Pharmacology_Katzung

Pharmacology_Katzung. Specific genotypic alterations that confer phenotypic resistance are fairly common with these agents, thus contraindicating mono-therapy. Some of the most common mutations conferring broad resistance to PIs are substitutions at the 10, 46, 54, 82, 84, and 90 codons; the number of mutations may predict the level of phenotypic resistance. The I50L substitution emerging during atazanavir therapy has been associated with increased susceptibility to other PIs. Darunavir and tipranavir appear to have improved virologic activity in patients harboring HIV-1 resistant to other PIs.


Pharmacology_Katzung

Pharmacology_Katzung. As a class, PIs are associated with gastrointestinal intolerance, which may be dose-limiting, and lipodystrophy, which includes both metabolic (hyperglycemia, hyperlipidemia) and morphologic (lipoatrophy, fat deposition) derangements. A syndrome of redistribution and accumulation of body fat that results in central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and a cushingoid appearance has been observed, least commonly with atazanavir. PIs may be associated with cardiac conduction abnormalities, including PR and QT interval prolongation. A baseline electrocardiogram and avoidance of other agents causing prolonged PR or QT intervals should be considered. Abacavir, lopinavir/ritonavir, and fosamprenavir/ritonavir have been associated with an increased risk of cardiovascular disease in some, but not all, studies. Drug-induced hepatitis and rare severe hepatotoxicity have been reported to varying degrees with all PIs; the


Pharmacology_Katzung

Pharmacology_Katzung. with an increased risk of cardiovascular disease in some, but not all, studies. Drug-induced hepatitis and rare severe hepatotoxicity have been reported to varying degrees with all PIs; the frequency of hepatic events is higher with tipranavir/ritonavir than with other PIs. Unconjugated hyperbilirubinemia may occur with atazanavir or indinavir. Whether PI agents are associated with bone loss and osteoporosis after long-term use is under investigation. PIs have been associated with increased spontaneous bleeding in patients with hemophilia A or B; an increased risk of intracranial hemorrhage has been reported in patients receiving tipranavir/ritonavir. Darunavir, amprenavir, fosamprenavir, and tipranavir are sulfonamides; caution should be used in patients with a history of sulfa allergy.


Pharmacology_Katzung

Pharmacology_Katzung. All of the antiretroviral PIs are extensively metabolized by CYP3A4, with ritonavir having the most pronounced inhibitory effect and saquinavir the least. Some PI agents, such as amprenavir and ritonavir, are also inducers of specific CYP isoforms. As a result, there is enormous potential for drug-drug interactions with other antiretroviral agents and other commonly used medications (Tables 49–3 and 49–4). Expert resources about drug-drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated. It is noteworthy that the potent CYP3A4 inhibitory properties of ritonavir are used to clinical advantage by having it “boost” the levels of other PI agents when given in combination, thus acting as a pharmacokinetic enhancer rather than an antiretroviral agent. Ritonavir boosting increases drug exposure, thereby prolonging the drug’s half-life and allowing reduction in frequency; in addition, the genetic barrier to resistance is


Pharmacology_Katzung

Pharmacology_Katzung. an antiretroviral agent. Ritonavir boosting increases drug exposure, thereby prolonging the drug’s half-life and allowing reduction in frequency; in addition, the genetic barrier to resistance is raised.


Pharmacology_Katzung

Pharmacology_Katzung. Atazanavir is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; therefore, it should be taken with meals. Separation of ingestion from acid-reducing agents by at least 12 hours is recommended and concurrent proton pump inhibitors are contraindicated. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6–7 hours, which increases to approximately 11 hours when co-administered with ritonavir. The primary route of elimination is biliary; atazanavir should not be given to patients with severe hepatic insufficiency. Boosted atazanavir is one of the recommended PI agents for use in pregnant women (Table 49–5).


Pharmacology_Katzung

Pharmacology_Katzung. Boosted atazanavir is one of the recommended PI agents for use in pregnant women (Table 49–5). The most common adverse effects in patients receiving atazanavir are diarrhea and nausea; vomiting, abdominal pain, headache, and peripheral neuropathy may also occur. Skin rash, reported in ~20% of patients, is generally mild; however severe rash and Stevens Johnson syndrome have been reported. As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur in approximately 10% of patients, owing to inhibition of the UGT1A1 glucuronidation enzyme. Elevation of serum aminotransferases has separately been observed, usually in patients with underlying HBV or HCV co-infection. Kidney stones, gallstones, PR prolongation, and decreased bone mineral density have also been reported. In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemia or hyperglycemia. The oral powder contains phenylalanine, which can be harmful to patients with phenylketonuria.


Pharmacology_Katzung

Pharmacology_Katzung. As an inhibitor of CYP3A4, CYP2C9, and UGT1A1, the potential for drug-drug interactions with atazanavir is great (Tables 49–3 and 49–4). Due to decreased atazanavir levels, atazanavir should not be administered with bosentan, elvitegravir/ cobicistat, etravirine, fosamprenavir, nevirapine, proton pump inhibitors, or tipranavir. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as irinotecan, may increase its levels. Atovaquone and voriconazole levels may be decreased with coadministration, and levels of maraviroc and ranolazine may be increased. Darunavir must be co-administered with ritonavir or cobicistat. Darunavir should be taken with meals to improve bioavailability. It is highly protein-bound and primarily metabolized by the liver. Boosted darunavir is one of the PI agents recommended for use in pregnancy (Table 49–5).


Pharmacology_Katzung

Pharmacology_Katzung. Boosted darunavir is one of the PI agents recommended for use in pregnancy (Table 49–5). Adverse effects include diarrhea, nausea, headache, and increases in amylase and hepatic aminotransferase levels. Rash occurs in 2–7% of patients and may occasionally be severe. Liver toxicity, including severe hepatitis, has been reported, such that liver function tests should be monitored; the risk may be higher for persons with HBV, HCV, or other chronic liver disease. Darunavir contains a sulfonamide moiety and may cause a hypersensitivity reaction, particularly in patients with sulfa allergy.


Pharmacology_Katzung

Pharmacology_Katzung. Darunavir both inhibits and is metabolized by the CYP3A enzyme system, conferring many possible drug-drug interactions (Tables 49–3 and 49–4). In addition, the co-administered ritonavir is a potent inhibitor of CYP3A and CYP2D6, and an inducer of other hepatic enzyme systems. Co-administration with elvitegravir/cobicistat or simeprevir is contraindicated due to bidirectional drug-drug interactions. Levels of cyclophosphamide, digoxin, and simeprevir may be increased when administered with darunavir, and levels of paroxetine and sertraline may be decreased. Fosamprenavir is a prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium. Because of its significantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. Fosamprenavir is most often administered in combination with low-dose ritonavir.


Pharmacology_Katzung

Pharmacology_Katzung. After hydrolysis of fosamprenavir, amprenavir is rapidly absorbed from the gastrointestinal tract, and its prodrug can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. The plasma half-life is relatively long (7–11 hours). Amprenavir is metabolized in the liver and should be used with caution in the setting of hepatic insufficiency. The most common adverse effects of fosamprenavir are headache, nausea, diarrhea, perioral paresthesias, depression. Fosamprenavir contains a sulfa moiety and may cause a rash in up to 19% of patients, sometimes severe enough to warrant drug discontinuation.


Pharmacology_Katzung

Pharmacology_Katzung. Amprenavir is both an inducer and an inhibitor of CYP3A4 (Tables 49–3 and 49–4). Co-administration of elvitegravir/cobicistat, etravirine, lopinavir/ritonavir, nevirapine, posaconazole, or ranolazine is contraindicated. The oral suspension, which contains propylene glycol, is contraindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disulfiram. Also, the oral solutions of amprenavir and ritonavir should not be co-administered because the propylene glycol in one and the ethanol in the other may compete for the same metabolic pathway, leading to accumulation of either. Because the oral solution contains vitamin E at several times the recommended daily dosage, supplemental vitamin E should be avoided.


Pharmacology_Katzung

Pharmacology_Katzung. Indinavir requires an acidic environment for optimum solubility and therefore must be consumed on an empty stomach or with a small, low-fat, low-protein meal for maximal absorption (60–65%). The serum half-life is 1.5–2 hours, protein binding is ~60%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Excretion is primarily fecal. An increase in AUC by 60% and in half-life to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects of indinavir are unconjugated hyperbilirubinemia and nephrolithiasis due to urinary crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Acute renal failure and interstitial fibrosis have also been reported. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration, and serum creatinine levels should be monitored. Nausea, diarrhea, sicca syndrome, headache, blurred vision, and elevations of serum aminotransferase levels have also been reported. Insulin resistance may be more common with indinavir than with the other PIs, occurring in 3–5% of patients. In some studies but not in others, indinavir has been associated with a higher risk of myocardial infarction. There have also been rare cases of acute hemolytic anemia.


Pharmacology_Katzung

Pharmacology_Katzung. Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur (Tables 49–3 and 49–4). Boosting with ritonavir allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with use of indinavir. However, there is potential for an increase in nephrolithiasis with this combination compared with indinavir alone; thus, a high fluid intake (1.5–2 L/d) is advised. Indinavir should not be co-administered with astemizole, cerivastatin, efavirenz, ergotamine, etravirine, lovastatin, pimozide, rifampin, simvastatin, terfenadine, or triazolam. Levels of amlodipine, levodopa, and trazodone may be increased with concurrent administration of indinavir. Lopinavir is available only in combination with low-dose ritonavir as a pharmacologic “booster” via inhibition of its CYP3Amediated metabolism, resulting in increased exposure and a reduced pill burden.


Pharmacology_Katzung

Pharmacology_Katzung. Lopinavir is highly protein bound (98–99%), and its half-life is 5–6 hours. It is extensively metabolized by CYP3A, which is inhibited by ritonavir. Lopinavir/ritonavir is one of the recommended antiretroviral agents for use in pregnant women (Table 49–5). The most common adverse effects of lopinavir are diarrhea, nausea, vomiting, increased serum lipids, and increased serum aminotransferases (more common in patients with HBV or HCV co-infection). Prolongation of the PR and/or QT interval may occur. In some studies but not in others, lopinavir/ritonavir has been associated with a higher risk of myocardial infarction. Pancreatitis has rarely been reported. Ritonavir-boosted lopinavir may be more commonly associated with gastrointestinal adverse events than other PIs.


