Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

The principal adverse effects of efavirenz involve the central nervous system (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria); these may occur in up to 50% of patients. They tend to occur during the first days of therapy and may resolve while medication is continued; administration at bedtime may be helpful. However, psychiatric symptoms may be severe. Skin rash has also been reported early in therapy in up to 28% of patients, is usually mild to moderate, and typically resolves despite continuation. Other potential adverse reactions include nausea and vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage of 600 mg/d. Therefore, pregnancy should be avoided in women receiving efavirenz.

Efavirenz is a substrate, an inhibitor, and a moderate inducer of CYP3A4, thus inducing its own metabolism and interacting with the metabolism of many other drugs. Decreased plasma concentrations would be expected if efavirenz is administered concurrently with agents that induce CYP3A4 activity, including phenobarbital, rifampin, and rifabutin. The AUC of ethinyl estradiol is increased if coadminstered with efavirenz, and levels of clarithromycin are decreased. Efavirenz may reduce plasma methadone levels by 50% and thus should not be concurrently used. Coadministration of efavirenz with drugs that are highly dependent on CYP3A for clearance is contraindicated (see Table 4–2). Interactions with other antiretroviral agents are summarized in Table 49–4. The dose of indinavir should be increased if coadministered with efavirenz. Coadministration of efavirenz with saquinavir is to be avoided because of decreases in saquinavir plasma concentrations.

Protease Inhibitors

During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products are translated into polyproteins and then become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core. By preventing cleavage of the Gag-Pol polyprotein, protease inhibitors result in the production of immature, noninfectious viral particles. Unfortunately, specific genotypic alterations that confer phenotypic resistance is fairly common with these agents, thus contraindicating monotherapy. The issue of cross-resistance among agents in this class of drugs is complex and requires further investigation; it appears to require a minimum of four substitutions in the gene.

A syndrome of redistribution and accumulation of body fat that includes central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and a cushingoid appearance has been observed in patients receiving antiretroviral therapy. Although controversial, these abnormalities appear to be particularly associated with the use of protease inhibitors. Concurrent increases in triglyceride and LDL levels, along with glucose intolerance and insulin resistance, have been noted as well. The cause is not yet known.

Protease inhibitors have also been associated with increased spontaneous bleeding in patients with hemophilia A or B.

All of the antiretroviral protease inhibitors are substrates of the CYP3A4 isoenzyme. As such, there is a potential for drug-drug interactions. In addition, however, certain of the protease inhibitors are CYP3A4 inhibitors as well (eg, amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), thus having the potential to cause decreased clearance and increased plasma concentrations of other substrate drugs. For this reason, the CYP3A4 inhibitors should not be administered concurrently with agents that are heavily metabolized by CYP3A (see Table 4–2). Ritonavir also functions as a CYP3A4 inducer, such that potential drug-drug interactions may be

clinically beneficial (see Ritonavir).

Saquinavir

In its original formulation as a hard gel capsule (saquinavir-H; Invirase), oral saquinavir was poorly bioavailable (about 4% in the fed state). It was therefore largely replaced in clinical use by a soft gel capsule formulation (saquinavir-S; Fortovase), in which absorption was increased approximately threefold. However, reformulation of saquinavir-H for once-daily dosing in combination with lowdose ritonavir (see Ritonavir) has both improved antiviral efficacy and decreased the gastrointestinal side effects typically associated with saquinavir-S. Moreover, coadministration of saquinavir-H with ritonavir results in blood levels of saquinavir similar to those associated with saquinavir-S, thus capitalizing on the pharmacokinetic interaction of the two agents.

Both formulations of saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir has a large volume of distribution but is 98% protein-bound; penetration into the cerebrospinal fluid is negligible. The elimination half-life is 12 hours. Excretion is primarily in the feces. Reported adverse effects include gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia; these are more common with Fortovase) and rhinitis. Although refrigeration is recommended for storage, the capsules are stable at room temperature for up to 3 months.

Saquinavir is subject to extensive first-pass metabolism by CYP3A4, and functions as a CYP3A4 inhibitor as well as a substrate; thus, it should be used with the same precautions regarding drugdrug interactions as the other protease inhibitors. Coadministration with the CYP3A4 inhibitor ritonavir has been adopted by clinicians because inhibition of first-pass metabolism of saquinavir by ritonavir can result in higher—and thus more efficacious—levels of saquinavir (see Table 49–3 and Table 49–4). Liver function tests should be monitored if saquinavir is coadministered with delavirdine.

