibited by the potent immunosuppressive effect of the corticosteroid. As of November 2013 more than 750 cases of fungal infection


Pharmacology_Katzung

Pharmacology_Katzung. molds, but the normal immune response to this infection was inhibited by the potent immunosuppressive effect of the corticosteroid. As of November 2013 more than 750 cases of fungal infection had been identified in 20 states, with over 60 deaths. Treatment of these infections was challenging, and the CDC recommended the use of intravenous voriconazole as first-line therapy, with the addition of liposomal amphotericin B in cases of severe infection.


Pharmacology_Katzung

Pharmacology_Katzung. Observed toxicities include rash and elevated hepatic enzymes. Visual disturbances are common, occurring in up to 30% of patients receiving intravenous voriconazole, and include blurring and changes in color vision or brightness. These visual changes usually occur immediately after a dose of voriconazole and resolve within 30 minutes. Photosensitivity dermatitis is commonly observed in patients receiving chronic oral therapy. Voriconazole is similar to itraconazole in its spectrum of action, having excellent activity against Candida sp (including some fluconazole-resistant species such as Candida krusei) and the dimorphic fungi. Voriconazole is less toxic than amphotericin B and is the treatment of choice for invasive aspergillosis and some environmental molds (see Box: Iatrogenic Fungal Meningitis). Measurement of voriconazole levels may predict toxicity and clinical efficacy, especially in immunocompromised patients. Therapeutic trough levels should be between 1 and 5 mcg/mL.


Pharmacology_Katzung

Pharmacology_Katzung. Posaconazole was originally available only in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or four doses. Absorption is improved when taken with meals high in fat. An intravenous form of posaconazole and a sustained acting tablet form with higher bioavailability are now available. Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. Measurement of posaconazole levels is recommended in patients with serious invasive fungal infections (especially mold infections); steady-state posaconazole levels should be between 0.5 and 1.5 mcg/mL. Drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented.


Pharmacology_Katzung

Pharmacology_Katzung. Posaconazole is the broadest-spectrum member of the azole family, with activity against most species of Candida and Aspergillus. It is the first azole with significant activity against the agents of mucormycosis. It is currently licensed for salvage therapy in invasive aspergillosis, as well as prophylaxis of fungal infections during induction chemotherapy for leukemia, and for allogeneic bone marrow transplant patients with graft-versushost disease.


Pharmacology_Katzung

Pharmacology_Katzung. Isavuconazonium sulfate is a prodrug of the newest triazole, isavuconazole; 186 mg of the water-soluble prodrug is equivalent to 100 mg of isavuconazole. It is available as highly bioavailable oral capsules and an intravenous formulation. Following a 2-day loading dose of 372 mg administered every 8 hours, isavuconazonium sulfate is given as a single 372-mg daily dose. Food does not significantly impact the oral absorption of isavuconazonium sulfate. Measurement of isavuconazole levels has not been demonstrated to be of benefit. Coadministration with strong 3A4 inhibitors (eg, ritonavir) or inducers (eg, rifampin) is not recommended. Isavuconazole has an antifungal spectrum similar to that of posaconazole. It is currently licensed for the treatment of invasive aspergillosis and invasive mucormycosis. Data from published clinical trials are limited. Preliminary evidence indicates that it is better tolerated than voriconazole.


Pharmacology_Katzung

Pharmacology_Katzung. Echinocandins are the newest class of antifungal agents to be developed. They are large cyclic peptides linked to a long-chain fatty acid. Caspofungin, micafungin, and anidulafungin are the only licensed agents in this category of antifungals, although other drugs are under active investigation. These agents are active against Candida and Aspergillus, but not C neoformans or the agents of zygomycosis and mucormycosis.


Pharmacology_Katzung

Pharmacology_Katzung. Echinocandins are available only in intravenous formulations. Caspofungin is administered as a single loading dose of 70 mg, followed by a daily dose of 50 mg. Caspofungin is water soluble and highly protein-bound. The half-life is 9–11 hours, and the metabolites are excreted by the kidneys and gastrointestinal tract. Dosage adjustments are required only in the presence of severe hepatic insufficiency. Micafungin displays similar properties with a half-life of 11–15 hours and is used at a dose of 150 mg/d for treatment of esophageal candidiasis, 100 mg/d for treatment of candidemia, and 50 mg/d for prophylaxis of fungal infections. Anidulafungin has a half-life of 24–48 hours. For esophageal candidiasis, it is administered intravenously at 100 mg on the first day and 50 mg/d thereafter for 14 days. For candidemia, a loading dose of 200 mg is recommended with 100 mg/d thereafter for at least 14 days after the last positive blood culture. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Echinocandins act at the level of the fungal cell wall by inhibiting the synthesis of β(1–3)-glucan (Figure 48–1). This results in disruption of the fungal cell wall and cell death. Caspofungin is currently licensed for disseminated and mucocutaneous candidal infections, as well as for empiric antifungal therapy during febrile neutropenia, and has largely replaced amphotericin B for the latter indication. Of note, caspofungin is licensed for use in invasive aspergillosis only as salvage therapy in patients who have failed to respond to amphotericin B, and not as primary therapy. Micafungin is licensed for mucocutaneous candidiasis, candidemia, and prophylaxis of candidal infections in bone marrow transplant patients. Anidulafungin is approved for use in esophageal candidiasis and invasive candidiasis, including candidemia.


Pharmacology_Katzung

Pharmacology_Katzung. Echinocandin agents are extremely well tolerated, with minor gastrointestinal side effects and flushing reported infrequently. Elevated liver enzymes have been noted in several patients receiving caspofungin in combination with cyclosporine, and this combination should be avoided. Micafungin has been shown to increase levels of nifedipine, cyclosporine, and sirolimus. Anidulafungin does not seem to have significant drug interactions, but histamine release may occur during intravenous infusion. Clinically significant echinocandin resistance is an emerging concern especially with invasive Candida glabrata infections in immunocompromised patients.


Pharmacology_Katzung

Pharmacology_Katzung. Griseofulvin is a very insoluble fungistatic drug derived from a species of penicillium. Its only use is in the systemic treatment of dermatophytosis (see Chapter 61). It is administered in a micro-crystalline oral form at a dosage of up to 1 g/d. Absorption is improved when it is given with fatty foods. Griseofulvin’s mechanism of action at the cellular level is unclear, but it is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection. Because its action is to prevent infection of these new skin structures, griseofulvin must be administered for 2–6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse. Adverse effects include an allergic syndrome much like serum sickness, serious skin reactions, a lupus-like syndrome, hepatotoxicity, and drug interactions with


Pharmacology_Katzung

Pharmacology_Katzung. nail and is often followed by relapse. Adverse effects include an allergic syndrome much like serum sickness, serious skin reactions, a lupus-like syndrome, hepatotoxicity, and drug interactions with warfarin and phenobarbital. Griseofulvin has been largely replaced by newer antifungal medications such as itraconazole and terbinafine.


Pharmacology_Katzung

Pharmacology_Katzung. Terbinafine is a synthetic allylamine that is available in an oral formulation and is used at a dosage of 250 mg/d. It is used in the treatment of dermatophytoses, especially onychomycosis (see Chapter 61). Like griseofulvin, terbinafine is a keratophilic medication, but unlike griseofulvin, it is fungicidal. Like the azole drugs, it interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase (Figure 48–1). This leads to the accumulation of the sterol squalene, which is toxic to the organism. One 250-mg tablet given daily for 12 weeks achieves a cure rate of up to 90% for onychomycosis and is more effective than griseofulvin or itraconazole. Adverse effects are rare, consisting primarily of gastrointestinal upset and headache, but serious hepatotoxicity has been reported. Terbinafine does not seem to affect the P450 system and has demonstrated no significant drug interactions to date.


Pharmacology_Katzung

Pharmacology_Katzung. Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration and is only used topically. Nystatin is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes. It is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, nystatin has little toxicity, although oral use is often limited by the unpleasant taste. Nystatin is active against most Candida sp and is most commonly used for suppression of local candidal infections. Some common indications include oropharyngeal thrush, vaginal candidiasis, and intertriginous candidal infections.