Pharmacology_Katzung

Pharmacology_Katzung. Potential drug-drug interactions are extensive (Tables 49–3 and 49–4). Levels of lamotrigine and methadone may be reduced with co-administration, and levels of bosentan may be increased. Concurrent use of darunavir, elvitegravir/cobicistat, fosamprenavir, and tipranavir is contraindicated. Since the oral solution of lopinavir/ritonavir contains alcohol, concurrent disulfiram and metronidazole are contraindicated. The oral solution also contains propylene glycol, contraindicating the co-administration of other drugs containing propylene glycol. Nelfinavir has high absorption in the fed state (70–80%), undergoes metabolism by CYP3A, and is excreted primarily in the feces. The plasma half-life in humans is 3.5–5 hours, and the drug is more than 98% protein-bound.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects associated with nelfinavir (10–30%) are diarrhea and flatulence. Diarrhea responds to anti-diarrheal medications but may be dose-limiting. Nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur (Tables 49–3 and 49–4). An increased dosage of nelfinavir is recommended when co-administered with rifabutin (with a decreased dose of rifabutin), whereas a decrease in saquinavir dose is suggested with concurrent nelfinavir. Do not co-administer with astemizole, cerivastatin, cisapride, ergotamine, lovastatin, omeprazole, pimozide, quinidine, rifampin, simvastatin, or terfenadine. The oral powder contains phenylalanine, which can be harmful to patients with phenylketonuria.


Pharmacology_Katzung

Pharmacology_Katzung. Ritonavir has a high bioavailability (~75%) that increases with food. It is 98% protein-bound and has a serum half-life of 3–5 hours. Metabolism to an active metabolite occurs via the CYP3A and CYP2D6 isoforms; excretion is primarily in the feces. Ritonavir as a pharmacologic “booster” is one of the recommended antiretroviral agents for use in pregnant women (Table 49–5). Adverse effects of full-dose ritonavir include asthenia, gastrointestinal disturbances, and hepatitis; these are greatly reduced with the lower doses used for boosting. Dose escalation over 1–2 weeks decreases these side effects. Other potential adverse effects include altered taste, paresthesias (circumoral or peripheral), elevated serum aminotransferase and lipid levels, headache, elevations in serum creatine kinase, and pancreatitis. 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. Ritonavir is a potent inhibitor of CYP3A4, resulting in many potential drug interactions (Tables 49–3 and 49–4). However, this characteristic has been used to great advantage when ritonavir is administered in low doses (100–200 mg twice daily) in combination with any of the other PI agents, to permit lower or less frequent dosing (or both) with greater tolerability as well as the potential for greater efficacy against resistant virus. Therapeutic levels of digoxin and theophylline should be monitored when co-administered with ritonavir. The concurrent use of saquinavir and ritonavir is contraindicated due to an increased risk of QT prolongation (with torsades de pointes arrhythmia) and PR interval prolongation. Concurrent simeprevir is also contraindicated.


Pharmacology_Katzung

Pharmacology_Katzung. In its original formulation as a hard gel capsule, oral saquinavir was poorly bioavailable (~4% after food). However, reformulation of saquinavir for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased gastrointestinal adverse effects. A previous formulation of saquinavir in soft gel capsules is no longer available.


Pharmacology_Katzung

Pharmacology_Katzung. Saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir is 97% protein-bound, and serum half-life is approximately 2 hours. Saquinavir has a large volume of distribution, but penetration into the cerebrospinal fluid is negligible. Excretion is primarily in the feces. Gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia) may occur. When administered in combination with low-dose ritonavir, there appears to be less dyslipidemia or gastrointestinal toxicity than with some of the other boosted PI regimens. Since prolongation of the QT interval and torsades de pointes have rarely been reported, saquinavir should not be used in patients with congenital long QT syndrome, AV block, refractory hypokalemia or hypomagnesemia, or in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval. The concurrent use of saquinavir and ritonavir may confer an increased risk of QT or PR


Pharmacology_Katzung

Pharmacology_Katzung. or in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval. The concurrent use of saquinavir and ritonavir may confer an increased risk of QT or PR prolongation.


Pharmacology_Katzung

Pharmacology_Katzung. Saquinavir is subject to extensive first-pass metabolism by CYP3A4 and functions as a CYP3A4 inhibitor as well as a substrate; thus, there are many potential drug-drug interactions (Tables 49–3 and 49–4). Increased saquinavir levels when co-administered with omeprazole necessitate close monitoring for toxicities. Digoxin levels should be monitored. Liver tests should be monitored if saquinavir is co-administered with delavirdine or rifampin. Concurrent darunavir or tipranavir is contraindicated. Tipranavir is a newer PI indicated for use in treatment-experienced patients who harbor strains resistant to other PI agents. It is used in combination with ritonavir to achieve effective serum levels.


Pharmacology_Katzung

Pharmacology_Katzung. Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system and is contraindicated in patients with hepatic insufficiency. Tipranavir contains a sulfonamide moiety and should not be administered to patients with known sulfa allergy.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects of tipranavir are diarrhea, nausea, vomiting, and abdominal pain. An urticarial or maculopapular rash occurs in 10–14%, and may be more common with co-administered ethinyl estradiol. Liver toxicity, including life-threatening hepatic decompensation, has been observed and may be more common than with other PIs, particularly in patients with chronic HBV or HCV infection. Because of an increased risk for intracranial hemorrhage in patients receiving tipranavir/ritonavir, the drug should be avoided in patients with head trauma or bleeding diathesis. Other potential adverse effects include depression, elevation in serum amylase, increased serum lipids, and decreased white blood cell count.


Pharmacology_Katzung

Pharmacology_Katzung. Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition. Tipranavir also induces the P-glycoprotein transporter and thus may alter the disposition of many other drugs (Tables 49–3 and 49–4). Concurrent use with atazanavir, elvitegravir/cobicistat, etravirine, fosamprenavir, lopinavir/ritonavir and saquinavir should be avoided. Supplemental vitamin E is contraindicated in patients receiving the oral solution.


Pharmacology_Katzung

Pharmacology_Katzung. The process of HIV-1 entry into host cells is complex; each step presents a potential target for inhibition. Viral attachment to the host cell entails binding of the viral envelope glycoprotein complex gp160 (consisting of gp120 and gp41) to its cellular receptor CD4. This binding induces conformational changes in gp120 that enable access to the chemokine receptors CCR5 or CXCR4. Chemokine receptor binding induces further conformational changes in gp120, allowing exposure to gp41 and leading to fusion of the viral envelope with the host cell membrane and subsequent entry of the viral core into the cellular cytoplasm. Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor that blocks HIV entry into the cell (Figure 49–3). Enfuvirtide binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.


Pharmacology_Katzung

Pharmacology_Katzung. Enfuvirtide, which must be administered by subcutaneous injection, is the only parenterally administered antiretroviral agent. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours. Resistance to enfuvirtide can result from mutations in gp41; the frequency and significance of this phenomenon are being investigated. However, enfuvirtide lacks cross-resistance with the other currently approved antiretroviral drug classes.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects are local injection site reactions, consisting of painful erythematous nodules. Although frequent, these are typically mild-to-moderate in severity and rarely lead to discontinuation. Other potential side effects include insomnia, headache, dizziness, and nausea. Hypersensitivity reactions may rarely occur, are of varying severity, and may recur on rechallenge. Eosinophilia is the primary laboratory abnormality seen with enfuvirtide administration. In Phase 3 studies, bacterial pneumonia was seen at a higher rate in patients who received enfuvirtide than in those who did not receive enfuvirtide. No drug-drug interactions have been identified that would require the alteration of the dosage of concomitant antiretroviral or other drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Maraviroc is approved for use in combination with other antiretroviral agents in adult patients infected only with CCR5-tropic HIV-1. Maraviroc binds specifically and selectively to the host protein CCR5, one of two chemokine receptors necessary for entrance of HIV into CD4+ cells. Since maraviroc is active against HIV that uses the CCR5 co-receptor exclusively, and not against HIV strains with CXCR4, dual, or mixed tropism, co-receptor tropism should be determined by specific testing before maraviroc is started. Substantial proportions of patients, particularly those with advanced HIV infection, are likely to have virus that is not exclusively CCR5-tropic.


Pharmacology_Katzung

Pharmacology_Katzung. The absorption of maraviroc is rapid but variable, with the time to maximum absorption generally 1–4 hours after ingestion of the drug. Most of the drug (≥ 75%) is excreted in the feces, whereas approximately 20% is excreted in urine. The recommended dose of maraviroc varies according to renal function and the concomitant use of CYP3A inducers or inhibitors (Table 49–3). Maraviroc is contraindicated in patients with severe or end-stage renal impairment and caution is advised when used in patients with preexisting hepatic impairment and in those co-infected with HBV or HCV. Maraviroc has excellent penetration into the cervicovaginal fluid, with levels almost four times higher than the corresponding concentrations in blood plasma.


Pharmacology_Katzung

Pharmacology_Katzung. Resistance to maraviroc is associated with one or more mutations in the V3 loop of gp120. However, emergence of CXCR4 virus (either previously undetected or newly developed) appears to be a more common cause of virologic failure than the development of resistance mutations. There appears to be no cross-resistance with drugs from any other class, including the fusion inhibitor enfuvirtide.


Pharmacology_Katzung

Pharmacology_Katzung. Maraviroc is a substrate for CYP3A4 and therefore requires adjustment in the presence of drugs that interact with these enzymes (Tables 49–3 and 49–4). It is also a substrate for P-glycoprotein, which limits intracellular concentrations of the drug. The dosage of maraviroc must be decreased if it is co-administered with strong CYP3A inhibitors (eg, delavirdine, ketoconazole, itraconazole, clarithromycin, or any protease inhibitor other than tipranavir) and must be increased if co-administered with CYP3A inducers (eg, efavirenz, etravirine, carbamazepine, phenytoin, or St. John’s wort). Concurrent use of rifampin is contraindicated.


Pharmacology_Katzung

Pharmacology_Katzung. Potential adverse effects of maraviroc include upper respiratory tract infection, cough, pyrexia, rash, dizziness, muscle and joint pain, diarrhea, sleep disturbance, and elevations in serum aminotransferases. Hepatotoxicity has been reported, which may be preceded by a systemic allergic reaction (ie, pruritic rash, eosinophilia, or elevated IgE); discontinuation of maraviroc should be prompt if this constellation occurs. Myocardial ischemia and infarction have been observed in patients receiving maraviroc; therefore caution is advised in patients at increased cardiovascular risk. There is an increased risk of postural hypotension in patients with severe renal impairment.