The most common critical mutations are L90M and G48V, conferring an approximately tenfold decrease in susceptibility.

Ritonavir

Ritonavir is an inhibitor of HIV-1 and HIV-2 proteases with high bioavailability (about 75%) that increases when the drug is given with food. Metabolism to an active metabolite occurs via the CYP3A and CYP2D6 isoforms; excretion is primarily in the feces. Caution is advised when administering the drug to persons with impaired hepatic function. Capsules (but not the oral solution) should be refrigerated for storage.

Resistance is associated with mutations at positions 84, 82, 71, 63, and 46, of which the I84V mutation appears to be the most critical.

The most common adverse effects of ritonavir are gastrointestinal disturbances, paresthesias (circumoral and peripheral), elevated serum aminotransferase levels, altered taste, and hypertriglyceridemia. Nausea, vomiting, and abdominal pain typically occur during the first few weeks of therapy, and patients should be told to expect them. Slow dose escalation over 4–5 days is recommended to decrease the frequency of dose-limiting side effects. Liver adenomas and carcinomas have been induced in male mice receiving ritonavir; no similar effects have been observed to date in humans.

Ease of administration is limited by ritonavir's numerous drug interactions. Ritonavir is both a

substrate and an inhibitor of CYP3A4; as such, coadministration with agents heavily metabolized by CYP3A must be approached with the same precautions discussed above. In addition, since ritonavir is an inhibitor of the CYP3A4 isoenzyme, concurrent administration with other PIs results in increased plasma levels of the latter drugs; these interactions have been exploited to permit more convenient dosing (see Table 49–3 and Table 49–4).

Lopinavir/Ritonavir

Several studies have shown enhanced efficacy or improved tolerability of two protease inhibitors administered together. Lopinavir 100/ritonavir 400 is a licensed combination in which subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to lopinavir. Trough levels of lopinavir are greater than the median HIV-1 wild type 50% inhibitory concentration, thus maintaining potent viral suppression as well as providing a pharmacologic barrier to the emergence of resistance. In addition to improved patient compliance because of the reduced pill burden with twice-daily dosing, lopinavir/ritonavir is generally well tolerated.

Absorption is enhanced with food. Lopinavir is 98–99% protein-bound and is extensively metabolized by the CYP3A isozyme of the hepatic cytochrome P450 system, which is inhibited by ritonavir. Serum levels of lopinavir may be increased in patients with hepatic impairment.

The most common adverse effects are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Potential drug-drug interactions are extensive (see Ritonavir and Table 49–4). Drugs that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations may be serious or clinically significant—including those listed in Table 49–4 as well as those listed in Table 4–2—should not be given with lopinavir/ritonavir. Coadministration with rifampin, carbamazepine, phenobarbital, phenytoin, dexamethasone, or St. John's wort (Hypericum perforatum) may reduce levels of lopinavir.

Indinavir

Indinavir must be consumed on an empty stomach for maximal absorption. Oral bioavailability is about 65%, and the drug is about 60% protein-bound. Indinavir has the highest cerebrospinal fluid penetration of the existing protease inhibitors—up to 76% of serum levels. Excretion is primarily fecal. An increase in AUC by 60% and in half-life from 1.8 to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction.

Resistance may be associated with multiple mutations, and the number of codon alterations (typically substitutions) present tends to predict the level of phenotypic resistance. Mutations at positions at 46 or 82 seem to predict phenotypic resistance most consistently. Resistance to indinavir is associated with a loss of susceptibility to ritonavir; however, susceptibility to other protease inhibitors in indinavir-resistant isolates is less predictable.

The most common adverse effects are indirect hyperbilirubinemia and nephrolithiasis due to crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of 3–15%, and may be associated with renal failure. Consumption of at least 48 oz of water daily is important to maintain adequate hydration and prevent nephrolithiasis. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, and irritability have also been reported. There have also been rare cases of acute hemolytic anemia. In rats, high doses of indinavir are associated with development of thyroid adenomas.

Since indinavir is a substrate as well as an inhibitor of CYP3A4, numerous and complex drug interactions can occur as described above. Indinavir levels decrease with concurrent use of rifabutin, fluconazole, St. John's wort, and rifampin. Caution is advised with other 3A4 inducers also, including phenobarbital, phenytoin, carbamezepine, and dexamethasone. Dose reduction of indinavir should be considered if coadministered with delavirdine, ketoconazole, or itraconazole, while an increase in the dose of indinavir is indicated if the drug is coadministered with efavirenz or rifabutin.

