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

1NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

2The following drugs are contraindicated as concurrent medications: astemizole, terfenadine, dihydroergotamine, cisapride, pimozide, midazolam, triazolam, flecainide, propafenone, rifampin, lovastatin, simvastatin, St. John's wort.

3Requires dose reduction in renal insufficiency.

4Should not be administered to patients with renal insufficiency.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can also be incorporated into the growing viral DNA chain to cause termination. Each requires intracytoplasmic activation as a result of phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1.

Lactic acidemia and severe hepatomegaly with steatosis have been reported with the use of NRTI agents, alone or in combination with other antiretroviral drugs. Obesity, prolonged nucleoside exposure, and risk factors for liver disease have been described as factors that increase risk for lactic acidemia; however, cases have also been reported in patients with no known risk factors. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic or lactic acidosis of unknown cause. Given their similar mechanism of action, it is probable that these cautions should be applied to treatment with nucleotide inhibitors as well (see Nucleotide Inhibitors).

Zidovudine

Zidovudine (azidothymidine; AZT) is a deoxythymidine analog (Figure 49–4) that is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Plasma protein binding is approximately 35%. The serum half-life averages 1 hour, and the intracellular half-life of the phosphorylated compound is 3.3 hours. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver. Clearance of zidovudine is reduced by approximately 50% in uremic patients, and toxicity may increase in patients with advanced hepatic insufficiency.

Figure 49–4.

Chemical structures of some reverse transcriptase inhibitors.

As the first licensed antiretroviral agent, zidovudine has been well studied. Zidovudine has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia. In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation (100 mg five times a day), intravenous zidovudine during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by continuous infusion), and zidovudine syrup to the neonate from birth through 6 weeks of age (2 mg/kg every 6 hours) has been shown to reduce the rate of vertical (mother-to- newborn) transmission of HIV by up to 23%.

As with other NRTI agents, resistance may limit clinical efficacy. High-level zidovudine resistance is generally seen in strains with three or more of the five most common mutations: M41L, D67N, K70R, T215F, and K219Q. However, the emergence of certain mutations that confer decreased susceptibility to one drug (eg, L74V in the case of didanosine and M184V in the case of lamivudine) seems to enhance susceptibility in previously zidovudine-resistant strains. Withdrawal of zidovudine exposure may permit the reversion of zidovudine-resistant HIV-1 isolates to the susceptible wild-type phenotype.

The most common adverse effect of zidovudine is myelosuppression, resulting in anemia or

neutropenia. Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Less frequent side effects include thrombocytopenia, hyperpigmentation of the nails, and myopathy. Very high doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no human cases of genital neoplasms have been reported to date. Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance. Zidovudine may decrease phenytoin levels, and this warrants monitoring of serum phenytoin levels in epileptic patients taking both agents. Hematologic toxicity may be increased during coadministration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. (See Treatment of HIV-Infected Individuals: Importance of Pharmacokinetic Knowledge.)

Didanosine

Didanosine (ddI) is a synthetic analog of deoxyadenosine (Figure 49–4). At acid pH, hydrolysis of the glycosidic bond between the sugar and the base moieties of ddI will inactivate the compound. Didanosine's AUC is reduced by 55% if it is ingested within 2 hours after a meal. Peak serum concentrations average 1 g/mL after a 300 mg dose. Cerebrospinal fluid concentrations of the drug are approximately 20% of serum concentrations. Plasma protein binding is low (< 5%). The elimination half-life is 0.6–1.5 hours, but the intracellular half-life of the activated compound is as long as 12–24 hours. The drug is eliminated by glomerular filtration and tubular secretion. Dosage reduction is therefore required for low creatinine clearance, after hemodialysis or during continuous ambulatory peritoneal dialysis, and for low body weight (Table 49–3).

The original formulation, a buffered powder, has been replaced by chewable and dispersible buffered tablets with greater bioavailability (30–40%); a new enteric-coated formulation further improves patient convenience and tolerability. Since the chewable tablets contain both phenylalanine (36.5 mg) and sodium (1380 mg), caution should be exercised in patients with phenylketonuria and those taking sodium-restricted diets. Didanosine should be taken on an empty stomach and, because of the buffered formulation, should be administered at least 2 hours after administration of drugs requiring acidity for optimal absorption (eg, ketoconazole, itraconazole, dapsone).

Resistance to didanosine, due typically to mutation at codon 74 (L74V), may partially restore susceptibility to zidovudine but may confer cross-resistance to abacavir, zalcitabine, and lamivudine. High-level resistance (> 100-fold decreased susceptibility) has not been reported to date.