Pharmacology_Katzung

Pharmacology_Katzung. There has been concern that blockade of the chemokine CCR5 receptor—a human protein—may result in decreased immune surveillance, with a subsequent increased risk of malignancy or infection. To date, however, there has been no evidence of an increased risk of either malignancy or infection in patients receiving maraviroc.


Pharmacology_Katzung

Pharmacology_Katzung. This class of agents binds integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. By doing so, it inhibits strand transfer, the third and final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells (Figure 49–3). As a class, these agents tend to be well tolerated, with headache and gastrointestinal effects the most commonly reported adverse events. Their use in combination antiretroviral regimens or with cobicistat (ie, elvitegravir) means that additional adverse events and/or drug-drug interactions need to be considered as well. The available data suggest that effects upon lipid metabolism are favorable compared with efavirenz and PIs. Rare severe events include systemic hypersensitivity reactions and rhabdomyolysis.


Pharmacology_Katzung

Pharmacology_Katzung. The frequency of dosing of dolutegravir depends on the presence or absence of integrase inhibitor-associated resistance mutations and the concurrent use of efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin. Dolutegravir should be taken 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications. Peak plasma concentrations occur within 2–3 hours of ingestion. Dolutegravir is highly protein bound (99%). The terminal half-life is ~14 hours. Serum levels may be reduced in patients with severe renal insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects of dolutegravir are infrequent but may include insomnia, headache, increased serum aminotransferase levels, and, rarely, rash. A hypersensitivity reaction, including rash and systemic symptoms, has been reported; the drug should be discontinued immediately if this occurs and not restarted. Dolutegravir increases serum creatinine by inhibiting tubular secretion of creatinine but has no effect on actual glomerular filtration rate.


Pharmacology_Katzung

Pharmacology_Katzung. Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. Therefore, multiple drug-drug interactions may occur (Table 49–3 and 49–4). Levels of dolutegravir may decrease when co-administered with efavirenz, etravirine, nevirapine, rifampin, or rifapentine, in some instances necessitating increased doses of dolutegravir or boosting or both. Co-administration with the metabolic inducers oxcarbazepine, phenytoin, phenobarbital, carbamazepine, and St. John’s wort should be avoided. Dolutegravir inhibits the renal organic cation transporter OCT2, thereby increasing plasma concentrations of drugs eliminated via OCT2 such as dofetilide and metformin. For this reason, co-administration with dofetilide is contraindicated and close monitoring, with potential for dose adjustment, is recommended for co-administration with metformin.


Pharmacology_Katzung

Pharmacology_Katzung. Elvitegravir should be taken with food, and it should be taken 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications. Peak levels occur within 4 hours of ingestion; elvitegravir is highly protein bound (>98%). Elvitegravir requires boosting with an additional drug, such as cobicistat (a pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins) or ritonavir. Cobicistat inhibits renal tubular secretion of creatinine; therefore, fixed-dose combinations need to be adjusted for renal function. There appear to be few adverse effects associated with elvitegravir per se but may include diarrhea, rash, and elevation in hepatic aminotransferases.


Pharmacology_Katzung

Pharmacology_Katzung. Elvitegravir is primarily metabolized by CYP3A enzymes, so drugs that induce or inhibit the action of CYP3A may affect serum levels of elvitegravir (Table 49–3 and 49–4). In addition, cobicistat and ritonavir strongly inhibit CYP3A. Elvitegravir levels may be lowered by concurrent efavirenz or nevirapine, rifampin, rifabutin, carbamazepine, phenytoin, or St. John’s wort. Concurrent use of azole antifungal drugs is contraindicated due to a potential increase in elvitegravir levels; rifabutin levels may also be increased by concurrent elvitegravir. Elvitegravir also induces CYP2D9 and may lower concentrations of substrates of this enzyme. With the fixed dose combination, concurrent alfuzosin or atazanavir, cisapride, darunavir, efavirenz, etravirine, fosamprenavir, ledipasvir, lopinavir/ ritonavir, methylprednisolone, midazolam, nevirapine, pimozide, prednisolone, rifampin, rifabutin are contraindicated.


Pharmacology_Katzung

Pharmacology_Katzung. Absolute bioavailability of the pyrimidinone analog raltegravir has not been established but does not appear to be food-dependent. Terminal half-life is ~ 9 hours. The drug does not interact with the cytochrome P450 system but is metabolized by glucuronidation, particularly UGT1A1. Therefore, concurrent use of inducers or inhibitors of UGT1A1 such as rifampin and rifapentine may necessitate dosage adjustment of raltegravir. The chewable tablets contain phenylalanine, which can be harmful to patients with phenylketonuria. Raltegravir is one of the antiretroviral agents recommended for use in pregnancy (Table 49–5). Adverse effects of raltegravir are uncommon but include nausea, headache, fatigue, muscle aches, and increased serum amylase and aminotransferase levels. Severe, potentially life-threatening and fatal skin reactions have been reported, including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis.


Pharmacology_Katzung

Pharmacology_Katzung. The advantages of nucleoside/nucleotide analogs (NA) therapy of hepatitis over interferons (IFN) include fewer adverse effects and a one-pill-a-day oral administration. The main advantages of IFN over NAs are the absence of resistance, and achievement of higher rates of viral agglutinin reduction. However, the disadvantages of IFN are that less than 50% of persons treated will respond, its high cost, administration by injection, and common adverse effects, which preclude its use in many persons, particularly in resource-limited settings. A number of relative and absolute contraindications to IFN also exist, which include the presence of decompensated cirrhosis and hypersplenism, thyroid disease, autoimmune diseases, severe coronary artery disease, renal transplant disease, pregnancy, seizures and psychiatric illness, concomitant use of certain drugs, retinopathy, thrombocytopenia and leucopenia. IFN also cannot be used in infants less than 1 year and in pregnant women.


Pharmacology_Katzung

Pharmacology_Katzung. Interferons are host cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions (see Chapter 55). Interferon alfa appears to function by induction of intracellular signals following binding to specific cell membrane receptors, resulting in inhibition of viral penetration, translation, transcription, protein processing, maturation, and release, as well as increased host expression of major histocompatibility complex antigens, enhanced phagocytic activity of macrophages, and augmentation of the proliferation and survival of cytotoxic T cells.


Pharmacology_Katzung

Pharmacology_Katzung. Interferon alfa-2b is licensed for the treatment for chronic HBV infection; interferon alfa-2a, interferon alfa-2b, and interferon alfacon-1 are licensed for treatment of chronic HCV infection (Table 49–6). Interferon alfa-2a and interferon alfa-2b may be administered either subcutaneously or intramuscularly; half-life is 2–5 hours, depending on the route of administration. Alfa interferons are filtered at the glomerulus and undergo rapid proteolytic degradation during tubular reabsorption, such that detection in the systemic circulation is negligible. Liver metabolism and subsequent biliary excretion are considered minor pathways. Pegylation (the attachment of polyethylene glycol to a protein) reduces the rate of absorption following subcutaneous injection, reduces renal and cellular clearance, and decreases TABLE 49–6 Drugs used to treat chronic hepatitis B virus infection.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 49–6 Drugs used to treat chronic hepatitis B virus infection. TABLE 49–7 Direct-acting antiviral combination regimens for the treatment of chronic hepatitis C infection in adult patients without cirrhosis.1 1 Regimens may differ in the presence of cirrhosis. 2 As an alternative regimen, elbasvir 50 mg/grazoprevir 100 mg once daily may be given in combination with weight-based ribavirin for 16 weeks. 3 Dose adjustment may be required if co-administered with a CYP 3A substrate. the immunogenicity of the protein, resulting in a longer half-life and steadier plasma concentrations. Renal elimination of pegylated interferon alfa-2a and pegylated interferon alfa-2b accounts for about 30% of clearance; dose must be adjusted in renal insufficiency due to impaired clearance. The polyethylene glycol moiety is a nontoxic polymer that is readily excreted in the urine.


Pharmacology_Katzung

Pharmacology_Katzung. Pegylated interferon alfa-2a is licensed to treat chronic HBV and HCV infection; pegylated interferon alfa-2b is licensed to treat chronic HCV infection. However, the availability of newer and highly effective antiviral agents for HCV infection has greatly diminished the use of the interferons for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. The adverse effects of interferon alfa include a flu-like syndrome (ie, headache, fevers, chills, myalgias, and malaise) that occurs within 6 hours after dosing in more than 30% of patients; it tends to resolve upon continued administration. Transient hepatic enzyme elevations may occur in the first 8–12 weeks of therapy and appear to be more common in responders. Potential adverse effects during chronic therapy include neurotoxicities (mood disorders, depression, somnolence, confusion, seizures), myelosuppression, profound fatigue, weight loss, rash, cough, myalgia, alopecia, tinnitus, reversible hearing loss, retinopathy, pneumonitis, and possibly cardiotoxicity. Induction of autoantibodies may occur, causing exacerbation or unmasking of autoimmune disease (particularly thyroiditis).


Pharmacology_Katzung

Pharmacology_Katzung. Contraindications to interferon alfa therapy include hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interactions include increased theophylline and methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias. No specific treatment is available for the treatment of acute hepatitis B infection, which most often resolves spontaneously.


Pharmacology_Katzung

Pharmacology_Katzung. The goals of chronic HBV therapy are the suppression of HBV DNA to undetectable levels, seroconversion of HBeAg (or more rarely, HBsAg) from positive to negative, and reduction in elevated serum aminotransferase levels. These endpoints are correlated with improvement in necroinflammatory disease, a decreased risk of hepatocellular carcinoma and cirrhosis, and a decreased need for liver transplantation. All of the currently licensed therapies achieve these goals. In contrast to the treatment of HCV infection (see below), cure is rare. In addition, because current therapies suppress HBV replication without eradicating the virus, initial responses may not be durable. The covalently closed circular (ccc) viral DNA exists in stable form indefinitely within the cell, serving as a reservoir for HBV throughout the life of the cell and resulting in the capacity to reactivate. Relapse is more common in patients co-infected with hepatitis D virus.


