Atovaquone suspension in HIV-infected volunteers: Pharmacokinetics, pharmacodynamics, and TMP-SMX interaction study

Study Objective. To evaluate the pharmacokinetics and safely of atovaquone suspension in volunteers infected with the human immunodeficiency virus ((H IV). Design. Open-label, nonrandomized study. Setting. Two clinical research centers. Patients. Twenty-two HIV-infected volunteers with a median CD4 cell count o f 37 cells/mm(3). Interventions. Patients received atovaquone suspension fasting or fed for 2 -week periods with crossover at dosages of 500 mg/day, and randomization to fasting or fed at dosages of 750 and 1000 mg/day. A subset of patients als o received 750 mg twice/day with food, and a subset of those who received 1 000 mg/day fasting also received 1000 mg with food. During a long-term dosi ng phase, a subset of subjects were evaluated for an interaction between at ovaquone and trimethoprim-sulfamethoxazole (TMP-SMX). Measurements and Main Results. Average steady-state atovaquone concentratio ns-at 500 mg were 6.7 +/- 3.2 mu g/ml fasted and 11.3 +/- 5.0 mu g/ml with food, at 750 mg, 9.9 +/- 7.1 mu g/ml fasted and 12.5 +/- 5.9 mu g/ml with f ood, at 1000 mg, 9.7 +/- 4.3 mu g/ml fasted and 13.6 +/- 5.0 mu g/ml with f ood; and at 1500 mg, 21.1 +/- 5.0 mu g/ml with food. Thus, plasma concentra tions were not proportional to dose. Concomitant food ingestion resulted in a 1.3- to 1.7-fold increase in values. Average steady-state concentrations were less than 10 mu g/ml in 21% and more than 15 mu g/ml in 36% of patien ts at 1000 mg/day with food; at 750 mg twice/day, all five patients had lev els above 15 mu g/ml. Atovaquone suspension was well tolerated; diarrhea, n ausea, fatigue, and rash were the most common adverse events. Concomitant a dministration of TMP-SMX did not change atovaquone concentrations and resul ted in small decreases in concentrations of TMP (16%) and SMX (10%). Conclusion. Plasma concentrations are significantly higher when atovaquone suspension is administered with food compared with fasting. Total doses of 1500 mg/day are likely to achieve concentrations effective for prophylaxis of Pneumocystis carinii pneumonia.