Atovaquone Suspension in HIV-Infected Volunteers: Pharmacokinetics, Pharmacodynamics, and TMP-SMX Interaction Study

• Published in: Pharmacotherapy Vol. 19; no. 9; pp. 1050 - 1056
• Main Authors: Falloon, Judith, Sargent, Susie, Piscitelli, Stephen C., Bechtel, Christine, LaFon, Stephen W., Sadler, Brian, Walker, Robert E., Kovacs, Joseph A., Polis, Michael A., Davey Jr, Richard T., Lane, H. Clifford, Masur, Henry
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-1999; Pharmacotherapy
• Subjects: Adult; AIDS-Related Opportunistic Infections - metabolism; AIDS-Related Opportunistic Infections - prevention & control; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal Agents - administration & dosage; Antifungal Agents - adverse effects; Antifungal Agents - pharmacokinetics; Antiparasitic agents; Atovaquone; Biological and medical sciences; Fasting; Female; Food-Drug Interactions; Human immunodeficiency virus; Humans; Male; Medical sciences; Middle Aged; Naphthoquinones - administration & dosage; Naphthoquinones - adverse effects; Naphthoquinones - pharmacokinetics; Pharmacology. Drug treatments; Pneumocystis carinii; Pneumonia, Pneumocystis - prevention & control; Trimethoprim, Sulfamethoxazole Drug Combination - pharmacokinetics; Sulfanilamide derivatives; Pneumonia; Trimethoprim; Pneumocystis carinii; Posology; Food drug interaction; Dose activity relation; Fungi; Prevention; Sulfamethoxazole; Parasiticid; Drug interaction; Fungi Imperfecti; Thallophyta; Human; Immunopathology; Lung disease; Drug combination; Sulfonamide; Atovaquone; Respiratory disease; Retroviridae; AIDS; Suspension; Immune deficiency; Lentivirus; Infection; Virus; Antibiotic; Chemotherapy; Viral disease; Human immunodeficiency virus; Pharmacokinetics
• ISSN: 0277-0008; 1875-9114
• DOI: 10.1592/phco.19.13.1050.31598

Study Objective. To evaluate the pharmacokinetics and safety of atovaquone suspension in volunteers infected with the human immunodeficiency virus ((HIV).
Design. Open‐label, nonrandomized study.
Setting. Two clinical research centers.
Patients. Twenty‐two HIV‐infected volunteers with a median CD4 cell count of 37 cells/mm3.
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 also received 750 mg twice/day with food, and a subset of those who received 1000 mg/day fasting also received 1000 mg with food. During a long‐term dosing phase, a subset of subjects were evaluated for an interaction between atovaquone and trimethoprim‐sulfamethoxazole (TMP‐SMX).
Measurements and Main Results. Average steady‐state atovaquone concentrations at 500 mg were 6.7 ± 3.2 μg/ml fasted and 11.3 ± 5.0 μg/ml with food; at 750 mg, 9.9 ± 7.1 μg/ml fasted and 12.5 ± 5.9 μg/ml with food; at 1000 mg, 9.7 ± 4.3 μg/ml fasted and 13.6 ± 5.0 μg/ml with food; and at 1500 mg, 21.1 ± 5.0 μg/ml with food. Thus, plasma concentrations 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 μg/ml in 21% and more than 15 μg/ml in 36% of patients at 1000 mg/day with food; at 750 mg twice/day, all five patients had levels above 15 μg/ml. Atovaquone suspension was well tolerated; diarrhea, nausea, fatigue, and rash were the most common adverse events. Concomitant administration of TMP‐SMX did not change atovaquone concentrations and resulted 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.