Pharmacology_Katzung

Pharmacology_Katzung. As of 2017 eight drugs were approved for treatment of chronic HBV infection in the United States: five oral nucleoside/nucleotide analogs (lamivudine, adefovir dipivoxil, tenofovir disoproxil, tenofovir alafenamide, entecavir, telbivudine) and two injectable interferon drugs (interferon alfa-2b, pegylated interferon alfa-2a) (Table 49–6). The use of standard interferon has been supplanted by long-acting pegylated interferon, allowing once-weekly rather than daily or thrice-weekly dosing. The advantages of interferon are its finite duration of treatment, the absence of selection of resistant variants, and a more durable response. However, adverse effects from interferon are more frequent, and may be severe. Furthermore, interferon cannot be used in patients with decompensated disease. In general, nucleoside/nucleotide analog therapies have better tolerability and produce a higher response rate than the interferons, and are now considered the first line of therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Combination therapies may reduce the development of resistance. The optimal duration of therapy remains unknown. Several anti-HBV agents have anti-HIV activity as well, including tenofovir disoproxil, tenofovir alafenamide, lamivudine, and adefovir dipivoxil. Emtricitabine, an NRTI used in HIV infection, has resulted in excellent biochemical, virologic, and histologic improvement in patients with chronic HBV infection, although it is not approved for this indication. Although agents with dual HBV and HIV activity are particularly useful as part of a first-line regimen in co-infected patients, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents; this may be severe or even fatal.


Pharmacology_Katzung

Pharmacology_Katzung. Although initially and abortively developed for treatment of HIV infection, adefovir dipivoxil gained approval, at lower and less toxic doses, for treatment of HBV infection. Adefovir dipivoxil is the diester prodrug of adefovir, an acyclic phosphonated adenine nucleotide analog. It is phosphorylated by cellular kinases to the active diphosphate metabolite and then competitively inhibits HBV DNA polymerase and causes chain termination after incorporation into viral DNA. Adefovir is active in vitro against a wide range of DNA and RNA viruses, including HBV, HIV, and herpesviruses.


Pharmacology_Katzung

Pharmacology_Katzung. Oral bioavailability of adefovir dipivoxil is ~ 59% and is unaffected by meals; it is rapidly and completely hydrolyzed to the parent compound by intestinal and blood esterases. Protein binding is low (<5%). The intracellular half-life of the diphosphate is prolonged, ranging from 5 to 18 hours in various cells; this makes once-daily dosing feasible. Adefovir is excreted by both glomerular filtration and active tubular secretion and requires dose adjustment for renal dysfunction; however, it may be administered to patients with decompensated liver disease. Of the oral agents, adefovir may be slower to suppress HBV DNA levels and the least likely to induce HBeAg seroconversion. Emergence of resistance is up to 29% after 5 years of use. However, there is no cross-resistance between adefovir and lamivudine or entecavir.


Pharmacology_Katzung

Pharmacology_Katzung. Adefovir is well tolerated at doses used to treat HBV infection. A reversible increase in serum creatinine has been reported in 3–9% of patients after 4–5 years of treatment. Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are a risk owing to mitochondrial dysfunction. Pivalic acid, a by-product of adefovir metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). Adefovir is embryo-toxic in rats at high doses and is genotoxic in preclinical studies.


Pharmacology_Katzung

Pharmacology_Katzung. Entecavir is an orally administered cyclopentyl guanosine nucleoside analog that competitively inhibits all three functions of HBV DNA polymerase, including base priming, reverse transcription of the negative strand, and synthesis of the positive strand of HBV DNA. Oral bioavailability approaches 100% but is decreased by food; therefore, entecavir should be taken on an empty stomach. The intracellular half-life of the active phosphorylated compound is 15 hours and plasma half-life is prolonged at 128–149 hours, allowing once-daily dosing. It is excreted by the kidney, undergoing both glomerular filtration and net tubular secretion, and dosage should be adjusted in the setting of renal insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. Suppression of HBV DNA levels was greater with entecavir than with lamivudine or adefovir in comparative trials. Entecavir appears to have a higher barrier to the emergence of resistance than lamivudine. Although selection of resistant isolates with the S202G mutation has been documented during therapy, clinical resistance is rare (<1% at 5 years). However, resistance is more frequent in lamivudine-refractory patients (~ 50% at 5 years). Entecavir has weak anti-HIV activity and can induce development of the M184V variant in HBV/HIV co-infected patients, resulting in resistance to emtricitabine and lamivudine.


Pharmacology_Katzung

Pharmacology_Katzung. Entecavir is well tolerated. Potential adverse events are headache, fatigue, dizziness, nausea, and upper abdominal pain. Co-administration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the co-administered drug. Severe lactic acidosis was reported in a case series of entecavir; thus caution is advised for administration in the setting of severe hepatic decompensation. Lung adenomas and carcinomas in mice, hepatic adenomas and carcinomas in rats and mice, vascular tumors in mice, and brain gliomas and skin fibromas in rats have been observed at varying exposures, although clinical relevance is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacokinetics of lamivudine are described earlier in this chapter (see Nucleoside and Nucleotide Reverse Transcriptase Inhibitors). The more prolonged intracellular half-life in HBV-infected cell lines (17–19 hours) than in HIV-infected cell lines (10.5–15.5 hours) allows for lower doses and less frequent administration. Lamivudine can be safely administered to patients with decompensated liver disease. Prolonged treatment has been shown to decrease clinical progression of HBV, as well as development of hepatocellular cancer by approximately 50%. Also, lamivudine has been effective in preventing vertical transmission of HBV from mother to newborn when given in the last 4 weeks of gestation.


Pharmacology_Katzung

Pharmacology_Katzung. Lamivudine inhibits HBV DNA polymerase and HIV reverse transcriptase by competing with deoxycytidine triphosphate for incorporation into the viral DNA, resulting in chain termination. Although lamivudine results in rapid and potent virus suppression, chronic therapy is limited by the emergence of lamivudineresistant HBV isolates (eg, L180M or M204I/V), estimated to occur in 15–30% of patients at 1 year and in up to 65% after 5 years of therapy. Resistance has been associated with flares of hepatitis and progressive liver disease. Cross-resistance between lamivudine and emtricitabine or entecavir may occur; however, adefovir and tenofovir maintain activity against lamivudineresistant strains of HBV. In the doses used for HBV infection, lamivudine has an excellent safety profile. Headache, nausea, diarrhea, dizziness, myalgia, and malaise are rare. Co-infection with HIV may increase the risk of pancreatitis.


Pharmacology_Katzung

Pharmacology_Katzung. Telbivudine is a thymidine nucleoside analog with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. The phosphorylated compound competitively inhibits HBV DNA polymerase, resulting in incorporation into viral DNA and chain termination. It is not active in vitro against HIV-1. Oral bioavailability is unaffected by food. Plasma protein binding is low (3%) and distribution wide. The serum half-life is approximately 15 hours and excretion is renal. There are no known metabolites and no known interactions with the CYP450 system or other drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Telbivudine induced greater rates of virologic response than either lamivudine or adefovir in comparative trials. However, emergence of resistance, typically due to the M204I mutation, may occur in up to 22% of patients with durations of therapy exceeding 1 year, and may result in virologic rebound. Telbivudine is not effective in patients with lamivudine-resistant HBV. Adverse effects are mild; they include fatigue, headache, cough, nausea, and diarrhea. Both uncomplicated myalgia and myopathy with elevated creatinine kinase levels have been reported, as has peripheral neuropathy. As with other nucleoside analogs, lactic acidosis and severe hepatomegaly with steatosis may occur during therapy as well as flares of hepatitis after discontinuation.


Pharmacology_Katzung

Pharmacology_Katzung. Tenofovir, a nucleotide analog of adenosine in use as an antiretroviral agent, has potent activity against HBV. The characteristics of tenofovir disoproxil are described earlier in this chapter. Tenofovir maintains activity against lamivudineand entecavir-resistant hepatitis virus isolates. Although similar in structure to adefovir dipivoxil, comparative trials show a higher rate of virologic response and histologic improvement, and a lower rate of emergence of resistance in patients with chronic HBV infection. Resistance to tenofovir has not been documented in clinical trials, even among patients who have been treated with tenofovir for up to 8 years. However, efficacy is lower in patients who have resistance to adefovir and double mutations (A181T/V and N236T).


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects of tenofovir in patients with HBV infection are nausea, abdominal pain, diarrhea, dizziness, and fatigue. Chronic renal insufficiency secondary to a proximal tubulopathy may occur, and may progress to renal failure. Decreases in bone mineral density and Fanconi’s syndrome, as observed in HIV-infected patients treated with tenofovir, have not been described in patients with HBV infection receiving tenofovir disoproxil. Tenofovir alafenamide fumarate (TAF) is an orally bioavailable prodrug of tenofovir that enables enhanced delivery of the parent nucleotide and its active diphosphate metabolite into lymphoid cells and hepatocytes, so that the dose of tenofovir can be reduced and toxicities minimized.


Pharmacology_Katzung

Pharmacology_Katzung. The nucleoside analog emtricitabine (see HIV) is under clinical investigation for treatment of HBV infection. The entry inhibitors Myrcludex B and cyclosporine, as well as cccDNA inhibitors, are being evaluated. Research is also ongoing to develop and test new agents that can “cure” HBV by eliminating all replicative forms, including covalently closed circular DNA (cccDNA). Broadly curative antiviral strategies include agents that could directly target infected cells as well as novel immunotherapeutic strategies that boost HBV-specific adaptive immune responses or activate innate intrahepatic immunity. New molecules under investigation include entry inhibitors and short-interfering RNAs (siRNAs), and capsid inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. In contrast to the treatment of patients with chronic HBV infection, the primary goal of treatment in patients with HCV infection is viral eradication. In clinical trials, the primary efficacy end point is typically achievement of sustained viral response (SVR), defined as the absence of detectable viremia 24 weeks after completion of therapy. SVR is associated with improvement in liver histology, reduction in risk of end-stage liver disease and hepatocellular carcinoma, and, occasionally, with regression of cirrhosis as well. Late relapse occurs in less than 5% of patients who achieve SVR. In acute hepatitis C, the rate of clearance of the virus without therapy is estimated at 20–35%. Therefore, most practitioners choose to delay therapy for a minimum of 6 months after the initial infection. If treatment is initiated thereafter due to persistent HCV RNA viremia, the regimens are the same as those administered or chronic HCV infection.


