title: Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms.
abstract: Raltegravir is a human immunodeficiency virus-1 (HIV-1) integrase strand transfer inhibitor metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). In this study, 30 subjects with a UGT1A1*28/*28 genotype (associated with decreased activity of UGT1A1) and 27 UGT1A1*1/*1 control subjects (matched by race, age, gender, and body mass index) received a single 400-mg dose of raltegravir after fasting. No serious adverse experiences were reported, and there were no discontinuations due to adverse experiences. The geometric mean ratio (GMR) (UGT1A1*28/*28 to UGT1A1*1/*1) and 90% confidence interval (CI) were 1.41 (0.96, 2.09) for raltegravir area under the concentration-time curve (AUC(0-infinity)), 1.40 (0.86, 2.28) for maximum plasma concentration (C(max)), and 1.91 (1.43, 2.55) for concentration at the 12-h time point (C(12 h)). No clinically important differences in time to maximum concentration (T(max)) or half-life were observed. Plasma concentrations of raltegravir are modestly higher in individuals with the UGT1A1*28/*28 genotype than in those with the UGT1A1*1/*1 genotype. This increase is not clinically significant, and therefore no dose adjustment of raltegravir is required for individuals with the UGT1A1*28/*28 genotype.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, a division of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. larissa_wenning@merck.com
authors.forename: L A
authors.initials: LA
authors.lastname: Wenning
authors.forename: A S
authors.initials: AS
authors.lastname: Petry
authors.forename: J T
authors.initials: JT
authors.lastname: Kost
authors.forename: B
authors.initials: B
authors.lastname: Jin
authors.forename: S A
authors.initials: SA
authors.lastname: Breidinger
authors.forename: I
authors.initials: I
authors.lastname: DeLepeleire
authors.forename: E J
authors.initials: EJ
authors.lastname: Carlini
authors.forename: S
authors.initials: S
authors.lastname: Young
authors.forename: T
authors.initials: T
authors.lastname: Rushmore
authors.forename: F
authors.initials: F
authors.lastname: Wagner
authors.forename: N M
authors.initials: NM
authors.lastname: Lunde
authors.forename: F
authors.initials: F
authors.lastname: Bieberdorf
authors.forename: H
authors.initials: H
authors.lastname: Greenberg
authors.forename: J A
authors.initials: JA
authors.lastname: Stone
authors.forename: J A
authors.initials: JA
authors.lastname: Wagner
authors.forename: M
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D000328:Adult; D019540:Area Under Curve; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000099148:UGT1A1 Enzyme