Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir.
BACKGROUND
* Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV-1 integrase inhibitor. * Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs. * As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them.


CONCLUSIONS
* Relative to individual monotherapy, co-administration resulted in a 20% and 33% decrease in mean C(max), and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively. * Co-administration was generally safe and well tolerated in healthy subjects. * These changes are not likely to be clinically relevant, thus no dose adjustment is necessary.


OBJECTIVE
To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir.


METHODS
In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1-3 raltegravir 400 mg q12h, days 4-5 washout, days 6-11 maraviroc 300 mg q12h, and days 12-14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters.


RESULTS
For maraviroc, the test/reference % ratio (95% CI) for AUC(tau) was 85.8 (78.7, 93.5), for C(max) was 79.5 (64.8, 97.5) and for C(min) was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC(tau) was 63.3 (41.0, 97.6), for C(max) was 66.8 (37.1, 120.0) and for C(min) was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC(tau) divided by 12) were >100 ng ml(-1), the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C(min) decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance.


CONCLUSIONS
Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.
Andrews
Emma
E
Pfizer Inc., New York, NY, USA.
Glue
Paul
P
Fang
Juanzhi
J
Crownover
Penelope
P
Tressler
Randall
R
Damle
Bharat
B
D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D023581:HIV Fusion Inhibitors / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000188:drug therapy; D018023:HIV Seronegativity; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D053719:Tandem Mass Spectrometry; D014230:Triazoles / Q000493:pharmacokinetics*
D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D011760:Pyrrolidinones; D014230:Triazoles; D000068898:Raltegravir Potassium; D000077592:Maraviroc