Pharmacology_Katzung

Pharmacology_Katzung. The advent of the first-generation direct-acting antiviral agents (DAAs) boceprevir and telaprevir dramatically altered the landscape for the optimal treatment of chronic HCV infection, which was previously treated with the combination of interferonalfa (replaced by pegylated interferon-alfa) and ribavirin. Since interferon-containing regimens tend to be associated with higher rates of serious adverse events (including anemia and rash), longer treatment durations, more frequent dosing, and clinically significant drug-drug interactions, they are gradually being replaced by combination regimens of DAAs (see Table 49–7). Moreover, while the first-generation HCV protease inhibitors (ie, boceprevir, telaprevir) markedly improved the effectiveness of pegylated interferon plus ribavirin, they have been replaced by newer DAAs over the past 2 years, which can be administered in all-oral, interferon-free combinations—with or without ribavirin—with improved efficacy and tolerability, improved


Pharmacology_Katzung

Pharmacology_Katzung. have been replaced by newer DAAs over the past 2 years, which can be administered in all-oral, interferon-free combinations—with or without ribavirin—with improved efficacy and tolerability, improved dosing schedules, lesser genotype specificity, and fewer potential drug-drug interactions. However, the DAA regimens are expensive.


Pharmacology_Katzung

Pharmacology_Katzung. There are four current classes of DAAs, which are defined by their mechanism of action and therapeutic target: nonstructural protein (NS) 3/4A protease inhibitors, NS5B nucleoside polymerase inhibitors, NS5B non-nucleoside polymerase inhibitors, and NS5A inhibitors. The main targets of the DAAs are the HCV-encoded proteins that are vital to the replication of the virus (Figure 49–1). The safety profiles of all the combination regimens (see Table 49–7) are generally excellent, with adverse events of mild severity and very low rates of discontinuation due to adverse events in clinical trials in the absence of concurrent ribavirin use. The NS5A protein plays a role in both viral replication and the assembly of HCV; however the exact mechanism of action of the HCV NS5A inhibitors remains unclear.


Pharmacology_Katzung

Pharmacology_Katzung. The NS5A protein plays a role in both viral replication and the assembly of HCV; however the exact mechanism of action of the HCV NS5A inhibitors remains unclear. Daclatasvir is used in combination with sofosbuvir for treatment of HCV genotypes 1, 2, and 3. It may be taken with or without food and does not require adjustment for renal or hepatic impairment. Exposure of daclatasvir was similar between healthy and HCV-infected subjects. Protein binding is ~99%. It is metabolized via CYP3A and excreted primarily in the feces. Terminal elimination half-life is 12–15 hours. Daclatasvir is generally well tolerated. The most common adverse effects in patients receiving daclatasvir/sofosbuvir were headache and fatigue, usually mild or moderate in severity. Serious symptomatic bradycardia has been reported in patients receiving daclatasvir with sofosbuvir and amiodarone.


Pharmacology_Katzung

Pharmacology_Katzung. Daclatasvir is primarily metabolized through CYP3A metabolism and should not be given with strong inducers of this enzyme. In addition, dose adjustment is required when co-administered with strong CYP3A inhibitors or moderate CYP3A inducers. Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Elbasvir has in vitro activity against most major HCV genotypes, as well as some viral variants resistant to earlier NS5A inhibitors. It is only available as a fixed-dose combination with grazoprevir, recommended for treatment of HCV genotypes 1 and 4 (see Table 49–7).


Pharmacology_Katzung

Pharmacology_Katzung. The presence of baseline NS5A resistance-associated variants (RAVs) significantly reduced rates of SVR at 12 weeks using elbasvir/grazoprevir regimen in patients with genotype 1a. Since 10–15% of patients without prior exposure will have NS5A RAVs, baseline testing should be considered prior initiation of therapy. Absorption is not food-dependent. Peak concentrations after ingestion occur at a median of 3 hours. Elbasvir is extensively bound to plasma proteins (>99.9%), partially eliminated by oxidative metabolism, and primarily excreted in the feces. Elbasvir/ grazoprevir should not be administered to patients with moderate or severe hepatic impairment or in conjunction with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong inducers or inhibitors of CYP3A, or efavirenz. The most commonly reported side effects during therapy with elbasvir/grazoprevir were fatigue, headache, and nausea. Elevations in serum aminotransferases may occur.


Pharmacology_Katzung

Pharmacology_Katzung. The most commonly reported side effects during therapy with elbasvir/grazoprevir were fatigue, headache, and nausea. Elevations in serum aminotransferases may occur. Ledipasvir was the first NS5A inhibitor to be available in the United States. It is available in a fixed-dose combination with sofosbuvir. Ledipasvir is not recommended for treatment of HCV genotype 2 infection (since potency is lost in the presence of the highly prevalent L31M polymorphism) or genotype 3 (due to the availability of more efficacious therapies (see Table 49–7).


Pharmacology_Katzung

Pharmacology_Katzung. Ledipasvir is not affected by food intake. Median peak plasma concentrations occur 4–4.5 hours after oral administration of ledipasvir/sofosbuvir. It is highly bound (>99.8%) to plasma proteins; unchanged ledipasvir is the major species present in feces. The median terminal half-life of ledipasvir following administration of ledipasvir/sofosbuvir is 47 hours. No dose adjustment is required in the setting of mild or moderate renal insufficiency or mild, moderate or severe hepatic insufficiency. The dose in patients with severe renal insufficiency has not yet been determined. Ledipasvir is an inhibitor of the drug transporters P-gp and BCRP and may increase intestinal absorption of co-administered substrates for these transporters. Additionally, co-administration of P-gp inducers (e.g., rifampin or St. John’s wort) with ledipasvir/ sofosbuvir may decrease plasma concentrations of both of these agents.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse reactions in patients receiving ledipasvir/sofosbuvir were fatigue, headache and asthenia. Serious symptomatic bradycardia has been reported in patients receiving ledipasvir with sofosbuvir and amiodarone. Ombitasvir is available only as a fixed-dose combination with paritaprevir and ritonavir for the treatment of HCV genotype 4, and is given in combination with dasabuvir, paritaprevir, and ritonavir to treat genotype 1 (see Table 49–7). As in HIV infection, ritonavir is administered as a pharmacologic “booster” to increase plasma concentrations of paritaprevir via its effect on CYP3A, although it does not have activity against HCV. The absolute bioavailability of ombitasvir is 48%. Peak plasma concentrations are reached 5 hours post-ingestion of the combination. It is 99.9% protein-bound; the route of metabolism is via biliary excretion. Ombitasvir/paritaprevir/ritonavir is contraindicated in patients with moderate or severe hepatic impairment.


Pharmacology_Katzung

Pharmacology_Katzung. Ombitasvir is an inhibitor of UGT1A1. Although ombitasvir is not metabolized by the CYP3A system, paritaprevir, ritonavir, and dasabuvir are, with the resulting potential for multiple drug-drug interactions. Co-administration of the combination with drugs that highly dependent on CYP3A for clearance, moderate or strong inducers of CYP3A, strong inducers of CYP2C8, or strong inhibitors of CYP2C8 is contraindicated. The most commonly reported adverse reactions in patients receiving ombitasvir were nausea, pruritus and insomnia. Increased serum aminotransferases have also been reported, particularly in women using concomitant ethinyl estradiol-containing contraceptive medications.


Pharmacology_Katzung

Pharmacology_Katzung. Velpatasvir is available only in a fixed-dose combination with the sofosbuvir. It is the first once-daily single-tablet regimen with pangenotypic activity. No dose adjustment is required for patients with mild or moderate renal insufficiency, or any degree of hepatic impairment. Sofosbuvir exposure is increased in patients with severe renal impairment, including those on dialysis. Velpatasvir is administered without regard to food; peak plasma concentrations are observed at 3 hours post-dose. It is >99% bound to plasma proteins. Metabolism is by CYP2B6 CYP2C8, and CYP3A4. Its median terminal half-lives is 15 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Velpatasvir and sofosbuvir are substrates of P-gp and BCRP; velpatasvir is also transported by OATP1B1 and OATP1B3. Inducers of P-gp and/or moderate or potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease plasma concentrations of velpatasvir and/or sofosbuvir; co-administration with drugs that inhibit P-gp and/ or BCRP may increase velpatasvir and/or sofosbuvir concentrations and drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. The most common adverse events in patients receiving velpatasvir/sofosbuvir were headache and fatigue.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse events in patients receiving velpatasvir/sofosbuvir were headache and fatigue. NS5B is an RNA-dependent RNA polymerase involved in post-translational processing that is necessary for replication of HCV. The enzyme has a catalytic site for nucleoside binding and at least four other sites at which a non-nucleoside compound can bind and cause allosteric alteration. The enzyme’s structure is highly conserved across all HCV genotypes, giving agents that inhibit NS5B efficacy against all six genotypes. There are two classes of polymerase inhibitors; these act at distinct stages of RNA synthesis. Nucleoside/nucleotide analogs (eg, sofosbuvir) target the catalytic site of NS5B, and are activated within the hepatocyte through phosphorylation to nucleoside triphosphate, which competes with nucleotides, resulting in chain termination. Non-nucleoside analogues (e.g., dasabuvir) act as allosteric inhibitors of NS5B.


Pharmacology_Katzung

Pharmacology_Katzung. Dasabuvir is a non-nucleoside NS5B polymerase inhibitor, available only as a fixed-dose combination with ombitasvir, paritaprevir, and ritonavir for treatment of HCV genotype 1. Ritonavir functions as a pharmacologic booster to increase paritaprevir plasma concentrations. The absolute bioavailability of dasabuvir is 70%. Peak plasma concentrations are reached 4 hours post-ingestion of the combination. It is >99.5% protein-bound. The primary route of metabolism is via CYP2C8, as well as CYP3A. This combination is contraindicated in patients with moderate or severe hepatic impairment. The metabolism of paritaprevir, ritonavir, and dasabuvir by the CYP3A system incurs multiple potential drug-drug interactions. Co-administration of the combination with drugs that highly dependent on CYP3A for clearance, moderate or strong inducers of CYP3A, strong inducers of CYP2C8, or strong inhibitors of CYP2C8 is contraindicated.