Nelfinavir

Nelfinavir has higher absorption in the fed state (increased AUC by twoto threefold), is extensively protein-bound (> 98%), undergoes metabolism by CYP3A, and is excreted primarily in the feces. The plasma half-life in humans is 3.5–5 hours. The D30N mutation appears to be particularly closely linked with phenotypic resistance in isolates obtained from clinical trials.

The most frequent adverse effects associated with nelfinavir are diarrhea and flatulence. Diarrhea can be dose-limiting but often responds to antidiarrheal medications. Like the other protease inhibitors, nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur as described above. Interactions with antiretroviral agents are summarized in Table 49–4; others may be found in Table 4–2.

Amprenavir

Amprenavir is rapidly absorbed from the gastrointestinal tract and can be taken with or without food. However, high-fat meals may decrease absorption and thus should be avoided. The plasma half-life is relatively long (7–10.6 hours). Protein binding is about 90%. Amprenavir is metabolized in the liver by CYP3A4; it is contraindicated in the setting of hepatic insufficiency.

The key in vitro resistance mutation to amprenavir appears to be I50V. Evidence to date suggests that cross-resistance to other members of the protease inhibitor class of drugs may be less prevalent with amprenavir than with previously available compounds.

The most common adverse effects of amprenavir have been nausea, diarrhea, vomiting, perioral paresthesias, depression, and rash. Up to 3% of patients in clinical trials to date have had rashes (including Stevens-Johnson syndrome) severe enough to warrant drug discontinuation.

Amprenavir is both a substrate and an inhibitor of CYP3A4 and is contraindicated with numerous other drugs (see Table 49–3 and Table 4–2). The oral solution, which contains propylene glycol, is contraindicated in young children, pregnant women, and in those using metronidazole or disulfiram.

Fusion Inhibitors

Enfuvirtide

Enfuvirtide (formerly called T-20) is a newly approved antiretroviral agent of a novel class, ie, a fusion inhibitor that blocks entry into the cell. Enfuvirtide, a synthetic 36-amino-acid peptide, binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.

Resistance to enfuvirtide can occur, and the frequency and mechanisms of this phenomenon are currently being investigated. However, enfuvirtide completely lacks cross-resistance to the other

currently approved antiretroviral drug classes.

The drug is administered subcutaneously in combination with other antiretroviral agents in treatment-experienced patients with persistent HIV-1 replication despite ongoing therapy. Protein binding is high (92%), and metabolism appears to be by proteolytic hydrolysis without involvement of the cytochrome p450 system. Elimination half-life is 3.8 hours, and time to peak concentration is 8 hours.

The most common side effects associated with enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions may occur, are of varying severity, and may recur on rechallenge. Eosinophilia has also been noted. No interactions have been identified that would require alteration of other antiretroviral drugs.

Investigational Antiretroviral Agents

New therapies are being sought offering the advantages of once-daily dosing, smaller pill size, lower incidences of adverse effects, new viral targets, and activity against virus that is resistant to other agents. Agents under evaluation or reformulation for once-daily dosing include stavudine and nevirapine. The NRTI agents amdoxovir and emtricitabine, the NNRTI agents DPC-083 and TMC125, and the protease inhibitors atazanavir, tipranavir, and fosamprenavir (the prodrug of amprenavir) are among the new agents currently in development. In addition, new drug classes such as entry inhibitors and integrase inhibitors are under clinical investigation.

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Treatment of HIV-Infected Individuals: Importance of Pharmacokinetic Knowledge

In addition to knowledge about the clinical efficacy, adverse effect profile, and likelihood of emergence of resistance, the physician caring for an HIV-infected patient must be well versed in basic pharmacokinetics as well. Such patients are frequently taking multiple medications, including combinations of antiretroviral agents, prophylaxis or treatment for opportunistic infections, and opioid pain medications or methadone for maintenance therapy.