The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcoholism, hypertriglyceridemia) are relative contraindications to administration of didanosine, and other drugs with the potential to cause pancreatitis should be avoided. Other reported adverse effects include painful peripheral distal neuropathy, diarrhea, hepatitis, esophageal ulceration, cardiomyopathy, and central nervous system toxicity (headache, irritability, insomnia). Asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals. Reports of retinal changes and optic neuritis in patients receiving didanosine— particularly in adults receiving high doses and in children—indicate the utility of periodic retinal examinations.

Fluoroquinolones and tetracyclines should be administered at least 2 hours before or after didanosine in order to avoid decreased antibiotic plasma concentrations due to chelation. Coadministration with ganciclovir results in an increased AUC of didanosine and a decreased AUC

of ganciclovir, while coadministration with methadone results in decreased didanosine serum levels.

Lamivudine

Lamivudine (3TC) is a cytosine analog (Figure 49–4) with in vitro activity against HIV-1 that is synergistic with a variety of antiretroviral nucleoside analogs—including zidovudine and stavudine—against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains. Activity against HBV is described below (see Anti-Hepatitis Agents).

Oral bioavailability exceeds 80% and is not food-dependent. Peak serum levels after standard doses are 1.5 ± 0.5 g/mL, and protein binding is less than 36%. In children, the mean CSF:plasma ratio of lamivudine was 0.2. Mean elimination half-life is 2.5 hours, while the intracellular half-life of the active 5'-triphosphate metabolite in HIV-1-infected cell lines is 10.5–15.5 hours. The majority of lamivudine is eliminated unchanged in the urine, and the dose should be reduced in patients with renal insufficiency or low body weight (Table 49–3). No supplemental doses are required after routine hemodialysis.

Lamivudine therapy rapidly selects—both in vitro and in vivo—for M184V-resistant mutants of HIV, which show high-level resistance to lamivudine and a reduction in susceptibility to abacavir, didanosine, and zalcitabine. Thus, lamivudine, like other antiretroviral agents, is best used in combination therapies that are fully suppressive of viral replication to reduce the generation of resistant mutants. The M184V mutation may restore phenotypic susceptibility to zidovudine, indicating that these two drugs in combination regimens may be particularly beneficial. However, HIV-1 strains resistant to both lamivudine and zidovudine have been isolated.

Potential side effects are headache, insomnia, fatigue, and gastrointestinal discomfort, though these are typically mild. Lamivudine's AUC increases when it is coadministered with trimethoprimsulfamethoxazole. Peak levels of zidovudine increase when the drug is administered with lamivudine, though this effect is not felt to have clinical significance.

Zalcitabine

Zalcitabine (ddC) is a cytosine analog (Figure 49–4) that has synergistic anti-HIV-1 activity with a variety of antiretroviral agents against both zidovudine-sensitive and zidovudine-resistant strains of HIV-1.

Zalcitabine has a relatively long intracellular half-life of 10 hours (despite its elimination half-life of 2 hours) and high oral bioavailability (> 80%). However, plasma levels decrease by 25–39% when the drug is administered with food or antacids. Plasma protein binding is low (< 4%). Cerebrospinal fluid concentrations are approximately 20% of those in the plasma.

Although a variety of mutations associated with in vitro resistance to zalcitabine have been described (eg, T69D, K65R, M186V), phenotypic resistance appears to be rare, particularly in combination regimens.

Zalcitabine therapy is associated with a dose-dependent peripheral neuropathy that can be treatment-limiting in 10–20% of patients but appears to be slowly reversible if treatment is stopped promptly. The potential for causing peripheral neuropathy constitutes a relative contraindication to use with other drugs that may cause neuropathy, including stavudine, didanosine, and isoniazid. Decreased renal clearance caused by amphotericin B, foscarnet, and aminoglycosides may increase the risk of zalcitabine neuropathy. The other major reported toxicity is oral and esophageal

ulcerations. Pancreatitis occurs less frequently than with didanosine administration, but coadministration of other drugs that cause pancreatitis may increase the frequency of this adverse effect. Headache, nausea, rash, and arthralgias may occur but tend to be mild or resolve during therapy. Cardiomyopathy has rarely been reported. Zalcitabine causes thymic lymphomas in rodents, but no clinical correlates have been observed in humans.

Potential drug interactions include an increased AUC of zalcitabine when administered in combination with probenecid or cimetidine and decreased bioavailability when zalcitabine is coadministered with antacids or metoclopramide. Lamivudine inhibits the phosphorylation of zalcitabine in vitro, potentially interfering with its efficacy.