Pharmacology_Katzung

Pharmacology_Katzung. The most commonly reported adverse reactions in patients receiving dasabuvir were nausea, pruritus and insomnia. Increased serum aminotransferases have also been reported, particularly in women using concomitant ethinyl estradiol-containing contraceptive medications. The nucleotide analog sofosbuvir is administered in combination with several other anti-HCV medications, including daclatasvir, simeprevir, peginterferon-alfa plus ribavirin, or ribavirin alone. It is also available in a fixed-dose combination with ledipasvir for treatment of HCV genotypes 1, 4, 5, and 6 (see Table 49–7). Sofosbuvir is a prodrug that is rapidly converted after ingestion to GS-331007, which is efficiently taken up by hepatocytes and converted by cellular kinase to its pharmacologically active uridine analog 5’-triphosphate form GS-461203. The triphosphate is incorporated by the HCV RNA polymerase into the elongating RNA primer strand, resulting in chain termination.


Pharmacology_Katzung

Pharmacology_Katzung. Sofosbuvir is administered without regard to food; peak plasma concentrations are observed at 0.5–1 hour post-dose. It is 61–65% bound to plasma proteins and is metabolized in the liver. Renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 are 0.4 and 27 hours, respectively. No dose adjustment is required for patients with mild or moderate renal insufficiency, or any degree of hepatic impairment. Sofosbuvir exposure is increased in patients with severe renal impairment, including those on dialysis. Sofosbuvir is a substrate of drug transporter P-gp; therefore, potent P-gp inducers in the intestine may decrease sofosbuvir concentrations and should not be co-administered.


Pharmacology_Katzung

Pharmacology_Katzung. Sofosbuvir is a substrate of drug transporter P-gp; therefore, potent P-gp inducers in the intestine may decrease sofosbuvir concentrations and should not be co-administered. Sofosbuvir is generally well tolerated. Drug-specific adverse effects are difficult to discern since it is always administered with other antiviral agents. In patients receiving sofosbuvir with ledipasvir, the most commonly reported adverse effects were fatigue, headache, and asthenia. Rare cases of symptomatic bradycardia have been reported patients taking sofosbuvir and amiodarone in combination with another DAAs, particularly in patients also receiving beta blockers, or in those with underlying cardiac comorbidities and/or advanced liver disease. NS3/4A protease inhibitors are inhibitors of the NS3/4A serine protease, an enzyme involved in post-translational processing and replication of HCV (Figure 49–4).


Pharmacology_Katzung

Pharmacology_Katzung. NS3/4A protease inhibitors are inhibitors of the NS3/4A serine protease, an enzyme involved in post-translational processing and replication of HCV (Figure 49–4). Capsid C NS3/4A protease inhibitors “ ... previr ” NS5A inhibitors “ ... asvir ” NS5B polymerase inhibitors “ ... buvir ” E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B glycoproteins RNA helicase Cofactors polymerase FIGURE 49–4 HCV genome and potential targets of drug action. C, E1, E2, etc, protein products of specific genes; Nucs, nucleoside inhibitors; Non-Nucs, nonnucleoside inhibitors. (Adapted, with permission, from Asselah T, Marcellin P: Direct-acting antivirals for the treatment of chronic hepatitis C: One pill a day for tomorrow. Liver Int 2012;32 Suppl 1:88.)


Pharmacology_Katzung

Pharmacology_Katzung. C: One pill a day for tomorrow. Liver Int 2012;32 Suppl 1:88.) Grazoprevir is a potent, pan-genotypic protease inhibitor, reversibly binding to HCV NS3/4A protease. It is distinct from earlier-generation protease inhibitors due to its pan-genotypic activity, as well activity against some of the major resistance-associated variants (R155K and D168Y) resulting in failure with first-generation protease inhibitors. It is only available in combination with elbasvir for treatment of HCV genotypes 1 and 4.


Pharmacology_Katzung

Pharmacology_Katzung. Grazoprevir can be taken without regard to food. Oral exposures are ~2-fold greater in HCV-infected subjects than in healthy subjects. Peak plasma concentrations are reached at a median of 2 hours after ingestion. Grazoprevir is extensively bound to plasma proteins (98.8%), and distributes predominantly to the liver, likely facilitated by active transport through the OATP1B1/3 liver uptake transporter. It is partially eliminated by oxidative metabolism, primarily by CYP3A and is mostly eliminated in the feces. Its geometric mean terminal half-life is 31 hours. Elbasvir/grazoprevir should not be administered to patients with moderate or severe hepatic impairment, or in conjunction with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong inducers or inhibitors of CYP3A, or efavirenz. The most commonly reported side effects during therapy with elbasvir/grazoprevir were fatigue, headache, and nausea. Elevations in serum aminotransferases may occur.


Pharmacology_Katzung

Pharmacology_Katzung. The most commonly reported side effects during therapy with elbasvir/grazoprevir were fatigue, headache, and nausea. Elevations in serum aminotransferases may occur. Paritaprevir is only available as a fixed-dose combination with ombitasvir and ritonavir for treatment of HCV genotype 4, and is administered in combination with dasabuvir for genotype 1 infection. Ritonavir functions as a pharmacologic booster of paritaprevir concentrations via its effect on CYP metabolism, although it does not have activity against HCV. The absolute bioavailability of paritaprevir is 53%. Peak plasma concentrations are reached 4–5 hours post-ingestion of the combination. It is ~98% protein-bound. The primary route of metabolism is via CYP3A4, as well as CYP3A5. Ombitasvir/ paritaprevir/ritonavir is contraindicated in patients with moderate or severe hepatic impairment.


Pharmacology_Katzung

Pharmacology_Katzung. The metabolism of paritaprevir, ritonavir, and dasabuvir by the CYP3A system incurs multiple potential drug-drug interactions. Co-administration of the combination with drugs highly dependent on CYP3A for clearance, moderate or strong inducers of CYP3A, strong inducers of CYP2C8, or strong inhibitors of CYP2C8 is contraindicated. The most commonly reported adverse reactions in patients receiving paritaprevir were nausea, pruritus and insomnia. Increased serum aminotransferases have also been reported, particularly in women using concomitant ethinyl estradiol–containing contraceptive medications.


Pharmacology_Katzung

Pharmacology_Katzung. Simeprevir was one of the earliest protease inhibitors available; however, it is considered a second-generation HCV protease inhibitor because of the enhanced binding affinity and specificity for NS3/4A. It is used in combination with sofosbuvir, with or without ribavirin, for treatment of HCV genotype 1, or it may be administered in combination with peg interferon-alfa and ribavirin. Simeprevir must be taken with food to maximize absorption. Mean absolute bioavailability is 62%. Peak plasma concentrations are reached 4–6 hours post-ingestion. It is extensively bound to plasma proteins (>99%), metabolized in the liver by CYP3A pathways, and undergoes biliary excretion. Simeprevir is not recommended in patients with moderate or severe hepatic impairment because of 2to 5-fold increases in exposure. In addition, mean simeprevir exposures are more than threefold higher in patients of East Asian ancestry compared with Caucasians, leading to potentially higher frequencies of adverse events.


Pharmacology_Katzung

Pharmacology_Katzung. Simeprevir is a substrate and mild inhibitor of CYP3A and a substrate and inhibitor of P-gp and OATP1B1/3. Co-administration with moderate or strong inhibitors or inducers of CYP3A may significantly increase or decrease the plasma concentration of simeprevir. In patients with genotype 1a, the presence of a baseline NS3A polymorphism Q80K was associated with significantly reduced SVR at 12 weeks in patients treated with simeprevir plus peginterferon and ribavirin. Therefore, baseline screening for the Q80K mutation is recommended prior to initiation of therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Simeprevir is generally well tolerated. Photosensitivity and rash have been reported, occasionally severe; pruritus or nausea may also occur. Transient, mild elevations in bilirubin have been observed with simeprevir due to decreased bilirubin elimination related to inhibition of the hepatic transporters OATP1B1 and MRP2, but no pattern to suggest liver toxicity has been observed. Since simeprevir contains a sulfa moiety, caution should be used in patients with a history of sulfa allergy.


Pharmacology_Katzung

Pharmacology_Katzung. Ribavirin is a guanosine analog that is phosphorylated intracellularly by host cell enzymes. Although its mechanism of action has not been fully elucidated, it appears to interfere with the synthesis of guano-sine triphosphate, to inhibit capping of viral messenger RNA, and to inhibit the viral RNA–dependent polymerase of certain viruses. Ribavirin triphosphate inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV, and HIV-1. The absolute oral bioavailability of ribavirin is 45–64%, increases with high-fat meals, and decreases with co-administration of antacids. Plasma protein binding is negligible, volume of distribution is large, and cerebrospinal fluid levels are about 70% of those in plasma. Ribavirin elimination is primarily through the urine; therefore, clearance is decreased in patients with creatinine clearances <30 mL/min.


Pharmacology_Katzung

Pharmacology_Katzung. Higher doses of ribavirin (ie, 1000–1200 mg/d rather than 800 mg/d) and/or a longer duration of therapy may be more efficacious, but the risk of toxicity is also increased. A dose-dependent hemolytic anemia occurs in 10–20% of patients, usually within the first weeks of therapy. Other potential adverse effects are depression, fatigue, irritability, rash, cough, insomnia, nausea, and pruritus. Contraindications include anemia, end-stage renal failure, ischemic vascular disease, and pregnancy. Ribavirin is teratogenic and embryotoxic in animals as well as mutagenic in mammalian cells. Therefore, two effective forms of contraception should be used by both sexual partners during treatment and for several months thereafter. The co-administration of ribavirin with didanosine causes significantly increased levels of didanosine; co-administration with azathioprine may result in myelotoxicity due to accumulation of azathioprine.


Pharmacology_Katzung

Pharmacology_Katzung. Influenza virus strains are classified by their core proteins (ie, A, B, or C), species of origin (eg, avian, swine), and geographic site of isolation. Influenza A, the only strain that causes pandemics, is classified into 16 H (hemagglutinin) and 9 N (neuraminidase) known subtypes based on surface proteins. Although influenza B viruses usually infect only people, influenza A viruses can infect a variety of animal hosts, including birds, providing an extensive reservoir. Current influenza A subtypes that are circulating among worldwide populations include H1N1, H1N2, and H3N2. Although avian influenza subtypes are typically highly species-specific, they have on rare occasions crossed the species barrier to infect humans and cats. Viruses of the H5 and H7 subtypes (eg, H5N1, H7N9) may rapidly mutate within poultry flocks from a low to high pathogenic form and have recently expanded their host range to cause both avian and human disease. However, person-to-person spread of these avian


Pharmacology_Katzung

Pharmacology_Katzung. mutate within poultry flocks from a low to high pathogenic form and have recently expanded their host range to cause both avian and human disease. However, person-to-person spread of these avian viruses to date has been rare, limited, and unsustained.


