Abacavir (1592U89) {(−)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol} is a 2′-deoxyguanosine analogue with potent activity against human immunodeficiency virus (HIV) type 1. To determine the metabolic profile, routes of elimination, and total recovery of abacavir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 μCi of [14C]abacavir. The metabolic disposition of the drug was determined through analyses of whole-blood, plasma, urine, and stool samples, collected for a period of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6 h postdosing. The radioactivity from abacavir and its two major metabolites, a 5′-carboxylate (2269W93) and a 5′-glucuronide (361W94), accounted for the majority (92%) of radioactivity detected in plasma. Virtually all of the administered dose of radioactivity (99%) was recovered, with 83% eliminated in urine and 16% eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of which <1% of the administered radioactivity was 1144U88, a minor metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 μg/ml, which is 8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in vitro (0.07 μg/ml). In conclusion, the main route of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite excretion is renal, with 83% of a dose recovered in urine. Two major metabolites, the 5′-carboxylate and the 5′-glucuronide, were identified in urine and, combined, accounted for 66% of the dose. Abacavir showed significant penetration into CSF.

While in vitro results at clinically relevant concentrations do not predict abacavir (1592U89) interactions with drugs highly metabolized by cytochrome P450, the potential does exist for a pharmacokinetic interaction between abacavir and ethanol, as both are metabolized by alcohol dehydrogenase. Twenty-five subjects were enrolled in an open-label, randomized, three-way-crossover, phase I study of human immunodeficiency virusinfected male subjects. The three treatments were administration of (i) 600 mg of abacavir, (ii) 0.7 g of ethanol per kg of body weight, and (iii) 600 mg of abacavir and 0.7 g of ethanol per kg. Twenty-four subjects completed the study with no unexpected adverse events reported. Ethanol pharmacokinetic parameters were unchanged with abacavir coadministration. The geometric least squares mean area under the concentration curve extrapolated to infinite time for abacavir increased 41% (from 11.07 to 15.62 g ⅐ h/ml), and the half-life increased 26% (from 1.42 to 1.79 h) in the presence of ethanol (mean ethanol maximum concentration in plasma of 498 g/ml). The percentages of abacavir dose recovered in urine as abacavir and its two major metabolites were each altered in the presence of ethanol, but there was no change in the total percentage (Ϸ50%) of administered dose recovered in the 12-h collection interval. In conclusion, while a single 600-mg dose of abacavir does not alter blood ethanol concentration, ethanol does increase plasma abacavir concentrations.Abacavir (1592U89) is a nucleoside analogue recently approved as an antiretroviral drug for treatment of human immunodeficiency virus type 1 infection. Studies with human cell lines have shown that abacavir is phosphorylated by a unique metabolic pathway to produce the bioactive form, carbocyclic GTP (1144U88 triphosphate), which is a potent reverse transcriptase inhibitor (5). Metabolic interactions between clinically relevant concentrations of abacavir and other drugs that undergo metabolism mainly by cytochrome P450 isozymes are not predicted since the major metabolic pathways are through cytosolic alcohol dehydrogenase (ADH) and UDP glucuronyl transferase (UDP-GT) (Glaxo Wellcome, Inc., data on file; J. R. Ravitch, B. J. Bryant, M. J. Reese, C. C. Boehlert, J. S. Walsh, J. P. McDowell, and B. M. Sadler, Abstr. 5th Conf. Retroviruses Opportunistic Infect., abstr. 634, 1998). Abacavir has a carboxylate and a glucuronide as its two major metabolites: cytosolic ADH catalyzes the formation of the carboxylate 2269W93, and UDP-GT catalyzes the formation of the glucuronide 361W94 (8). Ethanol metabolism also requires ADH, and there is evidence that ethanol interacts with other compounds through the glucuronidation pathway (11). Hence, it is reasonable to assume that there could be a pharmacokinetic interaction between abacavir and ethanol in either of the two major metabolic pathways for abacavir. The potential for ethanol to alter abacavir metabolism was studied in vitro with human liver slices (n ϭ 2)

Abacavir (1592U89) is a nucleoside analog reverse transcriptase inhibitor that has been demonstrated to have selective activity against human immunodeficiency virus (HIV) in vitro and favorable safety profiles in mice and monkeys. A phase I study was conducted to evaluate the safety and pharmacokinetics of abacavir following oral administration of single escalating doses (100, 300, 600, 900, and 1,200 mg) to HIV-infected adults. In this double-blind, placebo-controlled study, subjects with baseline CD4 ؉ cell counts ranging from <50 to 713 cells per mm 3 (median, 315 cells per mm 3 ) were randomly assigned to receive abacavir (n ‫؍‬ 12) or placebo (n ‫؍‬ 6). The bioavailability of the caplet formulation relative to that of the oral solution was also assessed with the 300-mg dose. Abacavir was well tolerated by all subjects; mild to moderate asthenia, abdominal pain, headache, diarrhea, and dyspepsia were the most frequently reported adverse events, and these were not dose related. No significant clinical or laboratory abnormalities were observed throughout the study. All doses resulted in mean abacavir concentrations in plasma that exceeded the mean 50% inhibitory concentration (IC 50 ) for clinical HIV isolates in vitro (0.07 g/ml) for almost 3 h. Abacavir was rapidly absorbed following oral administration, with the time to the peak concentration in plasma occurring at 1.0 to 1.7 h postdosing. Mean maximum concentrations in plasma (C max ) and the area under the plasma concentration-time curve from time zero to infinity (AUC 0-ؕ ) increased slightly more than proportionally from 100 to 600 mg (from 0.6 to 4.7 g/ml for C max ; from 1.0 to 15.7 g ⅐ h/ml for AUC 0-ؕ ) but increased proportionally from 600 to 1,200 mg (from 4.7 to 9.6 g/ml for C max ; from 15.7 to 32.8 g ⅐ h/ml for AUC 0-ؕ ). The elimination of abacavir from plasma was rapid, with an apparent elimination half-life of 0.9 to 1.7 h. Abacavir was well absorbed, with a relative bioavailability of the caplet formulation of 96% versus that of an oral solution (drug substance in water). In conclusion, this study showed that abacavir is safe and is well tolerated by HIV-infected subjects and demonstrated predictable pharmacokinetic characteristics when it was administered as single oral doses ranging from 100 to 1,200 mg.

Abacavir (1592U89) is a nucleoside reverse transcriptase inhibitor with potent activity against human immunodeficiency virus type 1 (HIV-1) when used alone or in combination with other antiretroviral agents. The present study was conducted to determine the multiple-dose pharmacokinetics and pharmacodynamics of abacavir in HIV-1-infected subjects following oral administration of daily doses that ranged from 600 to 1,800 mg, with and without zidovudine. Seventy-nine subjects received abacavir monotherapy for 4 weeks ( At the clinical abacavir dose (300 mg BID) zidovudine coadministration had no effect on the abacavir AUC tau , which is most closely associated with efficacy. Zidovudine pharmacokinetics appeared to be unaffected by abacavir. Statistically significant but weak relationships were found for the change in the log 10 HIV-1 RNA load from the baseline to week 4 versus total daily AUC tau and C tau (P < 0.05). The incidence of nausea was significantly associated with total daily AUC tau and C max . In conclusion, abacavir has predictable pharmacokinetic characteristics following the administration of multiple doses.

Based on our results, abacavir is safe and well tolerated and can be administered with or without meals.