Pharmacology_Katzung

Pharmacology_Katzung. The two azoles most commonly used topically are clotrimazole and miconazole; several others are available (see Preparations Available). Both are available over the counter and are often used for vulvovaginal candidiasis. Oral clotrimazole troches are available for treatment of oral thrush and are a pleasant-tasting alternative to nystatin. In cream form, both agents are useful for dermatophytic infections, including tinea corporis, tinea pedis, and tinea cruris. Absorption is negligible, and adverse effects are rare. Topical and shampoo forms of ketoconazole are also available and useful in the treatment of seborrheic dermatitis and pityriasis versicolor. Several other azoles are available for topical use (see Preparations Available). Terbinafine and naftifine are allylamines available as topical creams (see Chapter 61). Both are effective for treatment of tinea cruris and tinea corporis. These are prescription drugs in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Terbinafine and naftifine are allylamines available as topical creams (see Chapter 61). Both are effective for treatment of tinea cruris and tinea corporis. These are prescription drugs in the USA. Lipid formulations: Lower toxicity, higher doses can be used


Pharmacology_Katzung

Pharmacology_Katzung. Lipid formulations: Lower toxicity, higher doses can be used Fluconazole, voriconazole, posaconazole, isavuconazole: Fluconazole has excellent CNS penetration, used in fungal meningitis •FlucytosineInterferes with DNA and RNA synthesis selectively in fungi Synergistic with amphotericin•systemictoxicity in host due to DNA and RNA effects Cryptococcus and chromoblastomycosis infections Oral•duration,hours•renalexcretion•Toxicity: Myelosuppression PYRIMIDINE ANALOG • Micafungin, anidulafungin: Micafungin increases levels of nifedipine, cyclosporine, sirolimus; anidulafungin is relatively free of this interaction •TerbinafineInhibits epoxidation of squaleneinfungi•increasedlevels are toxic to fungi Reduces ergosterol •preventssynthesisoffungal cell membrane Mucocutaneous fungal infections Oral•duration,days•Toxicity: Gastrointestinal upset, headache, hepatotoxicity•Interactions: None reported ALLYLAMINE Lipid formulations Abelcet, AmBisome


Pharmacology_Katzung

Pharmacology_Katzung. Lipid formulations Abelcet, AmBisome Clotrimazole Generic, Lotrimin, Mycelex, others Econazole Generic, Ecoza Fluconazole Generic, Diflucan Flucytosine Generic, Ancobon Griseofulvin Grifulvin, Gris-Peg Itraconazole Generic, Sporanox, Onmel Ketoconazole Generic, Nizoral, others Miconazole Generic, Oravig, Micatin Oxiconazole Generic, Oxistat, others Terbinafine Generic, Lamisil Terconazole Generic, Terazol 3, Terazol 7 Tioconazole Vagistat-1, Monistat 1 Tolnaftate Generic, Aftate, Tinactin, others Ashbee HR et al: Therapeutic drug monitoring (TDM) of antifungal agents: Guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014;69:1162. Cornely OA et al: Posazonacole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348.


Pharmacology_Katzung

Pharmacology_Katzung. Cornely OA et al: Posazonacole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348. Diekema DJ et al: Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 2003;41:3623. Felton T, Troke PF, Hope WW: Tissue penetration of antifungal agents. Clin Microbiol Rev 2014:27:68. Herbrecht R et al: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408. Lewis RE: Current concepts in antifungal pharmacology. Mayo Clin Proc 2011;86:805. Nett JE, Andes DR: Antifungal agents: Spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am 2016;30:51. Pasqualotto AC, Denning DW: New and emerging treatments for fungal infection. J Antimicrob Chemother 2008;61(Suppl 1):i19.


Pharmacology_Katzung

Pharmacology_Katzung. Pasqualotto AC, Denning DW: New and emerging treatments for fungal infection. J Antimicrob Chemother 2008;61(Suppl 1):i19. Perlin DS: Echinocandin resistance, susceptibility testing and prophylaxis: Implications for patient management. Drugs 2014;74:1573. Rogers TR: Treatment of zygomycosis: Current and new options. J Antimicrob Chemother 2008;61(Suppl 1):i35. Wong-Beringer A, Jacobs RA, Guglielmo BJ: Lipid formulations of amphotericin B: Clinical efficacy and toxicities. Clin Infect Dis 1998;27:603. Voriconazole Generic, Vfend


Pharmacology_Katzung

Pharmacology_Katzung. Voriconazole Generic, Vfend The mold subsequently isolated from the patient’s CSF was identified as Coccidioides immitis. Patients of African-American and Southeast Asian descent as well as immuno-compromised patients are at an increased risk for developing chronic forms of coccidioidomycosis such as meningitis. C. immitis is a dimorphic fungus that grows in the soil of the San Joaquin Valley in California, while closely related C posadasii is found elsewhere in desert regions of the southwest USA, parts of Mexico, and Central and South America. Oral therapy with fluconazole was initiated at a dose of 800 mg/day and patient’s headache, fever, and double vision resolved within 7 days. Patients experiencing treatment failure with fluconazole may require treatment with intrathecal amphotericin B. Generally, coccidioidal meningitis requires lifelong therapy because of a high incidence of disease relapse with treatment discontinua-tion and is 100% fatal without antifungal treatment.


Pharmacology_Katzung

Pharmacology_Katzung. Sharon Safrin, MD A 35-year-old white woman who recently tested seropositive for both HIV and hepatitis B virus surface antigen is referred for evaluation. She is feeling well overall but reports a 25-pack-year smoking history. She drinks 3–4 beers per week and has no known medication allergies. She has a history of heroin use and is currently receiving methadone. Physical examination reveals normal vital signs and no abnormalities. White blood cell count is 5800 cells/mm3 with a normal differential, hemoglobin is 11.8 g/dL, all liver tests are within normal limits, CD4 cell count is 278 cells/mm3, and viral load (HIV RNA) is 110,000 copies/mL. What other laboratory tests should be ordered? Which antiretroviral medica-tions would you begin?


Pharmacology_Katzung

Pharmacology_Katzung. Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell. Therefore, to be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell. As a corollary, nonselective inhibitors of virus replication may interfere with host cell function and result in toxicity. Progress in antiviral chemotherapy began in the early 1950s, when the search for anti-cancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two first-generation antiviral agents, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cell DNA as well as viral DNA) that rendered them too toxic for systemic use. However, both agents are effective when used topically for the treatment of herpes keratitis.


Pharmacology_Katzung

Pharmacology_Katzung. Knowledge of the mechanisms of viral replication has provided insights into critical steps in the viral life cycle that can serve as potential targets for antiviral therapy. Recent research has focused on identifying agents with greater selectivity, higher potency, in vivo stability, and reduced toxicity. Antiviral therapy is now available for herpes simplex virus (HSV), cytomegalovirus (CMV), varicella zoster virus (VZV), hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV). Antiviral drugs share the common property of being virustatic; they are active only against replicating viruses and do not affect latent virus. Whereas some infections require monotherapy for brief periods of time (eg, HSV, influenza), others require multiple drug therapy for indefinite periods (HIV). In chronic illnesses such as viral hepatitis and HIV infection, potent inhibition of viral replication is crucial in limiting the


Pharmacology_Katzung

Pharmacology_Katzung. others require multiple drug therapy for indefinite periods (HIV). In chronic illnesses such as viral hepatitis and HIV infection, potent inhibition of viral replication is crucial in limiting the extent of systemic damage.


Pharmacology_Katzung

Pharmacology_Katzung. Viral replication requires several steps (see Figure 49–1). Antiviral agents can potentially target any of these steps. Three oral nucleoside analogs are licensed for the treatment of HSV and VZV infections: acyclovir, valacyclovir, and famciclovir. They have similar mechanisms of action and comparable indications for clinical use (see Table 49–1); all are well tolerated.


Pharmacology_Katzung

Pharmacology_Katzung. Comparative trials have demonstrated similar efficacies of these three agents for the treatment of HSV, with shortening of the duration of symptoms by approximately 2 days, the time to lesion healing by 4 days, and the duration of viral shedding by 7 days in first episodes of genital herpes and shortening of the overall time course by 1–2 days in recurrent genital herpes. Treatment of first-episode genital herpes does not alter the frequency or severity of recurrent outbreaks. Long-term suppression with antiherpes agents in patients with frequent recurrences of genital herpes decreases the frequency of symptomatic recurrences and of asymptomatic viral shedding, thus decreasing the rate of sexual transmission. However, outbreaks may resume upon discontinuation of suppression. The efficacy of the anti-herpes agents in orolabial herpes is generally less than that in anogenital herpes.


Pharmacology_Katzung

Pharmacology_Katzung. Integration (retroviruses) Transcription Blocked by INSTIs (HIV) Blocked by PIs (HIV, HCV) Blocked by NRTIs, NNRTIs (HIV), Nucleoside/nucleotide analogs (HSV, HBV) Viral attachment and entry Viral release Uncoating Nucleic acid synthesis Viral protein synthesis Packaging and assembly MammaliancellBlocked by amantadine, rimantadine (influenza) Blocked by enfuvirtide (HIV); docosanol (HSV), maraviroc (HIV), palivizumab (RSV) Blocked by neuraminidase inhibitors (influenza) Penetration Blocked by interferon-alfa (HBV, HCV) FIGURE 49–1 The major sites of antiviral drug action. Note: Interferon alfas are speculated to have multiple sites of action. (Modified and reproduced, with permission, from Trevor AJ, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 9th ed. McGraw-Hill, 2010. Copyright © The McGraw-Hill Companies, Inc.) TABLE 49–1 Agents to treat or prevent herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 49–1 Agents to treat or prevent herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. 1 Dose adjustment is necessary for renal insufficiency. 2 Higher doses may be necessary in HIV-infected patients. HIV, human immunodeficiency virus; HSV, herpes simplex virus; IV, intravenous; VZV, varicella-zoster virus.


