Pharmacokinetics, safety and tolerability of a single oral dose of maraviroc in HIV-negative subjects with mild and moderate hepatic impairment.
BACKGROUND
Maraviroc is the first CCR5 antagonist and only oral entry inhibitor approved for the treatment of HIV type-1 infection. Maraviroc is extensively metabolized, primarily by cytochrome P450 3A4 and hence its pharmacokinetics might be affected by impaired hepatic function. The objective of this study was to evaluate the pharmacokinetics of maraviroc in subjects with mild or moderate hepatic impairment compared with subjects with normal hepatic function. Safety and tolerability were also assessed.


METHODS
This was an open-label, non-randomized, single-centre, parallel-group study. A total of 24 subjects with mild (n=8) or moderate (n=8) hepatic impairment, or normal hepatic function (n=8) received a single dose of 300 mg maraviroc.


RESULTS
Relative to those with normal hepatic function, the geometric mean ratio (90% confidence interval) for the maximum observed plasma concentration (C(max)) of maraviroc was 111% (74.6-166) and 132% (89.6-194) for those with mild and moderate hepatic impairment, respectively; the area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC(last)) was 125% (84.7-185) and 146% (100-212); oral clearance was 89% (53.2-150) and 83% (49.2-139); and renal clearance was 94% (70.5-126) and 131% (98.6-173), respectively. Maraviroc was well tolerated in all subjects.


CONCLUSIONS
Although differences in maraviroc pharmacokinetics were noted in subjects with hepatic impairment compared with those with normal hepatic function, these do not currently support a dose modification. The single 300 mg dose of maraviroc was well tolerated by subjects with normal and impaired hepatic function.
Abel
Samantha
S
Pfizer Global Research and Development, Sandwich, UK.
Davis
John D
JD
Ridgway
Caroline E
CE
Hamlin
Julia C
JC
Vourvahis
Manoli
M
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc