Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A1*28 considered to be the main genetic variant associated with decreased UGT1A1 expression. This study investigated variability in RAL trough plasma concentrations (C trough) in the clinical setting, the effect of UGT1A1*28 and concomitant antiretrovirals.
A total of 86 patients, from Turin, Italy, and Madrid, Spain, were included in the analysis. Blood samples were obtained 10–14 hours postdose. Genotyping for UGT1A1*28 was conducted by sequencing.
High interpatient and intrapatient variabilities were observed; 13 patients had ≥3 samples available, and the median coefficient of variation was 128 (64–265). Coadministration of RAL with atazanavir (ATV, n = 9) resulted in higher raltegravir C trough, 517 (307–2706) ng/mL when compared with patients not receiving ATV (n = 77) 223 (95–552; P = 0.02). UGT1A1*28 did not influence RAL plasma exposure.
We have documented large intersubject and intrasubject variabilities in RAL plasma concentrations and confirmed the interaction with ATV. Further studies are required to better understand the mechanisms that influence the pharmacokinetics of RAL.
*Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom
†Department of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
‡Molecular Biology Laboratory, Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
S.B. has received grants, travel grants and consultancy fees from Abbott, Boehringer-Inghelheim, Bristol-Myers Squibb, Gilead-Sciences, GlaxoSmithKline (GSK), MSD, Pfizer and Janssen-Cilag. G.D.P. has received grants, travel grants and consultancy fees from Abbott, Boehringer-Inghelheim, Bristol-Myers Squibb, Gilead-Sciences, GSK, MSD, Pfizer, Roche and Tibotec (Johnson & Johnson). D.J.B., had received travel and research grants from and have been advisers for Tibotec, Roche, Pfizer, GSK, Bristol-Myers Squibb, Merck Sharp & Dohme, Abbott, and Boehringer Ingelheim. A.O. have received research funding from Boehringer Ingelheim, GSK, Abbott Laboratories, Pfizer, AstraZeneca, Tibotec, Merck Sharp & Dohme and Roche Pharmaceuticals. The other authors have no conflicts of interest.
Correspondence: Marco Siccardi, PhD, Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, United Kingdom (e-mail: firstname.lastname@example.org).
Received August 12, 2011
Accepted January 11, 2012