The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers.
OBJECTIVE
To assess the potential of cotrimoxazole and tenofovir, drugs which are inhibitors and/or substrates of renal transporters, to alter the pharmacokinetic profile of maraviroc.


METHODS
Two randomized, placebo-controlled, two-way crossover studies were conducted in healthy male and female subjects. In study 1, 16 subjects, aged 18-45 years, received maraviroc (300 mg b.i.d.) with and without cotrimoxazole (960 mg b.i.d.; 160 mg trimethoprim and 800 mg sulfamethoxazole). In study 2, 12 subjects, aged 21-45 years, received maraviroc (300 mg b.i.d.) with and without tenofovir (300 mg q.d.). For study 1, blood was collected predose and on days 1-7. In study 2, blood was collected predose, on day 1 and days 3-7. In both studies, blood was collected at intervals up to 12 h postdose on day 7. Urine was collected on day 7, 0-12 h post morning dose. Blood and urine were analysed for maraviroc using liquid chromatography/tandem mass spectrometry.


RESULTS
The geometric mean ratios for C(max) and AUC(12) were 119% and 111%, respectively, for maraviroc plus cotrimoxazole and 104% and 103%, respectively, for maraviroc plus tenofovir, compared with maraviroc plus placebo. Renal clearance of maraviroc plus placebo was 8.3 l h(-1) and 8.5 l h(-1) and was 7.8 l h(-1) for maraviroc plus cotrimoxazole and maraviroc plus tenofovir. There were no serious or severe adverse events or any clinically significant changes in laboratory tests, blood pressure, or electrocardiograms.


CONCLUSIONS
Neither cotrimoxazole nor tenofovir caused a clinically significant effect on the pharmacokinetics of maraviroc. Maraviroc 300 mg b.i.d. was well tolerated when co-administered with either cotrimoxazole or tenofovir.
Abel
Samantha
S
Pfizer Global R&D, Sandwich, UK.
Russell
Deborah
D
Whitlock
Lyndsey A
LA
Ridgway
Caroline E
CE
Muirhead
Gary J
GJ
D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics*; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D063065:Organophosphonates / Q000097:blood / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000097:blood; D013223:Statistics as Topic; D000068698:Tenofovir; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000097:blood / Q000494:pharmacology*
D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D063065:Organophosphonates; D019713:Receptors, CCR5; D014230:Triazoles; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000068698:Tenofovir; D000225:Adenine; D000077592:Maraviroc