Multiple-Dose Pharmacokinetics and Pharmacodynamics of Abacavir Alone and in Combination with Zidovudine in Human Immunodeficiency Virus-Infected Adults

Author:

McDowell James A.1,Lou Yu2,Symonds William S.3,Stein Daniel S.1

Affiliation:

1. Worldwide Clinical Pharmacology,1

2. Clinical Pharmacology Data Sciences,2 and

3. Clinical Development,3 Glaxo Wellcome Inc., Research Triangle Park, North Carolina

Abstract

ABSTRACT 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 (200, 400, or 600 mg every 8 hours [TID] and 300 mg every 12 h [BID]) and thereafter received either zidovudine (200 mg TID or 300 mg BID) or matching placebo with abacavir for 8 additional weeks. Pharmacokinetic parameters were calculated for abacavir after administration of the first dose and at week 4 and for abacavir, zidovudine, and its glucuronide metabolite at week 12. The concentrations of abacavir in cerebrospinal fluid were determined in a subset of subjects. Steady-state plasma abacavir concentrations were achieved by week 4 of monotherapy and persisted to week 12. At steady state, abacavir pharmacokinetic parameters (area under the plasma concentration-time curve for a dosing interval [AUC tau ] and peak concentration [ C max ]) were generally proportional to dose over the range of a 600- to 1,200-mg total daily dose. Coadministration of zidovudine with abacavir produced a small and inconsistent effect on abacavir pharmacokinetic parameters across the different doses. 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.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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