Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.
OBJECTIVE
To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers.


METHODS
Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed.


RESULTS
Maraviroc is rapidly absorbed following oral administration, and plasma T(max) is achieved within 0.5-4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3-1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10-12 l h(-1) and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses.


CONCLUSIONS
Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.
Abel
Samantha
S
Pfizer Global Research and Development, Sandwich, UK.
van der Ryst
Elna
E
Rosario
Maria C
MC
Ridgway
Caroline E
CE
Medhurst
Christine G
CG
Taylor-Worth
Richard J
RJ
Muirhead
Gary J
GJ
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D013223:Statistics as Topic; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc