Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms.
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.
Wenning
L A
LA
Department of Drug Metabolism, Merck Research Laboratories, a division of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. larissa_wenning@merck.com
Petry
A S
AS
Kost
J T
JT
Jin
B
B
Breidinger
S A
SA
DeLepeleire
I
I
Carlini
E J
EJ
Young
S
S
Rushmore
T
T
Wagner
F
F
Lunde
N M
NM
Bieberdorf
F
F
Greenberg
H
H
Stone
J A
JA
Wagner
J A
JA
Iwamoto
M
M
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
D014453:Glucuronosyltransferase; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000099148:UGT1A1 Enzyme