Pharmacology_Katzung

Pharmacology_Katzung. The antiherpes agents significantly decrease the total number of the latter agents were associated with a shorter duration of zosterlesions, duration of symptoms, and viral shedding in patients with associated pain. Since VZV is less susceptible to the antiherpes varicella (if begun within 24 hours after the onset of rash) or cutane-agents than HSV, higher doses are required (Table 49–1). ous zoster (if begun within 72 hours); the risk of post-herpetic neu-The antiherpes agents may also be administered prophylactiralgia is also reduced if treatment is initiated early. In comparative cally for the prevention of HSV or VZV infection in patients trials with acyclovir for the treatment of patients with zoster, rates of undergoing organ transplantation, as well as for the treatment of cutaneous healing with valacyclovir or famciclovir were similar, but these infections should they occur.


Pharmacology_Katzung

Pharmacology_Katzung. Acyclovir is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV, but it is approximately 10 times more potent against HSV-1 and HSV-2 than against VZV. In vitro activity against Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) is present but weaker. Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the diand triphosphate compounds by host cell enzymes (Figure 49–2). Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated—and the active metabolite accumulates— only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex; and chain termination following incorporation into the viral DNA.


Pharmacology_Katzung

Pharmacology_Katzung. The bioavailability of oral acyclovir is low (15–20%) and is unaffected by food. Topical formulations produce high concentrations in herpetic lesions, but systemic concentrations are undetectable by this route. Acyclovir is cleared primarily by glomerular filtration and tubular secretion. The half-life is 2.5–3 hours in patients with normal renal function and 20 hours in patients with anuria. Acyclovir enzymes (eg, thymidine kinase, UL97) FIGURE 49–2 Mechanism of action of antiherpes agents. diffuses readily into most tissues and body fluids. Cerebrospinal fluid concentrations are 20–50% of serum values.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 49–2 Mechanism of action of antiherpes agents. diffuses readily into most tissues and body fluids. Cerebrospinal fluid concentrations are 20–50% of serum values. Acyclovir is the only one of the three antiherpes agents that is available for intravenous use in the United States. Intravenous acyclovir is the treatment of choice for herpes simplex encephalitis, neonatal HSV infection, and serious HSV or VZV infections (Table 49–1). In neonates with central nervous system HSV, oral acyclovir suppression for 6 months following acute treatment improves neurodevelopmental outcomes. In immunocompromised patients with VZV infection, intravenous acyclovir reduces the incidence of cutaneous and visceral dissemination. Topical acyclovir cream is substantially less effective than oral therapy for primary HSV infection. It is of no benefit in treating recurrent genital herpes.


Pharmacology_Katzung

Pharmacology_Katzung. Topical acyclovir cream is substantially less effective than oral therapy for primary HSV infection. It is of no benefit in treating recurrent genital herpes. Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase, and clinically resistant infections have been reported in immunocompromised hosts. Most clinical isolates are resistant on the basis of deficient thymidine kinase activity and thus are cross-resistant to valacyclovir, famciclovir, and ganciclovir. Agents such as foscarnet, cidofovir, and trifluridine do not require activation by viral thymidine kinase and therefore have preserved activity against the most prevalent acyclovir-resistant strains (Figure 49–2).


Pharmacology_Katzung

Pharmacology_Katzung. Acyclovir is generally well tolerated, although nausea, diarrhea, and headache may occur. Intravenous infusion may be associated with reversible renal toxicity (ie, crystalline nephropathy or interstitial nephritis) or neurologic effects (eg, tremors, delirium, seizures). However, these are uncommon with adequate hydration and avoidance of rapid infusion rates. High doses of acyclovir cause chromosomal damage and testicular atrophy in rats, but there has been no evidence of teratogenicity, reduction in sperm production, or cytogenetic alterations in peripheral blood lymphocytes in patients receiving daily suppression of genital herpes for more than 10 years. A recent study found no evidence of increased birth defects in infants exposed to acyclovir during the first trimester. In fact, the American College of Obstetricians and Gynecologists recommends suppressive acyclovir therapy beginning at week 36 in pregnant women with active recurrent genital herpes to reduce the risk of


Pharmacology_Katzung

Pharmacology_Katzung. the American College of Obstetricians and Gynecologists recommends suppressive acyclovir therapy beginning at week 36 in pregnant women with active recurrent genital herpes to reduce the risk of recurrence at delivery and possibly the need for cesarean section.


Pharmacology_Katzung

Pharmacology_Katzung. Concurrent use of nephrotoxic agents may enhance the potential for nephrotoxicity. Probenecid and cimetidine decrease acyclovir clearance and increase exposure. Somnolence and lethargy may occur in patients receiving concomitant zidovudine and acyclovir. Valacyclovir is the l-valyl ester of acyclovir. It is rapidly converted to acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine, resulting in serum levels that are three to five times greater than those achieved with oral acyclovir and approximate those achieved with intravenous acyclovir. Oral bioavailability is 54–70%, and cerebrospinal fluid levels are about 50% of those in serum. Elimination half-life is 2.5–3.3 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Valacyclovir is generally well tolerated, although nausea, headache, vomiting, or rash may occur. At high doses, confusion, hallucinations, and seizures have been reported. AIDS patients who received high-dosage valacyclovir chronically (ie, 8 g/d) had increased gastrointestinal intolerance as well as thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome; this dose has also been associated with confusion and hallucinations in transplant patients. There is no evidence of an increased risk of birth defects in infants exposed to valacyclovir during pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog. After oral administration, famciclovir is rapidly deacetylated and oxidized by first-pass metabolism to penciclovir. It is active in vitro against HSV-1, HSV-2, VZV, EBV, and HBV. As with acyclovir, activation by phosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis. Unlike acyclovir, however, penciclovir does not cause chain termination. Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate, but it achieves higher intracellular concentrations. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient; these are cross-resistant to acyclovir and famciclovir.


Pharmacology_Katzung

Pharmacology_Katzung. The bioavailability of penciclovir from orally administered famciclovir is 70%. The intracellular half-life of penciclovir triphosphate is prolonged, at 7–20 hours. Penciclovir is excreted primarily in the urine. Oral famciclovir is generally well tolerated, although headache, nausea, or diarrhea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses. However, men receiving daily famciclovir (250 mg every 12 hours) for 18 weeks had no changes in sperm morphology or motility. In one study, there was no evidence of increased birth defects in infants exposed to famciclovir during the first trimester. The incidence of mammary adenocarcinoma was increased in female rats receiving famciclovir for 2 years.


Pharmacology_Katzung

Pharmacology_Katzung. The guanosine analog penciclovir, the active metabolite of famciclovir, is available for topical use. Penciclovir cream (1%) shortened the median duration of recurrent herpes labialis by ~17 hours compared to placebo when applied within 1 hour of the onset of prodromal symptoms and continued every 2 hours during waking hours for 4 days. Adverse effects are uncommon, other than application site reactions in ~1%. Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits fusion between the host cell plasma membrane and the HSV envelope, thereby preventing viral entry into cells and subsequent viral replication. Topical docosanol 10% cream is available without a prescription. When applied within 12 hours of the onset of prodromal symptoms, five times daily, median healing time was shortened by 18 hours compared with placebo in recurrent orolabial herpes. Application site reactions occur in ~2%.


Pharmacology_Katzung

Pharmacology_Katzung. Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intra-cellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49–2). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon-alfa, has been used successfully in the treatment of acyclovir-resistant HSV infections.


Pharmacology_Katzung

Pharmacology_Katzung. Two compounds (pritelivir and amenamevir) belong to the new class of helicase-primase inhibitors and are under development for HSV infection. Valomaciclovir, an inhibitor of the viral DNA polymerase, is currently under clinical evaluation for the treatment of patients with acute zoster and acute EBV infection (infectious mononucleosis). CMV infections occur primarily in the setting of advanced immunosuppression and are typically due to reactivation of latent infection. Dissemination of infection results in end-organ disease, including retinitis, colitis, esophagitis, central nervous system disease, and pneumonitis. Although the incidence in HIV-infected patients has markedly decreased with the advent of potent antiretroviral therapy, clinical reactivation of CMV infection after organ transplantation is still prevalent.


Pharmacology_Katzung

Pharmacology_Katzung. The availability of oral valganciclovir has decreased the use of intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir for the prophylaxis and treatment of end-organ CMV disease (Table 49–2). Oral valganciclovir has replaced oral ganciclovir because of its lower pill burden. TABLE 49–2 Agents to treat cytomegalovirus (CMV) infection. 1Dosage must be reduced in patients with renal insufficiency. Ganciclovir is an acyclic guanosine analog that requires activation by triphosphorylation before inhibiting the viral DNA polymerase. Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells. The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation (Figure 49–2). Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and HHV-8. Its activity against CMV is up to 100 times greater than that of acyclovir.