For example, an HIV-infected patient receiving ganciclovir for treatment of cytomegalovirus retinitis may be unable to tolerate concomitant therapies with the potential for additive myelosuppression, including zidovudine, ribavirin, or the interferons. Addition of colonystimulating factor therapy for cytopenias or substitution of a different, nonmyelodepressant drug for ganciclovir may ultimately be necessary. In a patient taking didanosine (ddI), the ingestion of many other antiretroviral agents that may comprise their combination regimen, including delavirdine, indinavir, amprenavir, and tenofovir, must be separated by 2 or more hours in order to avoid interference with their absorption. Prescription of abacavir may be complicated by the fact that alcohol decreases the AUC of abacavir by 41%; the patient should be made aware of this potentially harmful interaction. The NNRTI agents and protease inhibitors for treatment of HIV infection are all metabolized by the cytochrome P450 enzyme system, primarily the 3A4 isoform. Many are also either inducers or inhibitors of CYP3A4 as well. Their myriad potential drug-drug interactions necessitate great caution during the treatment of AIDS patients. For example, an increased incidence of rifabutin-associated uveitis due to increased levels when given in combination with ritonavir is an important consideration when considering the addition of an agent for the prophylaxis or treatment against Mycobacterium avium complex (MAC) infection in a patient already on an effective HAART regimen. Similarly, the addition of clarithromycin for prophylaxis

against MAC could potentially increase serum levels of delavirdine, ritonavir, and indinavir; conversely, levels of clarithromycin increase in the presence of indinavir and ritonavir but decrease with efavirenz. Most recently, however, these interactions have been used to advantage in the form of dual protease inhibitor regimens, based upon resultant increased plasma concentrations (Cmax, Cmin, and AUC ) of the substrate (eg, saquinavir) when coadministered with an inducer (eg, ritonavir). Improved drug exposure, increased antiviral potency, more convenient dosing, and improved tolerability due to the use of lower doses are some of the benefits, thus improving patient adherence to the regimen. A newly licensed coformulation of lopinavir with ritonavir takes advantage of this phenomenon, known as "protease inhibitor boosting." Thus, a thorough working knowledge of potential drug-drug interactions is essential in the care of patients.

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Anti-Hepatitis Agents

Agents effective against hepatitis B virus (HBV) and hepatitis C virus (HCV) are now available (see Table 49–5). Although treatment is suppressive rather than curative, the high prevalence of these infections worldwide, with their concomitant morbidity and mortality, reflect a critical need for improved therapeutics.

Table 49–5. Drugs Used to Treat Viral Hepatitis.

1Dosage must be reduced in patients with renal insufficiency.

2For all agents, combination therapy with oral ribavirin is recommended if tolerated (dosage, 1000– 1200 mg/d according to weight).

Lamivudine

The pharmacokinetics and safety profile of lamivudine are described above (see Lamivudine). The more prolonged intracellular half-life in HBV cell lines (17–19 hours) than in HIV-infected cell lines (see above) allows for lower doses, administered less frequently, for hepatitis. Lamivudine can be safely administered to patients with decompensated liver disease.

Lamivudine achieves almost universal HBV DNA suppression, with decreases in viral replication by about 3-4 log copies in most patients. Response to lamivudine is more rapid than to interferon (see below), with HBV DNA levels decreasing by approximately 97% after 2 weeks of therapy and 98% by 1 year. However, evidence of viral replication recurs in over 80% upon discontinuation of therapy. Seroconversion of HBeAg antigen from positive to negative occurs in only about 20% of patients; yet in patients who do achieve seroconversion with lamivudine, the response is typically sustained. Progression to liver fibrosis is less frequent in patients treated with lamivudine compared with placebo. The height of the pretreatment serum ALT level may be the best predictor of HBeAg seroconversion.

Chronic therapy with lamivudine in patients with hepatitis may ultimately be limited by the emergence of lamivudine-resistant HBV isolates with YMDD mutation. Emergence of this mutation, which typically occurs within 8–9 months of therapy, is associated with reappearance of detectable levels of HBV DNA. The estimated rate of YMDD mutation is about 20% per year.

In the doses used for HBV infection, lamivudine has an excellent safety profile. No evidence of mitochondrial toxicity has been reported.

Adefovir

Although initially and abortively developed for treatment of HIV infection, adefovir has been recently approved, at lower and less toxic doses, for treatment of HBV infection. Like tenofovir (see Antiretroviral Agents), adefovir is a nucleotide analog. As an analog of adenosine monophosphate, adefovir is phosphorylated by cellular kinases to the active disphosphate metabolite; it then competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into the viral DNA.

