Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.
OBJECTIVE
To assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive.


METHODS
Three randomized, double-blind, placebo-controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two-period crossover studies were conducted to assess (i) the effect of steady-state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady-state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two-way crossover study was conducted to evaluate the effect of steady-state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 microg ethinyloestradiol/150 microg levonorgestrel (Microgynon).


RESULTS
The geometric mean ratios for C(max) and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in T(max), t(1/2) or CL(R) (where measured) for any of the compounds.


CONCLUSIONS
Maraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel.
Abel
Samantha
S
Pfizer Global R&D, Sandwich, UK.
Russell
Deborah
D
Whitlock
Lyndsey A
LA
Ridgway
Caroline E
CE
Muirhead
Gary J
GJ
D000293:Adolescent; D000328:Adult; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics*; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D065100:CCR5 Receptor Antagonists; D003276:Contraceptives, Oral / Q000097:blood / Q000493:pharmacokinetics*; D003510:Cyclohexanes / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004997:Ethinyl Estradiol / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D019259:Lamivudine / Q000097:blood / Q000493:pharmacokinetics; D016912:Levonorgestrel / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D000077592:Maraviroc; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D013223:Statistics as Topic; D014230:Triazoles / Q000494:pharmacology*; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics
D014151:Anti-Anxiety Agents; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003276:Contraceptives, Oral; D003510:Cyclohexanes; D014230:Triazoles; D019259:Lamivudine; D004997:Ethinyl Estradiol; D015215:Zidovudine; D016912:Levonorgestrel; D000077592:Maraviroc; D008874:Midazolam