Pharmacology_Katzung

Pharmacology_Katzung. Ganciclovir is administered intravenously; the bioavailability of oral ganciclovir is poor, and it is no longer available in the USA. Ganciclovir gel is available for the treatment of acute herpetic keratitis. Cerebrospinal fluid concentrations are approximately 50% of serum concentrations. The elimination half-life is 4 hours, and the intracellular half-life is prolonged at 16–24 hours. Clearance of the drug is linearly related to creatinine clearance. Ganciclovir is readily cleared by hemodialysis.


Pharmacology_Katzung

Pharmacology_Katzung. Intravenous ganciclovir has been shown to delay progression of CMV retinitis in immunocompromised patients. Dual therapy with foscarnet and ganciclovir is more effective in delaying progression of retinitis than either drug alone in patients with AIDS (see Foscarnet), although adverse effects are compounded. Intravenous ganciclovir is also used to treat CMV colitis, esophagitis, and pneumonitis (the latter often in combination with intravenous cytomegalovirus immunoglobulin) in immunocompromised patients. Intravenous ganciclovir, followed by either oral ganciclovir or high-dose oral acyclovir, reduces the risk of CMV infection in transplant recipients. Limited data in infants with symptomatic congenital neurologic CMV disease suggest that treatment with IV ganciclovir may reduce hearing loss. The risk of Kaposi’s sarcoma is reduced in AIDS patients receiving long-term ganciclovir, presumably because of activity against HHV-8.


Pharmacology_Katzung

Pharmacology_Katzung. Intravitreal injections of ganciclovir or the intraocular ganciclovir implant may be used to treat CMV retinitis. Concurrent therapy with a systemic anti-CMV agent is necessary to prevent other sites of end-organ CMV disease. Resistance to ganciclovir increases with duration of use. The more common mutation, in UL97, results in decreased levels of the triphosphorylated (ie, active) form of ganciclovir. The less common UL54 mutation in DNA polymerase results in higher levels of resistance and potential cross-resistance with cidofovir and foscarnet. Antiviral susceptibility testing is recommended in patients in whom resistance is suspected clinically.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effect of intravenous ganciclovir treatment is myelosuppression, which although reversible may be dose-limiting. Other potential adverse effects are nausea, diarrhea, fever, rash, headache, insomnia, and peripheral neuropathy. Central nervous system toxicity (confusion, seizures, psychiatric disturbance) and hepatotoxicity have been rarely reported. Intravitreal ganciclovir has been associated with vitreous hemorrhage and retinal detachment. Ganciclovir is mutagenic in mammalian cells and carcinogenic and embryotoxic at high doses in animals and causes aspermatogenesis; the clinical significance of these preclinical data is unclear. Levels of ganciclovir may rise in patients concurrently taking probenecid or trimethoprim. Concurrent use of ganciclovir with didanosine may result in increased levels of didanosine.


Pharmacology_Katzung

Pharmacology_Katzung. Levels of ganciclovir may rise in patients concurrently taking probenecid or trimethoprim. Concurrent use of ganciclovir with didanosine may result in increased levels of didanosine. Valganciclovir is an l-valyl ester prodrug of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly hydrolyzed to ganciclovir by esterases in the intestinal wall and liver. Valganciclovir has a bioavailability of 60% and should be taken with food. The AUC0–24h resulting from oral valganciclovir (900 mg once daily) is similar to that after 5 mg/kg once daily of intravenous ganciclovir and approximately 1.65 times that of oral ganciclovir. The major route of elimination is renal, through glomerular filtration and active tubular secretion. Plasma concentrations of valganciclovir are reduced ~50% by hemodialysis.


Pharmacology_Katzung

Pharmacology_Katzung. Valganciclovir is as effective as intravenous ganciclovir for the treatment of CMV retinitis and is also indicated for the prevention of CMV disease in high-risk solid organ and bone marrow transplant recipients. Adverse effects, drug interactions, and resistance patterns are the same as those associated with ganciclovir. Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog that inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1, and HIV-2.


Pharmacology_Katzung

Pharmacology_Katzung. Foscarnet is available in an intravenous formulation only; poor oral bioavailability and gastrointestinal intolerance preclude oral use. Cerebrospinal fluid concentrations are 43–67% of steady-state serum concentrations. Although the mean plasma half-life is 3–7 hours, up to 30% of foscarnet may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance. Serum drug concentrations are reduced ~50% by hemodialysis.


Pharmacology_Katzung

Pharmacology_Katzung. Foscarnet is effective in the treatment of end-organ CMV disease (ie, retinitis, colitis, and esophagitis), including ganciclovirresistant disease; it is also effective against acyclovir-resistant HSV and VZV infections. The dosage of foscarnet must be titrated according to the patient’s calculated creatinine clearance before each infusion. Use of an infusion pump to control the rate of infusion is important to prevent toxicity, and large volumes of fluid are required because of the drug’s poor solubility. The combination of ganciclovir and foscarnet is synergistic in vitro against CMV and has been shown to be superior to either agent alone in delaying progression of retinitis; however, toxicity is also increased when these agents are administered concurrently. As with ganciclovir, a decrease in the incidence of Kaposi’s sarcoma has been observed in patients who have received long-term foscarnet.


Pharmacology_Katzung

Pharmacology_Katzung. Foscarnet has been administered intravitreally for the treatment of CMV retinitis in patients with AIDS, but data regarding efficacy and safety are incomplete. Resistance to foscarnet in HSV and CMV isolates is due to point mutations in the DNA polymerase gene and is typically associated with prolonged or repeated exposure to the drug. Mutations in the HIV-1 reverse transcriptase gene have also been described. Although foscarnet-resistant CMV isolates are typically cross-resistant to ganciclovir, foscarnet activity is usually maintained against ganciclovirand cidofovir-resistant isolates of CMV.


Pharmacology_Katzung

Pharmacology_Katzung. Potential adverse effects of foscarnet include renal impairment, hypoor hypercalcemia, hypoor hyperphosphatemia, hypokalemia, and hypomagnesemia. Saline preloading helps prevent nephrotoxicity, as does avoidance of concomitant administration of drugs with nephrotoxic potential (eg, amphotericin B, pentamidine, aminoglycosides). The risk of severe hypocalcemia, caused by chelation of divalent cations, is increased with concomitant use of pentamidine. Genital ulcerations associated with foscarnet therapy may be due to high levels of ionized drug in the urine. Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue have been reported; the risk of anemia may be additive in patients receiving concurrent zidovudine. Central nervous system toxicity includes headache, hallucinations, and seizures; the risk of seizures may be increased with concurrent use of imipenem. Foscarnet caused chromosomal damage in preclinical studies.


Pharmacology_Katzung

Pharmacology_Katzung. Cidofovir is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus. In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes (Figure 49–2); thus activity is maintained against thymidine kinase-deficient or altered strains of CMV or HSV. Cidofovir diphosphate acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain. Cidofovirresistant isolates tend to be cross-resistant with ganciclovir but retain susceptibility to foscarnet.


Pharmacology_Katzung

Pharmacology_Katzung. Although the terminal half-life of cidofovir is approximately 2.6 hours, the active metabolite cidofovir diphosphate has a prolonged intracellular half-life of 17–65 hours, thus allowing infrequent dosing. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Cerebrospinal fluid penetration is poor. Elimination is by active renal tubular secretion. High-flux hemodialysis reduces serum levels of cidofovir by approximately 75%.


Pharmacology_Katzung

Pharmacology_Katzung. Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus, human papillomavirus, BK polyomavirus, vaccinia, and poxvirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Before each infusion, cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The primary adverse effect of intravenous cidofovir is a dose-dependent proximal tubular nephrotoxicity, which may be reduced with prehydration using normal saline. Proteinuria, azotemia, metabolic acidosis, and Fanconi’s syndrome may occur. Concurrent administration of other potentially nephrotoxic agents (eg, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other potential adverse effects include uveitis, ocular hypotony, and neutropenia (15–24%). Concurrent probenecid use may result in other toxicities or drug-drug interactions (see Chapter 36). Cidofovir is mutagenic, gonadotoxic, and embryotoxic, and causes hypospermia and mammary adenocarcinomas in animals. Brincidofovir is a nucleoside agent with activity against HSV, CMV, adenovirus, BK virus, and poxvirus. It is currently under clinical investigation for CMV and adenovirus infections.


Pharmacology_Katzung

Pharmacology_Katzung. Brincidofovir is a nucleoside agent with activity against HSV, CMV, adenovirus, BK virus, and poxvirus. It is currently under clinical investigation for CMV and adenovirus infections. Substantial advances have been made in antiretroviral therapy since the introduction of the first agent, zidovudine, in 1987. Six classes of antiretroviral agents are currently available for use: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 co-receptor antagonists, and integrase strand transfer inhibitors (INSTIs) (Table 49–3). These agents inhibit HIV replication at different parts of the cycle (Figure 49–3).


