Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.
Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ≥3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C(tau), or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C(tau), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and raltegravir-glucuronide/raltegravir AUC(0-12) were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C(tau) with a once-daily raltegravir dose of 400 mg similar to the C(tau) with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.
Neely
Michael
M
Maternal Child Adolescent Program, University of Southern California, 1640 Marengo Street, Los Angeles, CA 90033, USA. mneely@usc.edu
Decosterd
Laurent
L
Fayet
Aurélie
A
Lee
Janice Soo Fern
JS
Margol
Ashley
A
Kanani
Meera
M
di Iulio
Julia
J
von Schoen-Angerer
Tido
T
Jelliffe
Roger
R
Calmy
Alexandra
A
D000328:Adult; D000069446:Atazanavir Sulfate; D004347:Drug Interactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011760:Pyrrolidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000068898:Raltegravir Potassium; D055815:Young Adult
D019428:HIV Integrase Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000069446:Atazanavir Sulfate
J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Apr 15;877(11-12):1057-69
19332396
Cancer Res. 2000 Feb 15;60(4):950-6
10706110
Clin Pharmacol Ther. 2009 Jun;85(6):623-7
19279563
Ann Pharmacother. 2008 Jul;42(7):1048-59
18577765
Ther Drug Monit. 1991 Jul;13(4):325-31
1780965
Clin Pharmacol Ther. 2008 Feb;83(2):293-9
17713476
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8170-4
9653159
Annu Rev Pharmacol Toxicol. 2009;49:377-94
18928385
Drug Metab Dispos. 2005 Mar;33(3):458-65
15572581
J Chromatogr B Analyt Technol Biomed Life Sci. 2005 May 25;819(2):259-76
15833290
Clin Infect Dis. 2008 Jul 1;47(1):137-40
18513146
Lancet. 1996 Mar 2;347(9001):578-81
8596320
Lancet. 2007 Apr 14;369(9569):1261-1269
17434401
J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33
17721395