Stavudine

The thymidine analog stavudine (D4T) (Figure 49–4) has high oral bioavailability (86%) that is not food-dependent. The plasma half-life is 1.22 hours; the intracellular half-life is 3.5 hours; and mean cerebrospinal fluid concentrations are 55% of those of plasma. Plasma protein binding is negligible. Excretion is by active tubular secretion and glomerular filtration. The dosage of stavudine should be reduced in patients with renal insufficiency, in those receiving hemodialysis, and for low body weight (Table 49–3).

V75T and I50T mutations are associated with decreased in vitro susceptibility to stavudine; the former also confers decreased susceptibility to didanosine and zalcitabine. Clinically significant resistance to stavudine has been rare.

The major dose-limiting toxicity is a dose-related peripheral sensory neuropathy. The frequency of neuropathy may be increased when stavudine is administered with other neuropathy-inducing drugs such as zalcitabine and didanosine. Symptoms typically resolve completely upon discontinuation of stavudine; in such cases, a reduced dosage may be cautiously restarted. Potential adverse effects other than neuropathy include pancreatitis, arthralgias, and elevation in serum aminotransferases. Since zidovudine may reduce the phosphorylation of stavudine, these two drugs should generally not be used together.

Abacavir

In contrast to earlier NRTIs, abacavir is a guanosine analog. It is well absorbed following oral administration (83%), is unaffected by food, and is about 50% bound to plasma proteins. In singledose studies, the elimination half-life was 1.5 hours. Cerebrospinal fluid levels are approximately one-third those of plasma. The drug is metabolized by alcohol dehydrogenase and glucuronosyltransferase to inactive metabolites that are eliminated primarily in the urine.

High-level resistance to abacavir appears to require at least two or three concomitant mutations (eg, M184V, L74V), and for that reason it tends to develop slowly. Although cross-resistance to lamivudine, didanosine, and zalcitabine has been noted in vitro in recombinant strains with abacavir-associated mutations, the clinical significance is unknown.

Hypersensitivity reactions, occasionally fatal, have been reported in 2–5% of patients receiving abacavir. Symptoms, which generally occur within the first 6 weeks of therapy, involve multiple organ systems and include fever, malaise, and gastrointestinal complaints. Skin rash may or may not be present. Laboratory abnormalities such as mildly elevated serum aminotransferase or creatine kinase levels are not specific for this reaction. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir following discontinuation results in return

of symptoms within hours and may be fatal. Other adverse events may include rash, nausea and vomiting, diarrhea, headache, and fatigue. Adverse effects that appear to be infrequent include pancreatitis, hyperglycemia, and hypertriglyceridemia. Clinically significant adverse drug interactions have not been reported to date, though coadministration of alcohol and abacavir may result in an increase in abacavir's AUC.

Nucleotide Inhibitors

Tenofovir

Tenofovir disoproxilfumarate is a prodrug that is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine. Like the NRTIs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA.

The oral bioavailability of tenofovir from tenofovir disopoxilfumarate, a water-soluble diester prodrug of the active ingredient tenofovir, in fasted patients is approximately 25%. Oral bioavailability is increased if the drug is ingested following a high-fat meal (increased AUC by about 40%); therefore, taking the drug along with a meal is recommended. Maximum serum concentrations are achieved in about 1 hour after taking the medication. Elimination occurs by a combination of glomerular filtration and active tubular secretion. However, only 70–80% of the dose is recovered in the urine, allowing for the possibility of hepatic metabolism as well as alteration in hepatic insufficiency; the latter has not been studied.

Tenofovir is indicated for use in combination with other antiretroviral agents. Initial studies demonstrated potent HIV-1 suppression in treatment-experienced adults with evidence of viral replication despite ongoing antiretroviral therapy; similar benefit in antiretroviral-naive patients has yet to be demonstrated. The once-daily dosing regimen of tenofovir lends added convenience.

Varying degrees of cross-resistance to tenofovir by preexisting zidovudine-associated mutations (eg, M41L, L210W) may occur and diminish virologic response; these appear to depend on the number of specific mutations present. Presence of the 65R mutation also reduces virologic response. However, virologic response to tenofovir is not diminished in the lamivudine-abacavir- associated M184V mutation. Cross-resistance with protease inhibitor agents is unlikely.

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, and flatulence) are the most common side effects but rarely require discontinuation of therapy. Preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia); however, to date there has been no evidence of bone toxicity in humans. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. Tenofovir is not metabolized by the cytochrome P450 system, so drug interactions with agents metabolized by this system are unlikely. As with the NRTIs, lactic acidosis and hepatomegaly with steatosis should be watched for.

