Atovaquone suspension in HIV-infected volunteers: pharmacokinetics, pharmacodynamics, and TMP-SMX interaction study.
OBJECTIVE
To evaluate the pharmacokinetics and safety of atovaquone suspension in volunteers infected with the human immunodeficiency virus ((HIV).


METHODS
Open-label, nonrandomized study.


METHODS
Two clinical research centers.


METHODS
Twenty-two HIV-infected volunteers with a median CD4 cell count of 37 cells/mm3.


METHODS
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).


RESULTS
Average steady-state atovaquone concentrations at 500 mg were 6.7 +/- 3.2 microg/ml fasted and 11.3 +/- 5.0 microg/ml with food; at 750 mg, 9.9 +/- 7.1 microg/ml fasted and 12.5 +/- 5.9 microg/ml with food; at 1000 mg, 9.7 +/- 4.3 microg/ml fasted and 13.6 +/- 5.0 microg/ml with food; and at 1500 mg, 21.1 +/- 5.0 microg/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 microg/ml in 21% and more than 15 microg/ml in 36% of patients at 1000 mg/day with food; at 750 mg twice/day, all five patients had levels above 15 microg/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%).


CONCLUSIONS
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.
Falloon
J
J
National Institute of Allergy and Infectious Diseases and the Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1880, USA.
Sargent
S
S
Piscitelli
S C
SC
Bechtel
C
C
LaFon
S W
SW
Sadler
B
B
Walker
R E
RE
Kovacs
J A
JA
Polis
M A
MA
Davey
R T
RT
Lane
H C
HC
Masur
H
H
D017088:AIDS-Related Opportunistic Infections / Q000378:metabolism / Q000517:prevention & control; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D053626:Atovaquone; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011020:Pneumonia, Pneumocystis / Q000517:prevention & control; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000493:pharmacokinetics
D000935:Antifungal Agents; D009285:Naphthoquinones; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D053626:Atovaquone