Effect of rifampin and rifabutin on the pharmacokinetics of lersivirine and effect of lersivirine on the pharmacokinetics of rifabutin and 25-O-desacetyl-rifabutin in healthy subjects.
Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile exhibiting potent antiviral activity against wild-type HIV and several clinically relevant NNRTI-resistant strains. Lersivirine, a weak inducer of the cytochrome P450 (CYP) enzyme CYP3A4, is metabolized by CYP3A4 and UDP glucuronosyltransferase 2B7 (UGT2B7). Two open, randomized, two-way (study 1; study A5271008) or three-way (study 2; study A5271043) crossover phase I studies were carried out under steady-state conditions in healthy subjects. Study 1 (n = 17) investigated the effect of oral rifampin on the pharmacokinetics (PKs) of lersivirine. Study 2 (n = 18) investigated the effect of oral rifabutin on the PKs of lersivirine and the effect of lersivirine on the PKs of rifabutin and its active metabolite, 25-O-desacetyl-rifabutin. Coadministration with rifampin decreased the profile of the lersivirine area under the plasma concentration-time curve from time zero to 24 h postdose (AUC(24)), maximum plasma concentration (C(max)), and plasma concentration observed at 24 h postdose (C(24)) by 85% (90% confidence interval [CI], 83, 87), 83% (90% CI, 79, 85), and 92% (90% CI, 89, 94), respectively, versus the values for lersivirine alone. Coadministration with rifabutin decreased the lersivirine AUC(24), C(max), and C(24) by 34% (90% CI, 29, 39), 25% (90% CI, 16, 33), and 58% (90% CI, 52, 64), respectively, compared with the values for lersivirine alone. Neither the rifabutin concentration profile nor overall exposure was affected following coadministration with lersivirine. Lersivirine and rifabutin reduced the 25-O-desacetyl-rifabutin AUC(24) by 27% (90% CI, 21, 32) and C(max) by 27% (90% CI, 19, 34). Lersivirine should not be coadministered with rifampin, which is a potent inducer of CYP3A4, UGT2B7, and P-glycoprotein activity and thus substantially lowers lersivirine exposure. No dose adjustment of rifabutin is necessary in the presence of lersivirine; an upward dose adjustment of lersivirine may be warranted when it is coadministered with rifabutin.
Pfizer Global Research and Development, New York, New York, USA. manoli.vourvahis@pfizer.com
Manoli
M
Vourvahis
John
J
Davis
Rong
R
Wang
Gary
G
Layton
Heng Wee
HW
Choo
Chew-Lan
CL
Chong
Margaret
M
Tawadrous
D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D017828:Rifabutin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; D017828:Rifabutin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D012293:Rifampin