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

The NNRTIs bind directly to a site on the HIV-1 reverse transcriptase, resulting in blockade of RNAand DNA-dependent DNA polymerase activities. The binding site is near to but distinct from that of the NRTIs. Unlike the latter group of agents, the NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. Resistance to an NNRTI is generally rapid with monotherapy and is associated with the K103N mutation as well as the less critical Y181C/I mutation; cross-resistance among this class of agents, although observed in vitro, is of unknown clinical significance. There is no cross-resistance between the NNRTIs and the NRTIs or the

protease inhibitors.

A syndrome of drug hypersensitivity has been described in patients receiving NNRTIs as well as in those receiving amprenavir or abacavir. Serious rashes, including Stevens-Johnson syndrome, have occurred.

Nevirapine

The oral bioavailability of nevirapine is excellent (> 90%) and is not food-dependent. The drug is highly lipophilic, approximately 60% protein-bound, and achieves cerebrospinal fluid levels that are 45% of those in plasma. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.

Nevirapine is typically used as a component of a combination antiretroviral regimen. In addition, a single dose of nevirapine (200 mg) has recently been shown to be effective in the prevention of transmission of HIV from mother to newborn when administered to women at the onset of labor and followed by a 2-mg/kg oral dose given to the neonate within 3 days after delivery.

Severe and life-threatening skin rashes have occurred during nevirapine therapy, including StevensJohnson syndrome and toxic epidermal necrolysis. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with rash accompanied by constitutional symptoms. Rash occurs in approximately 17% of patients, most typically in the first 4–8 weeks of therapy, and is dose-limiting in about 7% of patients. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the frequency of rash. Fulminant hepatitis may occur in association with rash and fever, typically within the first 6 weeks of initiation of therapy, or may occur without a concomitant rash. Therefore, serial monitoring of liver function tests is strongly recommended. Other frequently reported adverse effects associated with nevirapine therapy are fever, nausea, headache, and somnolence.

Nevirapine is both a substrate and a moderate inducer of CYP3A metabolism, thus resulting in a 1.5-fold to twofold increase in oral clearance of itself and a corresponding decrease in the terminal phase half-life with repeated dosing—as well as decreased levels of indinavir and saquinavir if administered concurrently (see Table 49–4). Owing to an increase in nevirapine and a decrease in ketoconazole levels during coadministration, these two agents should not be given together. Nevirapine levels may increase during coadministration with inhibitors of CYP3A metabolism, such as cimetidine and the macrolide agents, and decrease in the presence of CYP3A inducers such as rifabutin and rifampin (see Table 4–2). Such agents should be coadministered cautiously and only if good alternatives are lacking.

Table 49–4. Drug Interactions Pertaining to Two-Drug Antiretroviral Combinations.

Delavirdine

Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids. It is extensively bound (about 98%) to plasma proteins. Cerebrospinal fluid levels average only 0.4% of the corresponding plasma concentrations, representing about 20% of the fraction not bound to plasma proteins. Caution should be used when administering delavirdine to patients with hepatic insufficiency because clinical experience in this situation is limited.

Skin rash occurs in about 18% of patients receiving delavirdine; it typically occurs during the first month of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other adverse effects may include headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels. Delavirdine has been shown to be teratogenic in rats, causing ventricular septal defects and other malformations at exposures not unlike those achieved in humans. Thus, pregnancy should be avoided when taking delavirdine.

Delavirdine is extensively metabolized to inactive metabolites by the CYP3A and CYP2D6 enzymes. However, it also inhibits CYP3A and thus inhibits its own metabolism. In addition to its interactions with other antiretroviral agents (see Table 49–4), delavirdine will result in increased levels of numerous agents (Table 49–3). Dose reduction of indinavir and saquinavir should be considered if they are administered concurrently with delavirdine. Delavirdine plasma concentrations are reduced in the presence of antacids, phenytoin, phenobarbital, carbamazepine, rifabutin, and rifampin; concentrations are increased during coadministration with clarithromycin, fluoxetine, dexamethasone, and ketoconazole.

Efavirenz

Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%), and bioavailability is increased to about 65% following a high-fat meal. Peak plasma concentrations are seen 3–5 hours after administration of daily doses; steady state plasma concentrations are reached in 6–10 days. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (> 99%). Cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels; these are approximately three times higher than the free fraction of efavirenz in the plasma. Because there is limited experience to date, caution is advised with use in patients with hepatic impairment.