Pharmacology_Katzung

Pharmacology_Katzung. Knowledge of viral dynamics through the use of viral load and resistance testing has made it clear that combination therapy with maximally potent agents will reduce viral replication to the lowest possible level, thereby reducing the number of cumulative mutations and decreasing the likelihood of emergence of resistance. Thus, administration of combination antiretroviral therapy, typically including at least three antiretroviral agents with differing susceptibility patterns, has become the standard of care. Viral susceptibility to specific agents varies among patients and may change with time. Therefore, such combinations must be chosen with care and tailored to the individual, as must changes to a given regimen. In addition to potency and susceptibility, important factors in the selection of agents for any given patient are tolerability, convenience, and optimization of adherence. New drugs with high potency, low toxicity, and good tolerability increase the feasibility of early,


Pharmacology_Katzung

Pharmacology_Katzung. of agents for any given patient are tolerability, convenience, and optimization of adherence. New drugs with high potency, low toxicity, and good tolerability increase the feasibility of early, lifelong treatment. As new agents have become available, several older ones have had diminished usage, because of either suboptimal safety or inferior efficacy. Zalcitabine (ddC; dideoxycytidine) is no longer marketed, and regimens containing zidovudine (AZT; azidothymidine), ddI (didanosine), or stavudine (d4T) are infrequently recommended as first-line regimens.


Pharmacology_Katzung

Pharmacology_Katzung. Decrease of the circulating viral load by antiretroviral therapy is correlated with enhanced survival as well as decreased morbidity. Also, the use of antiretroviral therapy strongly reduces the risk for heterosexual and same-sex HIV transmission. Discussion of antiretroviral agents in this chapter is specific to HIV-1. Patterns of susceptibility of HIV-2 to these agents may vary; however, there is innate resistance to the NNRTIs and enfuvirtide as well as a lower barrier of resistance to NRTIs and PIs. The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase; incorporation into the growing viral DNA chain causes premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49–3). Each agent requires intra-cytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form.


Pharmacology_Katzung

Pharmacology_Katzung. Typical resistance mutations include M184V, L74V, D67N, and M41L. Lamivudine or emtricitabine therapy tends to select rapidly for the M184V mutation in regimens that are not fully suppressive. While the M184V mutation confers reduced susceptibility to abacavir, didanosine, and zalcitabine, its presence may restore phenotypic susceptibility to zidovudine. The K65R/N mutation is associated with reduced susceptibility to tenofovir, abacavir, lamivudine, and emtricitabine.


Pharmacology_Katzung

Pharmacology_Katzung. All NRTIs may be associated with mitochondrial toxicity, which may manifest as peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis. Less commonly, lactic acidosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. Lipoatrophy and insulin resistance may occur most frequently with use of the thymidine analogs stavudine and zidovudine, and least frequently with use of tenofovir, lamivudine, emtricitabine, and abacavir.


Pharmacology_Katzung

Pharmacology_Katzung. Abacavir is a guanosine analog that is well absorbed following oral administration (83%) and is unaffected by food. The serum half-life is 1.5 hours. The drug undergoes hepatic glucuronidation and carboxylation. Dosage reduction is recommended in mild hepatic impairment; no data are available for patients with moderate or severe liver disease. Since the drug is metabolized by alcohol dehydrogenase, serum levels of abacavir may be increased with concurrent alcohol (ie, ethanol) ingestion. Cerebrospinal fluid levels are approximately one-third those of plasma. Abacavir is one of the NRTI agents recommended for use in pregnancy (Table 49–5).


Pharmacology_Katzung

Pharmacology_Katzung. Hypersensitivity reactions, occasionally fatal, have been reported in up to 8% of patients receiving abacavir and may be more severe in association with once-daily dosing. Symptoms, which generally occur within the first 6 weeks of therapy, include fever, fatigue, nausea, vomiting, diarrhea, and abdominal pain. Dyspnea, pharyngitis, and cough, and elevations in serum aminotransferase or creatine kinase levels may also be present, with skin rash in ~50% of patients. Rechallenge is contraindicated. Screening for HLA-B*5701 before initiation of abacavir therapy is important to identify patients with an increased risk for abacavirassociated hypersensitivity reaction (see Table 5–4). Although the positive predictive value of this test is only about 50%, it has a negative predictive value approaching 100%.


Pharmacology_Katzung

Pharmacology_Katzung. Rash occurs in approximately 5% of patients, typically in the first 6 weeks of treatment. Less frequent adverse events are fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue, and pancreatitis. In some studies but not in others, abacavir has been associated with an increased risk of myocardial infarction. The class effects of mitochondrial toxicity and disorders of lipid metabolism seem to be less common with abacavir than with other nucleoside analogs. TABLE 49–3 Currently available antiretroviral agents. Abacavir NRTI1 300 mg bid or 600 mg qd Test to rule out the presence Rash, hypersensitivity Avoid alcohol. of the HLA-B5701 allele prior reaction, nausea; to initiation of therapy. possible increase in


Pharmacology_Katzung

Pharmacology_Katzung. Atazanavir PI2 400 mg qd or 300 mg qd with ritonavir Take with food. Avoid Nausea, rash, myalgia, See footnote 4. Avoid elvitegravir/ 100 mg qd or cobicistat 150 mg qd; adjust concomitant antacids. indirect hyperbilirubinemia, cobicistat, etravirine, fosamprenavir, dose in hepatic insufficiency Separate dosing acid-diarrhea, ↑ liver enzymes, nevirapine, tipranavir. Avoid in severe reducing agents by ≥10 h. prolonged PR interval hepatic insufficiency. The oral powder contains phenylalanine. Darunavir PI2 Treatment-naïve: 800 mg qd with ritonavir Take with food. Diarrhea, headache, nausea, See footnote 4. Avoid elvitegravir/ 100 mg qd or cobicistat 150 mg qd rash, hyperlipidemia, ↑ liver cobicistat and simeprevir. Avoid in enzymes, ↑ serum amylase patients with sulfa allergy. Treatment-experienced: 600 mg bid with ritonavir 100 mg bid


Pharmacology_Katzung

Pharmacology_Katzung. Treatment-experienced: 600 mg bid with ritonavir 100 mg bid Delavirdine NNRTI 400 mg tid Separate dosing from ddI or Rash, ↑ liver enzymes, head-See footnote 4. Avoid concurrent antacids by ≥1 h. ache, nausea, diarrhea fosamprenavir. Teratogenic in rats. Didanosine NRTI1 Tablets, 400 mg qd or 200 mg bid3 Take on an empty stomach. Peripheral neuropathy, pan-Avoid concurrent neuropathic drugs (eg, (ddI) creatitis, diarrhea. stavudine, zalcitabine, isoniazid), ribavirin, or allopurinol. Chewable tablets contain Buffered powder, 250 mg bid3 phenylalanine. Dolutegravir INSTI INSTI-naïve: 50 mg qd Separate dosing from antac-Insomnia, headache, Avoid carbamazepine, dofetilide, nevirapine, ids and polyvalent cations hypersensitivity reaction, phenobarbital, phenytoin. If co-administered with efavirenz, fosam by ≥2 h. ↑ liver enzymes prenavir/ritonavir, tipranavir/ritonavir, or rifampin or if certain INSTI mutations: 50 mg bid


Pharmacology_Katzung

Pharmacology_Katzung. If co-administered with efavirenz, fosam by ≥2 h. ↑ liver enzymes prenavir/ritonavir, tipranavir/ritonavir, or rifampin or if certain INSTI mutations: 50 mg bid Efavirenz NNRTI 600 mg qd Take on an empty stomach, Neuropsychiatric symptoms, See footnote 4. Avoid elvitegravir/ at bedtime. rash, ↑ liver enzymes, head-cobicistat, etravirine, indinavir, simeprevir. ache, nausea Teratogenic in primates. Elvitegravir INSTI Treatment-naïve: 150 mg qd with cobici-Take with food. Separate dos-Diarrhea, rash, ↑ liver See footnote 4. Avoid efavirenz and stat 150, emtricitabine 200, and tenofovir ing from antacids by ≥2 h. enzymes nevirapine. Treatment-experienced: 85 mg–150 mg qd with a protease inhibitor Emtricitabine NRTI1 200 mg qd3 Headache, diarrhea, nausea, Avoid concurrent lamivudine. rash, hyperpigmentation TABLE 49–3 Currently available antiretroviral agents. (Continued) Etravirine NNRTI 200 mg bid Take with food. Rash, nausea, diarrhea


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 49–3 Currently available antiretroviral agents. (Continued) Etravirine NNRTI 200 mg bid Take with food. Rash, nausea, diarrhea Fosamprenavir PI2 1400 mg bid or 700 mg bid with ritonavir Rash, diarrhea, nausea, head100 mg bid or 1400 mg daily with ritonavir ache, ↑ liver enzymes Indinavir PI2 800 mg tid or 800 mg bid with ritonavir Best on an empty stomach. Nephrolithiasis, nausea, 100–200 mg bid; adjust dose in cirrhosis Drink at least 48 oz liquid indirect hyperbilirubinemia, daily. Separate dosing from headache, diarrhea; posddI by ≥1 h. sible increase in myocardial infarction See footnote 4. Avoid atazanavir, efavirenz, elvitegravir/cobicistat, fosamprenavir, indinavir, tipranavir. See footnote 4. Avoid elvitegravir/ cobicistat, etravirine, lopinavir/ritonavir, nevirapine. Avoid in patients with sulfa allergy or severe hepatic insufficiency. Avoid cimetidine, disulfiram, metronidazole, vitamin E, ritonavir oral solution, and alcohol with the oral solution.