Pharmacology_Katzung

Pharmacology_Katzung. There are 5 anti-influenza drugs approved for use: 3 are neuraminidase inhibitors (oral oseltamivir, inhaled zanamivir, IV peramivir) and 2 are adamantanes (amantadine, rimantadine). Treatment is recommended for individuals with severe infection or at high risk for complications. The neuraminidase inhibitors have activity against both influenza A and influenza B, and there is currently a low level of resistance. The adamantanes have activity against influenza A viruses only, and in recent past seasons there was a high level of resistance (>99%) among both influenza H3N2 and influenza A H1N1.


Pharmacology_Katzung

Pharmacology_Katzung. The neuraminidase inhibitors oseltamivir and zanamivir, analogs of sialic acid, interfere with release of progeny influenza A and B virus from infected host cells, thus halting the spread of infection within the respiratory tract. These agents competitively and reversibly interact with the active enzyme site to inhibit viral neuraminidase activity at low nanomolar concentrations, resulting in clumping of newly released influenza virions to each other and to the membrane of the infected cell. Early administration is crucial because replication of influenza virus peaks at 24–72 hours after the onset of illness. Initiation of a 5-day course of therapy within 48 hours after the onset of illness (75 mg twice daily) modestly decreases the duration of symptoms, as well as duration of viral shedding and viral titer; some studies have also shown a decrease in the incidence of complications. Once-daily prophylaxis (75 mg once daily) is 70–90% effective in preventing disease after exposure.


Pharmacology_Katzung

Pharmacology_Katzung. Oseltamivir is an orally administered prodrug that is activated by hepatic esterases and widely distributed throughout the body. Oral bioavailability is ~ 80%, plasma protein binding is low, and concentrations in the middle ear and sinus fluid are similar to those in plasma. The half-life of oseltamivir is 6–10 hours, and excretion is by glomerular filtration and tubular secretion. Probenecid reduces renal clearance by 50%. Serum concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function; therefore, dosage should be adjusted in patients with renal insufficiency. Potential adverse effects include nausea, vomiting, and headache. Taking oseltamivir with food does not interfere with absorption and may decrease nausea and vomiting. Fatigue and diarrhea have also been reported and appear to be more common with prophylactic use. Rash is rare. Neuropsychiatric events (self-injury or delirium) have been reported, particularly in


Pharmacology_Katzung

Pharmacology_Katzung. Fatigue and diarrhea have also been reported and appear to be more common with prophylactic use. Rash is rare. Neuropsychiatric events (self-injury or delirium) have been reported, particularly in adolescents and adults living in Japan.


Pharmacology_Katzung

Pharmacology_Katzung. Zanamivir is administered directly to the respiratory tract via inhalation. Of the active compound, 10–20% reaches the lungs; the remainder is deposited in the oropharynx. The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase, and the pulmonary half-life is 2.8 hours. Of the total dose (10 mg twice daily for 5 days for treatment or 10 mg once daily for prevention), 5–15% is absorbed and excreted in the urine with minimal metabolism. Potential adverse effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort. Zanamivir administration is not recommended for patients with underlying airway disease.


Pharmacology_Katzung

Pharmacology_Katzung. Although resistance to oseltamivir and zanamivir may emerge during therapy and be transmissible, >98% of H1N1 and H3N2 strains as well as 100% of influenza B virus tested by the Centers for Disease Control in the 2014–2015 season retained susceptibility to both agents. The neuraminidase inhibitor peramivir, a cyclopentane analog, has activity against both influenza A and B viruses, and is approved as a single 600-mg IV dose for the treatment of acute uncomplicated influenza in adults. As with the other neuraminidase inhibitors, early treatment is optimal (ie, within 48 hours). Less than 30% of peramivir is protein-bound. Peramivir is not significantly metabolized in humans and the major route of elimination is the kidney. Dose adjustment is required for renal insufficiency. The elimination half-life following IV administration is ~20 hours.


Pharmacology_Katzung

Pharmacology_Katzung. The main potential side effect is diarrhea, although serious skin or hypersensitivity reactions (e.g., Stevens-Johnson syndrome, erythema multiforme) have been rarely reported. In addition, as with the other neuraminidase inhibitors, an increased risk of hallucinations, delirium, and abnormal behavior in patients with influenza receiving peramivir has been reported.


Pharmacology_Katzung

Pharmacology_Katzung. Amantadine (1-aminoadamantane hydrochloride) and its α-methyl derivative, rimantadine, are tricyclic amines of the adamantane family that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication. They are active against influenza A only. Rimantadine is four to ten times more active than amantadine in vitro. Amantadine is well absorbed and 67% protein-bound, with a plasma half-life of 12–18 hours that varies by creatinine clearance. Rimantadine is about 40% protein-bound and has a half-life of 24–36 hours. Nasal mucus concentrations of rimantadine average 50% higher than those in plasma, and cerebrospinal fluid levels are 52–96% of those in the serum. Amantadine is excreted unchanged in the urine, whereas rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly and in


Pharmacology_Katzung

Pharmacology_Katzung. whereas rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly and in patients with renal insufficiency, and for rimantadine in patients with severe hepatic insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. In the absence of resistance, both amantadine and rimantadine are 70–90% protective in the prevention of clinical illness when initiated before exposure and limit the duration of clinical illness by 1–2 days when administered as treatment. However, due to high rates of resistance in both H1N1 and H3N2 viruses, these agents are no longer recommended for the prevention or treatment of influenza.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects are gastrointestinal (nausea, anorexia) and central nervous system (nervousness, difficulty in concentrating, insomnia, light-headedness). More serious side effects (eg, marked behavioral changes, delirium, hallucinations, agitation, and seizures) may be due to alteration of dopamine neurotransmission (see Chapter 28); are less frequent with rimantadine than with amantadine; are associated with high plasma concentrations; may occur more frequently in patients with renal insufficiency, seizure disorders, or advanced age; and may increase with concomitant antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Clinical manifestations of anticholinergic activity tend to be present in acute amantadine overdose. Both agents are teratogenic and embryotoxic in rodents, and birth defects have been reported after exposure during pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. An IV formulation of zanamivir is being evaluated in clinical trials and is available for compassionate use from the manufacturer. A long-acting neuraminidase inhibitor, laninamivir octanoate, may retain activity against oseltamivir-resistant virus. DAS181 is a host-directed antiviral agent with activity against influenza and parainfluenza that acts by removing the virus receptor, sialic acid, from adjacent glycan structures. Interferons have been studied for numerous clinical indications. In addition to HBV and HCV infections (see Antihepatitis Agents), intralesional injection of interferon alfa-2b or alfa-n3 may be used for treatment of condylomata acuminata (see Chapter 61).


Pharmacology_Katzung

Pharmacology_Katzung. In addition to oral administration for HCV infection in combination with interferon alfa (see Antihepatitis Agents), aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12–18 hours continuously per day) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia to reduce the severity and duration of illness. Systemic absorption is low (<1%). Aerosolized ribavirin may cause conjunctival or bronchial irritation and the aerosolized drug may precipitate on contact lenses. Ribavirin is teratogenic and embryotoxic. Health care workers and pregnant women should be protected against extended inhalation exposure. Ribavirin has in vitro activity against a number of viruses, including Lassa, West Nile, measles, influenza, and parainfluenza. However, clinical data regarding effectiveness are lacking.


Pharmacology_Katzung

Pharmacology_Katzung. Palivizumab is a humanized monoclonal antibody directed against an epitope in the A antigen site on the F surface protein of RSV. It is licensed for the prevention of RSV infection in high-risk infants and children, such as premature infants and those with bronchopulmonary dysplasia or congenital heart disease. A placebo-controlled trial using once-monthly intramuscular injections (15 mg/kg) for 5 months beginning at the start of the RSV season demonstrated a 55% reduction in the risk of hospitalization for RSV in treated patients, as well as decreases in the need for supplemental oxygen, the illness severity score, and need for intensive care. Although resistant strains have been isolated in the laboratory, no resistant clinical isolates have yet been identified. Potential adverse effects include upper respiratory tract infection, fever, rhinitis, rash, diarrhea, vomiting, cough, otitis media, and elevation in serum aminotransferase levels.


Pharmacology_Katzung

Pharmacology_Katzung. Agents under investigation for the treatment or prophylaxis of patients with RSV infection include small molecule inhibitors that interfere with RSV fusion through interaction with the F protein of RSV (e.g., GS-5806) and the oral nucleoside analog ALS-008176. Imiquimod is an immune response modifier shown to be effective in the topical treatment of external genital and perianal warts (ie, condyloma acuminatum; see Chapter 61). The 5% cream is applied three times weekly and washed off 6–10 hours after each application. Recurrences appear to be less common than after ablative therapies. Imiquimod may also be effective against molluscum contagiosum but is not licensed in the USA for this indication. Local skin reactions are the most common adverse effect; these tend to resolve within weeks after therapy. However, pigmentary skin changes may persist. Systemic adverse effects such as fatigue and influenza-like syndrome have occasionally been reported.


