Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir.
Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor that is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin (rifampicin). Two pharmacokinetic studies were performed in healthy subjects: study 1 examined the effect of administration of 600-mg rifampin once daily on the pharmacokinetics of a single dose of 400-mg raltegravir, and study 2 examined the effect of 600-mg rifampin once daily on the pharmacokinetics of 800-mg raltegravir twice daily compared to 400-mg raltegravir twice daily without rifampin. Raltegravir coadministered with rifampin resulted in lower plasma raltegravir concentrations: in study 1, the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the plasma raltegravir concentration determined 12 h postdose (C(12)), area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), and maximum concentration of drug in plasma (C(max)) (400-mg raltegravir plus rifampin/400-mg raltegravir) were 0.39 (0.30, 0.51), 0.60 (0.39, 0.91), and 0.62 (0.37, 1.04), respectively. In study 2, the GMRs and 90% CIs for raltegravir C(12), AUC(0-12), and C(max) (800-mg raltegravir plus rifampin/400-mg raltegravir) were 0.47 (0.36, 0.61), 1.27 (0.94, 1.71), and 1.62 (1.12, 2.33), respectively. Doubling the raltegravir dose to 800 mg when coadministered with rifampin therefore compensates for the effect of rifampin on raltegravir exposure (AUC(0-12)) but does not overcome the effect of rifampin on raltegravir trough concentrations (C(12)). Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used, since raltegravir trough concentrations in the presence of rifampin are likely to be at the lower limit of clinical experience.
Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Larissa_Wenning@merck.com
Larissa A
LA
Wenning
William D
WD
Hanley
Diana M
DM
Brainard
Amelia S
AS
Petry
Kalyan
K
Ghosh
Bo
B
Jin
Eric
E
Mangin
Thomas C
TC
Marbury
Jolene K
JK
Berg
Jeffrey A
JA
Chodakewitz
Julie A
JA
Stone
Keith M
KM
Gottesdiener
John A
JA
Wagner
Marian
M
Iwamoto
D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult
D000904:Antibiotics, Antitubercular; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D012293:Rifampin