Pharmacology_Katzung

Pharmacology_Katzung. See footnote 4. Avoid efavirenz and etravirine. Lamivudine NRTI1 150 mg bid or 300 mg qd3 Nausea, headache, dizziness, Do not administer with emtricitabine or fatigue zalcitabine. Lopinavir/ PI/PI2 400/100 mg bid or 800/200 mg qd Separate dosing from ddI Diarrhea, nausea, hyper-See footnote 4. Avoid darunavir, elvitegravir/ ritonavir by 1 h. triglyceridemia, ↑ liver cobicistat, fosamprenavir, tipranavir. Avoid enzymes; possible increase in disulfiram and metronidazole with oral myocardial infarction solution. Maraviroc CCR5 inhibitor 300 mg bid; 150 bid with CYP3A inhibitors; Cough, muscle pain, diarrhea, See footnote 4. Do not administer in 600 mg bid with CYP3A inducers sleep disturbance, ↑ liver patients with severe renal dysfunction. enzymes; possible increase in myocardial infarction Nelfinavir PI2 750 mg tid or 1250 mg bid Take with food. Diarrhea, nausea, flatulence See footnote 4. The oral powder contains phenylalanine.


Pharmacology_Katzung

Pharmacology_Katzung. Nelfinavir PI2 750 mg tid or 1250 mg bid Take with food. Diarrhea, nausea, flatulence See footnote 4. The oral powder contains phenylalanine. Nevirapine NNRTI 200 mg bid Dose-escalate from 200 mg Rash, hepatitis (occasionally See footnote 4. Avoid atazanavir, dolutedaily over 14 days. fulminant), nausea, headache gravir, elvitegravir/cobicistat, fosamprenavir. Contraindicated with moderate or severe hepatic impairment. Raltegravir INSTI 400 mg bid Nausea, headache, fatigue, The chewable tablets contain muscle aches, ↑ amylase phenylalanine. levels, ↑ liver enzymes Rilpivirine NNRTI 25 mg qd Take with food. Separate Headache, insomnia, depres-See footnote 4. dosing from antacids or H2 sion, rash, ↑ liver enzymes blockers by ≥4 h.


Pharmacology_Katzung

Pharmacology_Katzung. Rilpivirine NNRTI 25 mg qd Take with food. Separate Headache, insomnia, depres-See footnote 4. dosing from antacids or H2 sion, rash, ↑ liver enzymes blockers by ≥4 h. Rilpivirine PI2 1000 mg bid with ritonavir 100 mg bid Take within 2 h of a full meal. Nausea, diarrhea, abdominal See footnote 4. Avoid darunavir, garlic pain, dyspepsia, rash capsules, tipranavir and drugs that increase the QT interval. Avoid in severe hepatic insufficiency. Stavudine NRTI1 30–40 mg bid, depending on weight3 Peripheral neuropathy, pan-Avoid zidovudine and neuropathic drugs creatitis, rapidly progressive (eg, ddI, zalcitabine, isoniazid). ascending neuromuscular weakness (rare) Tenofovir NRTI1 10 mg qd with emtricitabine plus


Pharmacology_Katzung

Pharmacology_Katzung. Tenofovir NRTI1 10 mg qd with emtricitabine plus Gastrointestinal symptoms, Avoid inducers of p-glycoprotein alafenamide elvitegravir/cobicistat; 25 mg qd with headache, ↑ creatinine, (rifampin, rifabutin, phenytoin, emtricitabine ± rilpivirine proteinuria phenobarbital, St John’s Wort, tipranavir/ ritonavir). Also avoid in severe renal insufficiency. Nausea, diarrhea, vomiting, Avoid atazanavir, didanosine, probenecid. proxil fumarate flatulence, headache, renal insufficiency Tipranavir PI2 500 mg bid with ritonavir 200 mg bid Take with food. Separate Diarrhea, nausea, vomiting, See footnote 4. Avoid concurrent atafrom ddI by ≥2 h. Avoid abdominal pain, rash, ↑ liver zanavir, elvitegravir/cobicistat, etravirine, antacids. enzymes, hyperlipidemia fosamprenavir, lopinavir/ritonavir, saquinavir. Avoid in patients with severe hepatic insufficiency, who are at risk for bleeding, or with sulfa allergy. Avoid vitamin E with the oral solution.


Pharmacology_Katzung

Pharmacology_Katzung. 1All NRTI agents carry the risk of lactic acidosis with hepatic steatosis as a potential adverse event. 2All PI agents carry the risk of hyperlipidemia, fat maldistribution, hyperglycemia, and insulin resistance as potential adverse events. 3Adjust dose in renal insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. 4Because of altered systemic exposures, concurrent drugs that interact with the CYP3A4 system should be used with caution, including alfuzosin, amiodarone, aprepitant, artemether/lumefantrine, astemizole, atovaquone, benzodiazepines (diazepam, midazolam, triazolam), bexarotene, bepridil, bosentan, bupropion, calcium channel blockers (diltiazem, felodipine, nifedipine, nimodipine, verapamil), carbamazepine, ceritinib , cimetidine, cisapride, clopidogrel, colchicine, conivaptan, corticosteroids, cyclosporine, dabrafenib, dapsone, desipramine, direct Factor Xa inhibitors (apixaban, rivaroxaban), disopyramide, dofetilide, dronedarone, enzalutamide, ergot alkaloid derivatives, ethinyl estradiol/norethindrone acetate, flecainide, fluticasone, gestodene, idelalisib, irinotecan, ivacaftor, levodopa, lidocaine, lumacaftor, lurasidone, macrolide agents (clarithromycin, telithromycin), methadone, mitotane, nafcillin, PDE5 inhibitors, phenobarbital, phenytoin, pimozide, primidone, propafenone,


Pharmacology_Katzung

Pharmacology_Katzung. lidocaine, lumacaftor, lurasidone, macrolide agents (clarithromycin, telithromycin), methadone, mitotane, nafcillin, PDE5 inhibitors, phenobarbital, phenytoin, pimozide, primidone, propafenone, protein pump inhibitors, quinidine, ranolazine, rifabutin, salmeterol, spironolactone, statin agents, St. John’s wort, tacrolimus, triazole antifungal agents (itraconazole ketoconazole, posaconazole, voriconazole), terfenadine, and warfarin.


Pharmacology_Katzung

Pharmacology_Katzung. INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; PI, protease inhibitor. FIGURE 49–3 Life cycle of HIV. Binding of viral glycoproteins to host cell CD4 and chemokine receptors leads to fusion of the viral and host cell membranes via gp41 and entry of the virion into the cell. After uncoating, reverse transcription copies the single-stranded HIV RNA genome into double-stranded DNA, which is integrated into the host cell genome. Gene transcription by host cell enzymes produces messenger RNA, which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Maturation into fully infectious virions is through proteolytic cleavage. NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. The drug is eliminated by both cellular metabolism and renal excretion. Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral The major clinical toxicities associated with didanosine therapy bioavailability is approximately 40%. Buffered or enteric-coated are peripheral distal sensory neuropathy and dose-dependent pan-formulations are necessary to prevent inactivation by gastric acid. creatitis. Therefore, co-administration with drugs or conditions that Cerebrospinal fluid concentrations of the drug are approximately increase the risk of either (eg, alcohol abuse, hypertriglyceridemia, 20% of serum concentrations. Serum half-life is 1.5 hours, but the pregnancy, zalcitabine, stavudine, isoniazid, vincristine, ribavirin, intracellular half-life of the activated compound is 20–24 hours. and hydroxyurea), should be avoided. Other reported adverse effects include diarrhea (particularly with the buffered formulation), hepatitis, esophageal ulceration, cardiomyopathy, central


Pharmacology_Katzung

Pharmacology_Katzung. hours. and hydroxyurea), should be avoided. Other reported adverse effects include diarrhea (particularly with the buffered formulation), hepatitis, esophageal ulceration, cardiomyopathy, central nervous system toxicity (headache, irritability, insomnia), and hypertriglyceridemia. Concurrent stavudine increases the risk of lactic acidosis. Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations.