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS Abacavir/lamivudine Epzicom Acyclovir Generic, Zovirax Amantadine Generic, Symmetrel GENERIC NAME AVAILABLE AS Etravirine Intelence Fosamprenavir Lexiva Ganciclovir Generic, Cytovene Indinavir Crixivan Interferon alfa-2a Roferon-A Abacavir Abacavir/lamivudine/zidovudine Adefovir Atazanavir Generic, Ziagen Trizivir Generic, Hepsera Reyataz Cidofovir Generic, Vistide Didanosine (dideoxyinosine, ddI) Generic, Videx, Videx-EC Entecavir Baraclude Famciclovir Generic, Famvir Foscarnet Generic, Foscavir Imiquimod Generic, Aldara, others Lamivudine Generic, Epivir, Epivir-HBV Nevirapine Generic, Viramune


Pharmacology_Katzung

Pharmacology_Katzung. Lamivudine Generic, Epivir, Epivir-HBV Nevirapine Generic, Viramune GENERIC NAME AVAILABLE AS Palivizumab Synagis Peginterferon alfa-2a (pegylated interferon alfa-2a) Pegasys Peginterferon alfa-2b (pegylated interferon alfa-2b) PEG-Intron Penciclovir Denavir Raltegravir Isentress Ribavirin Generic, Rebetol Ribavirin/interferon alfa-2b Rebetron Ribavirin Aerosol Virazole Rilpivirine Edurant Rilpivirine/emtricitabine/-tenofovir Complera Rimantadine Generic, Flumadine Ritonavir Norvir Saquinavir Invirase GENERIC NAME AVAILABLE AS Sofosbuvir Sovaldi Stavudine Generic, Zerit, Zerit XR Telaprevir Incivek Telbivudine Tyzeka Tenofovir Viread Tipranavir Aptivus Trifluridine Generic, Viroptic Valacyclovir Generic, Valtrex Valganciclovir Valcyte Zalcitabine (dideoxycytidine, ddC) Hivid (withdrawn) Zanamivir Relenza Zidovudine (azidothymidine, AZT) Generic, Retrovir Zidovudine/lamivudine Combivir Zidovudine/lamivudine/abacavir Trizivir


Pharmacology_Katzung

Pharmacology_Katzung. American Association for the Study of Liver Diseases (AASLD)-Infectious Diseases Society of America (IDSA): Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Günthard HF et al: Antiretroviral Treatment of Adult HIV Infection: 2014 Recommendations of the International Antiviral Society–USA Panel. JAMA 2014;312:410. Medical Letter: Antiviral drugs. Med Lett Drugs Ther 2013;11:19. Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. https://www.aidsinfo.nih.gov/guidelines.


Pharmacology_Katzung

Pharmacology_Katzung. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. https://www. aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Terrault NA et al: AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology 2016;63:261. https://www.aidsinfo.nih.gov www.hiv-druginteractions.org www.hivinsite.com www.iasusa.org www.hepatitisc.uw.edu/page/treatment/drugs


Pharmacology_Katzung

Pharmacology_Katzung. Combination antiviral therapy against both HIV and hepa-titis B virus (HBV) is indicated in this patient, given the high viral load and low CD4 cell count. However, the use of methadone and possibly excessive alcohol consumption necessitate caution. Tenofovir plus emtricitabine (two nucle-oside/nucleotide reverse transcriptase inhibitors) would be excellent choices as the NRTI “backbone” of a fully sup-pressive regimen, since both are active against HIV-1 and HBV, do not interact with methadone, and are available in a once-daily, fixed-dose combination. A strand inhibitor such as raltegravir or dolutegravir, or the boosted combina-tion of darunavir/ritonavir could be added. There are other alternatives as well. Prior to initiation of this regimen, renal and liver function should be checked, HBV DNA level should be assessed, the patient should be screened for Hepa-titis A and HCV infection, and a bone mineral density test should be considered. Pregnancy should be ruled out, and the


Pharmacology_Katzung

Pharmacology_Katzung. HBV DNA level should be assessed, the patient should be screened for Hepa-titis A and HCV infection, and a bone mineral density test should be considered. Pregnancy should be ruled out, and the patient should be counseled that efavirenz should not be taken during pregnancy. Avoidance of alcohol should be rec-ommended. The potential for lowered methadone levels with darunavir, if used, necessitates close monitoring and possibly an increased dose of methadone. Finally, the patient should be made aware that abrupt cessation of these medications may precipitate an acute flare of hepatitis.


Pharmacology_Katzung

Pharmacology_Katzung. Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants Camille E. Beauduy, PharmD, & Lisa G. Winston, MD* A 56-year-old man is admitted to the intensive care unit of a hospital for treatment of community-acquired pneumonia. He receives ceftriaxone and azithromycin upon admission, rapidly improves, and is transferred to a semiprivate ward room. On day 7 of his hospitalization, he develops copi-ous diarrhea with eight bowel movements but is otherwise clinically stable. Clostridium difficile infection is confirmed by stool testing. What is an acceptable treatment for the patient’s diarrhea? The patient is transferred to a single-bed room. The housekeeping staff asks what product should be used to clean the patient’s old room. ■ METRONIDAZOLE, FIDAXOMYCIN, RIFAXIMIN, MUPIROCIN, POLYMYXINS, & URINARY ANTISEPTICS


Pharmacology_Katzung

Pharmacology_Katzung. ■ METRONIDAZOLE, FIDAXOMYCIN, RIFAXIMIN, MUPIROCIN, POLYMYXINS, & URINARY ANTISEPTICS Metronidazole is a nitroimidazole antiprotozoal drug (see Chapter 52) that also has potent antibacterial activity against anaerobes, including Bacteroides and Clostridium species. Metronidazole is selectively absorbed by anaerobic bacteria and sensitive protozoa. Once taken up by anaerobes, it is nonenzymatically reduced by reacting with reduced ferredoxin. This reduction * The authors thank Henry F. Chambers, MD and Daniel H. Deck, PharmD, for their contributions to previous editions of this chapter. results in products that accumulate in and are toxic to anaerobic cells. The metabolites of metronidazole are taken up into bacterial DNA, forming unstable molecules. This action occurs only when metronidazole is partially reduced, and, because this reduction usually happens only in anaerobic cells, it has relatively little effect on human cells or aerobic bacteria.


Pharmacology_Katzung

Pharmacology_Katzung. Metronidazole is well absorbed after oral administration, is widely distributed in tissues, and reaches serum levels of 4–6 mcg/mL after a 250-mg oral dose. It can also be given intravenously. The drug penetrates well into the cerebrospinal fluid and brain, reaching levels similar to those in serum. Metronidazole is metabolized in the liver and may accumulate in hepatic insufficiency. Metronidazole is indicated for treatment of anaerobic or mixed intra-abdominal infections (in combination with other agents with activity against aerobic organisms), vaginitis (trichomonas infection, bacterial vaginosis), Clostridium difficile infection, and brain abscess. The typical dosage is 500 mg three times daily orally or intravenously (30 mg/kg/d). Vaginitis may respond to a single 2-g dose. A vaginal gel is available for topical use.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects include nausea, diarrhea, stomatitis, and peripheral neuropathy with prolonged use. Metronidazole has a disulfiram-like effect, and patients should be instructed to avoid alcohol. Although teratogenic in some animals, metronidazole has not been associated with this effect in humans. Other properties of metronidazole are discussed in Chapter 52. A structurally similar agent, tinidazole, is a once-daily drug approved for treatment of trichomonas infection, giardiasis, amebiasis, and bacterial vaginosis. It also is active against anaerobic bacteria, but is not approved in the USA for treatment of anaerobic infections.


Pharmacology_Katzung

Pharmacology_Katzung. Fidaxomicin is a narrow-spectrum, macrocyclic antibiotic that is active against Gram-positive aerobes and anaerobes but lacks activity against Gram-negative bacteria. Fidaxomicin inhibits bacterial protein synthesis by binding to the sigma subunit of RNA polymerase. When administered orally, systemic absorption is negligible but fecal concentrations are high. Fidaxomicin has been approved by the U.S. Food and Drug Administration (FDA) for the treatment for C difficile infection in adults. It is as effective as oral vancomycin and may be associated with lower rates of relapsing disease. Fidaxomicin is administered orally as a 200 mg tablet twice daily for 10 days.


Pharmacology_Katzung

Pharmacology_Katzung. Rifaximin is a derivative of rifampin. It is active against Gram-positive and Gram-negative aerobes and anaerobes. Rifaximin inhibits bacterial protein synthesis by binding to the beta subunit of DNA-dependent RNA polymerase. When administered orally, systemic absorption is <0.5%, but fecal concentrations are high; following a three day course for travelers’ diarrhea, the fecal concentrations were 8000 mcg/g. Rifaximin was originally approved by the FDA for the treatment of travelers’ diarrhea, and it is now used in the management of hepatic encephalopathy, irritable bowel syndrome with diarrhea, and, occasionally, as an adjunct in cases of recurrent or refractory C difficile infection in adults. Typical doses of rifaximin range from 200 mg to 550 mg administered orally twice to three times daily depending on the indication. Unlike other rifamycins, rifaximin is not thought to be associated with cytochrome-P450-mediated drug interactions due to its limited absorption.


Pharmacology_Katzung

Pharmacology_Katzung. Mupirocin (pseudomonic acid) is a natural substance produced by Pseudomonas fluorescens. It is rapidly inactivated after absorption, and systemic levels are undetectable. It is available as an ointment for topical application.


Pharmacology_Katzung

Pharmacology_Katzung. Mupirocin is active against Gram-positive cocci, including methicillin-susceptible and methicillin-resistant strains of Staphylococcus aureus. Mupirocin inhibits staphylococcal isoleucyl tRNA synthetase. Low-level resistance, defined as a minimum inhibitory concentration (MIC) of up to 100 mcg/mL, is due to point mutation in the gene of the target enzyme. Low-level resistance has been observed after prolonged use. However, local concentrations achieved with topical application are well above this MIC, and this level of resistance does not lead to clinical failure. High-level resistance, with MICs exceeding 1000 mcg/mL, is due to the presence of a second isoleucyl tRNA synthetase gene, which is plasmid-encoded. High-level resistance results in complete loss of activity. Strains with high-level resistance have caused hospital-associated outbreaks of staphylococcal infection and colonization. Although higher rates of resistance are encountered with extensive use of mupirocin, most


Pharmacology_Katzung

Pharmacology_Katzung. high-level resistance have caused hospital-associated outbreaks of staphylococcal infection and colonization. Although higher rates of resistance are encountered with extensive use of mupirocin, most staphylococcal isolates are still susceptible.


Pharmacology_Katzung

Pharmacology_Katzung. Mupirocin is indicated for topical treatment of minor skin infections, such as impetigo (see Chapter 61). Topical application over large open areas, such as pressure ulcers or surgical wounds, is an important factor leading to emergence of mupirocin-resistant strains and is not recommended. Mupirocin temporarily eliminates S aureus nasal carriage by patients or health care workers, but results are mixed with respect to its ability to prevent subsequent staphylococcal infection. Patients most likely to benefit from decolonization are those undergoing orthopedic or cardiothoracic procedures. The polymyxins are a group of basic peptides active against Gram-negative bacteria and include polymyxin B and polymyxin E (colistin). Polymyxins act as cationic detergents. They attach to and disrupt bacterial cell membranes. They also bind and inactivate endotoxin. Gram-positive organisms, Proteus sp, and Neisseria sp are resistant.