Oral bioavailability is about 59% and is unaffected by meals. Peak serum levels occur at a median of 1.75 hours after dosing, and the terminal elimination half-life is approximately 7.5 hours. Protein binding is less than 4%. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. Dosing interval should be modified in patients with impaired renal

function. Approximately 35% of the adefovir dose is removed during a 4-hour hemodialysis.

Recent placebo-controlled trials showed that adefovir resulted in significant suppression of HBV replication and improvement in liver histology and fibrosis at 1 year. However, as with lamivudine, serum HBV DNA reappeared following cessation of therapy.

Adefovir maintains activity against lamivudine-resistant strains of HBV, and no resistance to adefovir was detected in patients who had received continuous treatment for up to 1 year.

Adefovir is associated with a dose-dependent nephrotoxicity. The risk is low for treatment durations of up to 1 year at its recommended dosage for HBV but may rise in patients with preexisting renal dysfunction or in those treated for longer durations. Also, as with the antiretroviral nucleoside analogs (see Nucleoside Reverse Transcriptase Inhibitors), lactic acidosis and severe hepatomegaly with steatosis may occur. When coadministered with ibuprofen, the AUC of adefovir is increased by about 23%, apparently due to higher oral bioavailabilty.

Interferon Alfa

Interferons are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving synthesis of both RNA and protein (see Chapter 56: Immunopharmacology). They appear to function by binding to specific membrane receptors on the cell surface and initiating a series of intracellular events that include enzyme induction, suppression of cell proliferation, immunomodulatory activities, and inhibition of virus replication. They are classified according to the cell type from which they were derived, and each of the three immunologically distinct major classes of human interferons has unique physicochemical characteristics and different producer cells, inducers, and biologic effects.

Interferon alfa preparations are available for treatment of both HBV and HCV virus infections. Interferon alfa-2b is the only preparation licensed for treatment of HBV infection and for acute hepatitis C. Interferon alfa-2b leads to loss of HBeAg, normalization of serum aminotransferases, and sustained histologic improvement in approximately one-third of patients with chronic hepatitis B, thus reducing the risk of progressive liver disease.

In acute hepatitis C, the rate of clearance of the virus without therapy is estimated to be 15–30%. No therapy has yet been proved effective in the treatment of acute hepatitis C; however, a recent study suggested that interferon alfa-2b, in doses higher than those used for treatment of chronic hepatitis C (see Table 49–5), resulted in a sustained rate of clearance of 98%.

Several interferon alfa preparations are available for the treatment of patients with chronic hepatitis C infection, including interferon alfa-2a, interferon alfa-2b, interferon alfacon-2, pegylated interferon alfa-2a, and pegylated interferon alfa-2b, as described below. Factors associated with a favorable response to therapy include HCV genotype 2 or 3, absence of cirrhosis on liver biopsy, and low pretreatment HCV RNA levels. For all agents, combination therapy with oral ribavirin in patients with chronic hepatitis C is more effective than monotherapy with either interferon or ribavirin alone, increasing the percentage of previously untreated patients with a sustained virologic response from approximately 16% to approximately 40%. Therefore, monotherapy is recommended only in patients who cannot tolerate ribavirin. The time to maximal response may range from 24 weeks to 48 weeks of therapy.

Interferon alfa-2a and interferon alfa-2b may be administered subcutaneously or intramuscularly, while interferon alfacon-1 is administered subcutaneously (see Table 49–5). Maximum serum

concentrations occur approximately 4 hours after intramuscular administration and approximately 7 hours after subcutaneous administration; elimination half-life is 2–5 hours for interferon alfa-2a and 2b, depending on the route of administration. The half-life of interferon alfacon-1 in patients with chronic hepatitis C ranged from 6 hours to 10 hours. Alfa interferons are filtered at the glomeruli 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.

Typical side effects are constitutional in nature, including a flu-like syndrome within 6 hours after dosing in more than 30% of patients that tends to resolve upon continued administration. Other potential adverse effects include thrombocytopenia, granulocytopenia, elevation in serum aminotransferase levels, induction of autoantibodies, nausea, fatigue, headache, arthralgias, rash, alopecia, anorexia, hypotension, and edema. Severe neuropsychiatric side effects may occur. Absolute contraindications to therapy are psychosis, severe depression, neutropenia, thrombocytopenia, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, and a history of organ transplantation (other than liver). Alfa interferons are abortifacient in primates and should not be administered in pregnancy.

