title: Lack of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in vivo correlation.
abstract: Raltegravir is an HIV-1 integrase strand transfer inhibitor with potent activity against HIV-1. A prior investigation of raltegravir coadministered with rifampin demonstrated a decrease in plasma concentrations of raltegravir likely secondary to induction of UGT1A1, the enzyme primarily responsible for the metabolism of raltegravir. Little is known regarding the induction of UGT1A1 by rifabutin, an alternate rifamycin. In vitro characterization of the induction potency of rifampin and rifabutin on UGT1A1 was performed. In vitro studies indicate that rifabutin is a less potent inducer of UGT1A1 messenger RNA expression than is rifampin. A fixed-sequence, 2-period, clinical crossover study was conducted to assess the effect of rifabutin on plasma levels of raltegravir: period 1, 400 mg of raltegravir every 12 hours for 4 days; period 2, 400 mg of raltegravir every 12 hours and 300 mg of rifabutin once daily for 14 days. Geometric mean ratio (GMR) (coadministration of rifabutin and raltegravir vs raltegravir alone) of raltegravir area under the concentration-time curve from 0 to 12 hours post dose (AUC(0-12h)) and the 90% confidence interval (CI) was 1.19 (0.86-1.63); GMR of concentration at 12 hours (C(12h)) and 90% CI was 0.80 (0.68-0.94); and GMR of time to maximal concentration (C(max)) and 90% CI was 1.39 (0.87-2.21). Overall, coadministration of rifabutin did not alter raltegravir pharmacokinetics to a clinically meaningful degree.
authors.affiliation: Merck & Co, Inc, 126 E. Lincoln Ave, P.O. Box 2000, Rahway, NJ 07065, USA. diana_brainard@merck.com
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.forename: Kelem
authors.initials: K
authors.lastname: Kassahun
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Wenning
authors.forename: Amelia S
authors.initials: AS
authors.lastname: Petry
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.forename: Jared
authors.initials: J
authors.lastname: Lunceford
authors.forename: Niresh
authors.initials: N
authors.lastname: Hariparsad
authors.forename: Roy
authors.initials: R
authors.lastname: Eisenhandler
authors.forename: Alisha
authors.initials: A
authors.lastname: Norcross
authors.forename: Emanuel P
authors.initials: EP
authors.lastname: DeNoia
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stone
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018929:Cell Culture Techniques; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D017828:Rifabutin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D000099148:UGT1A1 Enzyme
chemical_list: D000900:Anti-Bacterial Agents; D014453:Glucuronosyltransferase; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D017828:Rifabutin; D012293:Rifampin; D000099148:UGT1A1 Enzyme