Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults

Abacavir (1592U89) is a nucleoside reverse transcriptase inhibitor with pot ent 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 pharmaco dynamics of abacavir in HIV-1-infected subjects following oral administrati on of daily doses that ranged from 600 to 1,800 mg, with and without zidovu dine. 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 therea fter received either zidovudine (200 mg TID or 300 mg BID) or matching plac ebo with abacavir for 8 additional weeks. Pharmacokinetic parameters were c alculated for abacavir after administration of the first dose and at week 4 and for abacavir, zidovudine, and its glucuronide metabolite at week 12. T he concentrations of abacavir in cerebrospinal fluid were determined in a s ubset of subjects. Steady-state plasma abacavir concentrations were achieve d by week 4 of monotherapy and persisted to week 12. At steady state, abaca vir pharmacokinetic parameters (area under the plasma concentration-time cu rve for a dosing interval [AUC(tau)] and peak concentration [C-max]) were g enerally proportional to dose over the range of a 600- to 1,200-mg total da ily dose. Coadministration of zidovudine with abacavir produced a small and inconsistent effect on abacavir pharmacokinetic parameters across the diff erent doses. At the clinical abacavir dose (300 mg BID) zidovudine coadmini stration had no effect on the abacavir AUG,,,, which is most closely associ ated with efficacy. Zidovudine pharmacokinetics appeared to be unaffected b y 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 versu s total daily AUC(tau) and C-max (P < 0.05). The incidence of nausea was si gnificantly associated with total daily AUC(tau) and C-max. In conclusion, abacavir has predictable pharmacokinetic characteristics following the admi nistration of multiple doses.