Pegylated Interferon Alfa

Pegylated interferon alfa-2a (peginterferon alfa-2a) and pegylated interferon alfa-2b (peginterferon alfa-2b) have recently been introduced for the treatment of patients with chronic hepatitis C infection. In these agents, a linear or branched polyethylene glycol (PEG) moiety is attached to interferon by a covalent bond. Reduced clearance and sustained absorption results in an increased half-life and steadier drug concentrations, allowing for less frequent dosing.

In comparison with the nonpegylated interferon alfa compounds, the pegylated products have substantially longer terminal half-lives and slower clearance. Maximum serum concentrations occur between 15 hours and 44 hours after dosing and are sustained for up to 48–72 hours. For pegylated interferon alfa-2a, maximum serum concentrations occur at 72–96 hours after dosing and are sustained for up to 168 hours. In patients with chronic hepatitis C, the mean terminal half-life was 80 hours for pegylated interferon alfa-2a (versus 5.1 hours for interferon alfa-2a) and was about 40 hours for pegylated interferon alfa-2b (versus 2–3 hours for interferon alfa-2b). Renal elimination accounts for about 30% of clearance, and clearance is reduced by approximately half in subjects with impaired renal function. Although dose reduction in renal insufficiency is not specifically recommended, caution is advised in this setting.

Efficacy appears to be superior to therapy with nonpegylated interferons in controlled clinical trials, particularly as regards the proportion of patients with sustained virologic responses. As with the nonpegylated interferon alfa agents, combination therapy of the pegylated interferon alfa compounds with ribavirin is more effective than monotherapy.

Adverse events are similar to those of the interferon alfa agents described above. The PEG molecule is a nontoxic polymer that is readily excreted in the urine.

Ribavirin

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 guanosine triphosphate, to inhibit capping of viral messenger RNA, and to inhibit the viral RNA-dependent RNA 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 about 64%, increases with high-fat meals, and decreases with coadministration of antacids. Since elimination is mostly through the urine, clearance is decreased in patients with creatinine clearances less than 30 mL/min.

Ribavirin capsules in combination with subcutaneous interferon alfa-2b are effective for the treatment of chronic hepatitis C infection in patients with compensated liver disease (see AntiHepatitis Agents, above). Monotherapy with ribavirin alone is not effective.

Approximately 10–20% of patients experience a dose-dependent hemolytic anemia that may be dose-limiting. Other side effects are depression, fatigue, irritability, rash, cough, insomnia, nausea, and pruritus. Absolute contraindications to ribavirin therapy include anemia, end-stage renal failure, severe heart disease, and pregnancy. Ribavirin is both teratogenic in animals and mutagenic in mammalian cells.

Investigational Agents

The nucleoside analogs entecavir and clevudine, the nucleotide analog emtricitabine, and the immunologic modulators theradigm-HBV and thymosin alpha-1 are new agents under evaluation for the treatment of HBV infection.

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Anti-Influenza Agents

Amantadine & Rimantadine

Amantadine (1-aminoadamantane hydrochloride) and its -methyl derivative, rimantadine, are cyclic amines that inhibit uncoating of the viral RNA of influenza A within infected host cells, thus preventing its replication. Rimantadine is four to ten times more active than amantadine in vitro. Steady state peak plasma levels in healthy young adults average 0.5—0.8 g/mL for amantadine; elderly persons require only one half of the weight-adjusted dose for young adults to achieve equivalent trough plasma levels of 0.3 g/mL. While amantadine is excreted unmetabolized in the urine, rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly, in renal insufficiency, and for rimantadine in patients with marked hepatic insufficiency. No supplemental doses of either agent are required after hemodialysis. Plasma half-life is 12–18 hours for amantadine and 24–36 hours for rimantadine.

Both amantadine and rimantadine, in doses of 100 mg twice daily or 200 mg once daily, are approximately 70–90% protective in the prevention of clinical illness by influenza A. The effectiveness of postexposure prophylaxis is inconsistent. When begun within 1–2 days after the onset of clinical symptoms of influenza, both drugs reduce the duration of fever and systemic complaints by 1–2 days.

The primary target for both agents is the M2 protein within the viral membrane; this target incurs both specificity against influenza A (since influenza B contains a different protein in its membrane) and a mutation-prone site, causing the rapid development of resistance in up to 50% of treated