Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.
OBJECTIVE
To assess the potential of known CYP3A4 inducers, with and without CYP3A4 inhibitors, to alter the pharmacokinetic profile of maraviroc.


METHODS
Two separate, open, randomized, placebo-controlled studies were conducted in healthy subjects. Study 1 was a 28-day parallel-group study with three treatment groups of 12 subjects each. On days 1-7, all subjects received maraviroc 100 mg b.i.d.; on days 8-21, subjects received maraviroc 100 mg b.i.d. plus either rifampicin 600 mg q.d., efavirenz (EFV) 600 mg q.d., or placebo q.d. as assigned; on days 22-28, the maraviroc dose was increased to 200 mg b.i.d. for patients receiving either rifampicin or EFV. Study 2 was a 21-day, two-way crossover study with three cohorts (12 subjects per cohort). On days 1-21, subjects received maraviroc 300 mg b.i.d. and boosted lopinavir (LPV/r, lopinavir 400 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 1, maraviroc 100 mg b.i.d. and boosted saquinavir (SQV/r, saquinavir 1000 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 2, and maraviroc 100 mg b.i.d. and 1000 mg saquinavir + LPV/r (400 mg/100 mg) or placebo b.i.d. in cohort 3. On days 8-21, subjects in all three cohorts also received EFV 600 mg or placebo q.d.


RESULTS
Maraviroc (100 mg b.i.d.) exposure (AUC(12) and C(max)) was reduced in the presence of rifampicin and EFV by approximately 70% and 50%, respectively. Maraviroc AUC(12) and C(max) approached preinduction values when the maraviroc dose was increased to 200 mg b.i.d. for both the rifampicin-treated and EFV-treated groups. Co-administration of LPV/r with maraviroc (300 mg b.i.d.) resulted in geometric mean ratios (GMRs) of 395% and 197% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 253% and 125% for AUC(12) and C(max), respectively. Co-administration of SQV/r with maraviroc (100 mg b.i.d.) resulted in GMRs of 977% and 478% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 500% and 226% for AUC(12) and C(max), respectively. No pharmacokinetic data are reported for cohort 3 because all subjects were discontinued during period 1 due to poor toleration of the drug regimen. There were no serious adverse events reported in either study, and most adverse events were mild or moderate in severity and resolved without intervention.


CONCLUSIONS
As expected with a CYP3A4 substrate, maraviroc exposure (C(max) and AUC(12)) was significantly reduced by the known CYP3A4 inducers, rifampicin and EFV, by approximately 70% and 50%, respectively. Upward adjustment of the maraviroc dose during co-administration with rifampicin or EFV appears to compensate for this reduction. Protease inhibitors (PIs) significantly increased maraviroc exposure; however, the addition of EFV to the maraviroc + PI regimens reduced the magnitude of PI-mediated increase in maraviroc exposure (by approximately 50%), but the net effect was still CYP3A4 inhibition.
Abel
Samantha
S
Pfizer Global R&D, Sandwich, UK.
Jenkins
Timothy M
TM
Whitlock
Lyndsey A
LA
Ridgway
Caroline E
CE
Muirhead
Gary J
GJ
D000293:Adolescent; D000328:Adult; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D013223:Statistics as Topic; D014230:Triazoles / Q000493:pharmacokinetics*
D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D017320:HIV Protease Inhibitors; D014230:Triazoles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077592:Maraviroc