Pharmacology_Katzung

Pharmacology_Katzung. Increased levels of didanosine when administered with tenofovir necessitate dose reduction. Concurrent allopurinol or ribavirin is contraindicated. The buffer in didanosine tablets interferes with the absorption of delavirdine and nelfinavir, necessitating separation in time. The chewable tablets contain phenylalanine, which can be harmful to patients with phenylketonuria. Emtricitabine (FTC) is a fluorinated analog of lamivudine with a long intracellular half-life (>24 hours), allowing for once-daily dosing. Oral bioavailability of the capsules is 93% and is unaffected by food, but penetration into the cerebrospinal fluid is low. Elimination is by both glomerular filtration and active tubular secretion. The serum half-life is about 10 hours. Emtricitabine is one of the NRTI agents recommended for use in pregnancy (Table 49–5). The combination of tenofovir and emtricitabine is recommended as pre-exposure prophylaxis to reduce HIV acquisition in high-risk persons.


Pharmacology_Katzung

Pharmacology_Katzung. Both emtricitabine and lamivudine may select for the M184V/I mutation and therefore should not be used together. The most common adverse effects observed in patients receiving emtricitabine are headache, diarrhea, nausea, and rash. Hyperpigmentation of the palms or soles may be observed (~ 3%), particularly in African Americans (up to 13%). Clinically significant drug-drug interactions involving emtricitabine have not been identified. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV. Lamivudine (3TC) is a cytosine analog with in vitro activity against both HIV-1 and HBV.


Pharmacology_Katzung

Pharmacology_Katzung. Lamivudine (3TC) is a cytosine analog with in vitro activity against both HIV-1 and HBV. Oral bioavailability exceeds 80% and is not food-dependent. The mean cerebrospinal fluid:plasma ratio of lamivudine is 0.1–0.2. Serum half-life is 2.5 hours, whereas the intracellular half-life of the triphosphorylated compound is 11–14 hours. Lamivudine is predominantly eliminated in the urine by active organic cation secretion. Lamivudine is one of the recommended NRTI agents for use in pregnant women (Table 49–5).


Pharmacology_Katzung

Pharmacology_Katzung. Lamivudine is one of the recommended NRTI agents for use in pregnant women (Table 49–5). Adverse effects are uncommon but include headache, dizziness, insomnia, fatigue, dry mouth, and gastrointestinal discomfort. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV and HBV. Since both emtricitabine and lamivudine may select for the M184V/I mutation, these agents should not be used together. Levels of lamivudine may increase when administered with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another; therefore, their concurrent use should be avoided if possible.


Pharmacology_Katzung

Pharmacology_Katzung. The thymidine analog stavudine (d4T) has high oral bioavailability (86%) that is not food-dependent. The serum half-life is 1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean cerebrospinal fluid concentrations are 55% of those of plasma. Excretion is by active tubular secretion and glomerular filtration.


Pharmacology_Katzung

Pharmacology_Katzung. The major toxicity is a dose-related peripheral sensory neuropathy; incidence may be increased with concomitant neurotoxic drugs such as didanosine, vincristine, isoniazid, or ribavirin, or in patients with advanced immunosuppression. Other potential adverse effects are pancreatitis, arthralgias, and elevation in serum aminotransferases. Caution is advised in patients with liver dysfunction. A rare adverse effect is a rapidly progressive ascending neuromuscular weakness. Lactic acidosis with hepatic steatosis, as well as lipodystrophy, appear to occur more frequently in patients receiving stavudine than in those receiving other NRTI agents. Stavudine should not be administered with didanosine due to increased risk of both lactic acidosis and pancreatitis. This combination has been implicated in several deaths in HIV-infected pregnant women. Since zidovudine may reduce the intracellular phosphorylation of stavudine, these two drugs should not be used together.


Pharmacology_Katzung

Pharmacology_Katzung. Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine with activity against HIV and HBV. Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis. Tenofovir disoproxil fumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability increases from 25% in the fasted state to 39% after a high-fat meal. The prolonged serum (12–17 hours) and intracellular half-lives allow once-daily dosing. Elimination occurs by both glomerular filtration and active tubular secretion, and dosage adjustment in patients with renal insufficiency is recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Tenofovir disoproxil fumarate is one of the NRTI agents recommended for use in pregnancy (Table 49–5). The combination of tenofovir and emtricitabine is recommended as pre-exposure prophylaxis to reduce HIV acquisition in high-risk persons.


Pharmacology_Katzung

Pharmacology_Katzung. Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation. Since tenofovir is formulated with lactose, these may occur more frequently in patients with lactose intolerance. Cumulative loss of renal function has been observed, possibly increased with concurrent use of boosted PI regimens. Acute renal failure and Fanconi’s syndrome have also been reported. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Serum creatinine levels should be monitored during therapy and tenofovir discontinued for new proteinuria, glycosuria, or calculated glomerular filtration rate <30 mL/min. Tenofovir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D; loss of bone mineral density and osteomalacia have been reported. Tenofovir may compete with other drugs that are actively secreted by the


Pharmacology_Katzung

Pharmacology_Katzung. and calcium losses and 1-hydroxylation defects of vitamin D; loss of bone mineral density and osteomalacia have been reported. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. Concurrent use of probenecid is contraindicated. Tenofovir levels may increase, and levels of telaprevir decrease, when these agents are co-administered. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV and HBV.


Pharmacology_Katzung

Pharmacology_Katzung. Tenofovir alafenamide is a phosphonoamidate prodrug of tenofovir that is currently available in co-formulation with other antiretroviral agents (with emtricitabine, with elvitegravir plus cobicistat plus emtricitabine, and with rilpivirine plus emtricitabine). Plasma levels of active tenofovir in plasma are approximately 90% lower with tenofovir alafenamide than with tenofovir disoproxil, since metabolism occurs in lymphocytes and macrophages (as well as hepatocytes and some other cells) rather than blood. Tenofovir alafenamide is a substrate of P-glycoprotein, and levels of tenofovir can be affected by inhibitors or inducers of P-glycoprotein. Ritonavir and cobicistat can increase plasma concentrations of tenofovir, while darunavir can decrease tenofovir concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. Tenofovir alafenamide appears to have less renal and bone toxicity than tenofovir disoproxil fumarate; however this is still under investigation. It does not require dose adjustment in patients with creatinine clearance >30 mL/min. Tenofovir alafenamide is a substrate of P-glycoprotein, and levels of tenofovir can be affected by inhibitors or inducers of P-glycoprotein. Ritonavir and cobicistat can increase plasma concentrations of tenofovir, while darunavir can decrease tenofovir concentrations. Adverse effects appear to be uncommon but may include gastrointestinal symptoms or headache. Tenofovir alafenamide is active against hepatitis B and has been approved for treatment of HBV infection.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects appear to be uncommon but may include gastrointestinal symptoms or headache. Tenofovir alafenamide is active against hepatitis B and has been approved for treatment of HBV infection. Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Although the serum half-life averages 1 hour, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver.


Pharmacology_Katzung

Pharmacology_Katzung. Zidovudine was the first antiretroviral agent to be approved and has been well studied. Studies evaluating the use of zidovudine during pregnancy, labor, and postpartum showed significant reductions in the rate of vertical transmission, and zidovudine remains one of the NRTI agents recommended for use in pregnant women (Table 49–5). Zidovudine is also recommended as an option for postexposure prophylaxis in individuals exposed to HIV. The most common adverse effects of zidovudine are macrocytic anemia (1–4%) and neutropenia (2–8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. A symptomatic myopathy may occur with prolonged use. Lipoatrophy appears to be more common in patients receiving zidovudine or other thymidine analogs. High doses can cause anxiety, confusion, and tremulousness.


Pharmacology_Katzung

Pharmacology_Katzung. Induction or inhibition of glucuronidation may alter serum levels of zidovudine when co-administered with atovaquone, lopinavir/ritonavir, probenecid, or valproic acid. Concurrent stavudine is contraindicated due to competitive inhibition of intracellular phosphorylation. The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49–3), resulting in allosteric inhibition of RNAand DNA-dependent DNA polymerase activity. The binding site of NNRTIs is near to but distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. The second-generation NNRTIs (etravirine, rilpivirine) have higher potency, longer half-lives and reduced side-effect profiles compared with older NNRTIs (delavirdine, efavirenz, nevirapine).


Pharmacology_Katzung

Pharmacology_Katzung. The second-generation NNRTIs (etravirine, rilpivirine) have higher potency, longer half-lives and reduced side-effect profiles compared with older NNRTIs (delavirdine, efavirenz, nevirapine). Baseline genotypic testing is recommended prior to initiating NNRTI treatment because primary resistance rates range from approximately 2% to 8%. NNRTI resistance occurs rapidly with monotherapy and can result from a single mutation. The K103N and Y181C mutations confer resistance to the first-generation NNRTIs, but not to etravirine or rilpivirine. Other mutations (eg, L100I, Y188C, G190A) may also confer cross-resistance among the NNRTI class. However, there is no cross-resistance between the NNRTIs and the NRTIs; in fact, some nucleoside-resistant viruses display hypersusceptibility to NNRTIs.


Pharmacology_Katzung

Pharmacology_Katzung. As a class, NNRTI agents tend to be associated with varying levels of gastrointestinal intolerance and skin rash, the latter of which may infrequently be serious (eg, Stevens-Johnson syndrome). A further limitation to use of NNRTI agents as a component of antiretroviral therapy is their metabolism by the CYP450 system, leading to innumerable potential drug-drug interactions (Tables 49–3 and 49–4). All NNRTI agents are substrates for CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine), or mixed inducers and inhibitors (efavirenz, etravirine). TABLE 49–4 Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1 Raltegravir Atazanavir Etravirine, tipranavir


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 49–4 Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1 Raltegravir Atazanavir Etravirine, tipranavir Rilpivirine2 Darunavir, lopinavir/ritonavir 1Dose adjustment may be necessary if co-administered. 2NNRTI-NNRTI drug-drug interactions are not listed. 3Drug-drug interactions are rare with elvitegravir as a single agent but multiple if co-administered with either cobicistat or ritonavir. Given the large number of non-HIV medications that are also metabolized by this pathway (see Chapter 4), drug-drug interactions must be expected and looked for; dosage adjustments are frequently required and some combinations are contraindicated. Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids or H2-blockers. It is extensively bound (~98%) to plasma proteins and has correspondingly low cerebrospinal fluid levels. Serum half-life is approximately 6 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Skin rash occurs in up to 38% of patients receiving delavirdine; it typically occurs during the first 1–3 weeks of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other possible adverse effects are headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels. Delavirdine has been shown to be teratogenic in rats, causing ventricular septal defects and other malformations at dosages not unlike those achieved in humans. Thus, pregnancy should be avoided when taking delavirdine.


Pharmacology_Katzung

Pharmacology_Katzung. Delavirdine is extensively metabolized by CYP3A and CYP2D6 enzymes. Therefore, there are numerous potential drug-drug interactions to consider (Tables 49–3 and 49–4). The concurrent use of delavirdine with fosamprenavir is not recommended because of bidirectional interactions. Co-administration of delavirdine with indinavir or saquinavir prolongs the elimination half-life of the latter agents, thus allowing them to be dosed twice rather than thrice daily.


Pharmacology_Katzung

Pharmacology_Katzung. Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%). Since toxicity may increase owing to increased bioavailability after a high-fat meal, efavirenz should be taken on an empty stomach. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (~ 99%), and cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels.


Pharmacology_Katzung

Pharmacology_Katzung. The principal adverse effects of efavirenz involve the central nervous system. Dizziness, drowsiness, insomnia, nightmares, and headache tend to diminish with continued therapy; dosing at bedtime may also be helpful. Psychiatric symptoms such as depression, mania, and psychosis have been observed in the weeks following initiation and may necessitate discontinuation. Skin rash has been reported early in therapy in up to 28% of patients; the rash is usually mild to moderate in severity and typically resolves despite continuation. Rarely, rash has been severe or life-threatening. Other potential adverse reactions are nausea, vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities, such as neural tube defects, occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage; several cases of congenital anomalies have been reported in humans. Efavirenz is one of the


Pharmacology_Katzung

Pharmacology_Katzung. defects, occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage; several cases of congenital anomalies have been reported in humans. Efavirenz is one of the NNRTI agents recommended for use in pregnancy (Table 49–5), but should be initiated after the first 8 weeks due to birth defects observed in a primate study.


Pharmacology_Katzung

Pharmacology_Katzung. As both an inducer and an inhibitor of CYP3A4, efavirenz induces its own metabolism and interacts with the metabolism of many other drugs (Tables 49–3 and 49–4). Co-administration with boceprevir, elvitegravir/cobicistat, etravirine, indinavir, itraconazole, ketoconazole, and simeprevir is contraindicated. Levels of efavirenz may be reduced by concomitant nevirapine. Levels of lopinavir/ritonavir, maraviroc, methadone, and telaprevir may be reduced when administered with efavirenz. Etravirine, a diarylpyrimidine, was designed to be effective against strains of HIV that had developed resistance to first-generation NNRTIs due to mutations such as K103N and Y181C. Although etravirine has a higher genetic barrier to resistance than the other NNRTIs, mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, and delavirdine.


Pharmacology_Katzung

Pharmacology_Katzung. Etravirine should be taken with a meal to increase systemic exposure. It is highly protein-bound and is primarily metabolized by the liver. Mean terminal half-life is ~41 hours. The most common adverse effects of etravirine are rash, nausea, and diarrhea. The rash is typically mild and usually resolves after 1–2 weeks without discontinuation of therapy. Rarely, rash has been severe or life-threatening. Laboratory abnormalities include elevations in serum cholesterol, triglyceride, glucose, and hepatic aminotransferase levels. Aminotransferase elevations are more common in patients with HBV or HCV co-infection.


Pharmacology_Katzung

Pharmacology_Katzung. Etravirine is a substrate as well as an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19 and thus has potential for numerous drug-drug interactions (Tables 49–3 and 49–4). Some of the interactions are difficult to predict. For example, etravirine may decrease itraconazole and ketoconazole concentrations but increase voriconazole concentrations. Etravirine should not be given with atazanavir, clopidogrel, efavirenz, elvitegravir/ cobicistat, fosamprenavir, indinavir, and tipranavir. In addition, co-administration with clarithromycin or with the antimalarial agent artemether/lumefantrine should be avoided if possible. The oral bioavailability of nevirapine is excellent (>90%) and is not food-dependent. The drug is highly lipophilic and achieves cerebrospinal fluid levels that are 45% of those in plasma. Serum half-life is 25–30 hours. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.


Pharmacology_Katzung

Pharmacology_Katzung. A single dose of nevirapine (200 mg) is effective in the prevention of transmission of HIV from mother to newborn when administered at the onset of labor and followed by a 2-mg/kg dose to the neonate within 3 days of delivery. However, nevirapine is no longer recommended for use in pregnancy due to the potential for adverse events and low barrier to resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Rash, usually a maculopapular eruption that spares the palms and soles, occurs in up to 20% of patients, usually in the first 4–6 weeks of therapy. Although typically mild and self-limited, rash is dose-limiting in about 7% of patients. Women appear to have an increased incidence of rash. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash. Severe and life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, are rare but are more common than with other NNRTIs. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with accompanying constitutional symptoms; since rash may accompany hepatotoxicity, liver tests should be assessed. Symptomatic liver toxicity may occur in up to 4% of patients, may be severe, and is more frequent in those with higher pretherapy CD4 cell counts (ie, >250 cells/mm3 in women and >400 cells/mm3 in men), in women, and in


Pharmacology_Katzung

Pharmacology_Katzung. may occur in up to 4% of patients, may be severe, and is more frequent in those with higher pretherapy CD4 cell counts (ie, >250 cells/mm3 in women and >400 cells/mm3 in men), in women, and in those with HBV or HCV co-infection. Fulminant, life-threatening hepatitis has been reported, typically within the first 18 weeks of therapy. Other adverse effects include fever, nausea, headache, and somnolence.


Pharmacology_Katzung

Pharmacology_Katzung. Nevirapine is a moderate inducer of CYP3A metabolism, resulting in numerous potential drug-drug interactions (see Tables 49–3 and 49–4). Co-administration of artemether/lumefantrine, atazanavir, dolutegravir, elvitegravir/cobicistat, fosamprenavir, ketoconazole, and rifampin should be avoided. Rilpivirine, a diarylpyrimidine, must be administered with a meal (preferably high fat or >400 kcal). Its oral bioavailability is dependent on an acid gastric environment for optimal absorption; thus antacids and H2-receptor antagonists should be separated in time and proton pump inhibitors are contraindicated. The drug is highly protein bound and the terminal elimination half-life is 50 hours. Rilpivirine is one of the NNRTI agents recommended for use in pregnancy (Table 49–5). Rilpivirine is primarily metabolized by CYP3A4, and drugs that induce or inhibit CYP3A4 may thus TABLE 49–5 The use of antiretroviral agents in pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 49–5 The use of antiretroviral agents in pregnancy. Abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, zidovudine Atazanavir/ritonavir, darunavir/ritonavir Lopinavir/ritonavir affect the clearance of rilpivirine (see Table 49–3). However, clinically significant drug-drug interactions with other antiretroviral agents have not been identified to date. The most common adverse effects associated with rilpivirine therapy are rash, depression, headache, insomnia, and increased serum aminotransferases. Increased serum cholesterol, and fat redistribution syndrome have also been reported. Higher doses have been associated with QTc prolongation. Inhibition of renal tubular secretion of creatinine causes a reversible elevation in serum creatinine, but glomerular filtration rate is not affected.


Pharmacology_Katzung

Pharmacology_Katzung. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are translated into polyproteins, and these become immature budding particles. The HIV protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core. By preventing post-translational cleavage of the Gag-Pol polyprotein, protease inhibitors (PIs) prevent the processing of viral proteins into functional conformations, resulting in the production of immature, noninfectious viral particles (Figure 49–3). Unlike the NRTIs, PIs do not need intracellular activation.