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Atazanavir modestly increases plasma levels of MK-0518
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Reported by Jules Levin
4th IAS Conference, 22-25, July 2007, Sydney, Australia
G Mistry1, L Wenning1, A Petry1, S Liou1, S Merschman1, K Ghosh1, M Gutierrez2, J Stone1,
K Gottesdiener1, J Wagner1, M Iwamoto1
1Merck & Co., Inc., Whitehouse Station, NJ, and
2Comprehensive Neuroscience Inc., Fort Lauderdale, FL, United States
AUTHORS CONCLUDE:
--Multiple doses of ATV modestly increase plasma levels of MK-0518.
--MK-0518 is generally well tolerated when coadministered with ATV.
--Based on the safety and tolerability profile of MK-0518 to date, no dose adjustment of MK-0518 is anticipated.
ABSTRACT
Objective
MK-0518 is a novel HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 (IC95 = 33 nM in 50% human serum). MK-0518 is primarily metabolized by UGT1A1 mediated glucuronidation and has no inhibitory or inductive potential in vitro. The protease inhibitor (PI) atazanavir (ATV) is known to inhibit UGT1A1. MK-0518 may be coadministered with ATV. The purpose of this study was to examine the effects of ATV on the pharmacokinetics (PK) of MK-0518.
Methods
In this randomized, double-blind, placebo-controlled, sequential, 2-period study, 12 healthy male subjects received a single oral 100-mg dose of MK-0518 in Period 1. In Period 2, 400 mg ATV was administered qd for 9 days and, on Day 7, a 100-mg dose of MK-0518 was coadministered with ATV. There was a 4-day washout interval between the periods. Plasma samples were collected for MK-0518 assay after single dose administration in Period 1 and on Day 7 of Period
2 following coadministration with ATV. Adverse experiences (AEs) were monitored throughout the study. Geometric mean ratios with 90% confidence intervals (GMR [90% CI]) were reported for the MK-0518 PK parameters.
Results
All subjects completed the study and no serious AEs were reported. MK-0518 trough concentrations (C12 hr) increased by 95% in the presence of ATV (GMR=1.95 [1.30, 2.92]) versus alone.
Higher AUC0-∞ (increased 72%) and Cmax (increased 53%) values were also observed when MK-0518 was coadministered with ATV (GMR= 1.72 [1.47, 2.02] for AUC and 1.53 [1.11, 2.12] for Cmax).
No substantial differences were observed in the Tmax or half-life of MK-0518 in the presence of ATV.
Conclusions
Multiple doses of ATV modestly increase plasma levels of MK-0518. MK-0518 is generally well tolerated when coadministered with ATV. Based on the safety and tolerability profile of MK-0518 to date, no dose adjustment of MK-0518 is anticipated.
INTRODUCTION
MK-0518 (raltegravir) is a novel HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 (IC95 = 33 nM in 50% human serum).
MK-0518 is primarily metabolized by glucuronidation via UGT1A1 and has a low propensity to act as a perpetrator of drug-drug interactions.
Atazanavir (ATV), a protease inhibitor (PI), inhibits UGT1A1, as well as CYP3A, CYP1A2, and CYP2C9.
ATV is a commonly prescribed PI as part of Highly Active Anti-Retroviral Therapy (HAART) used to treat HIV-1 infection. The recommended efficacious dose of ATV is 400 mg once daily with food in treatment-na•ve patients and 300 mg ATV + 100 mg ritonavir (RTV) once daily with food in treatment-experienced patients.
MK-0518 may eventually be coadministered with ATV.
Therefore, the purpose of this Phase I study was to examine the effects of ATV on the pharmacokinetics of MK-0518. Effect of MK-0518 on ATV pharmacokinetics was not evaluated since the available data indicates that MK-0518 does not interfere with the CYP pathways mediating metabolism of ATV.
METHODS
Study Design
This was a randomized, double-blind, placebo-controlled, sequential, 2-period study in healthy male subjects.
Twelve (12) subjects, aged 25 to 43 years, received single MK-0518 (or matching placebo) doses alone in Period 1 and then, after a washout interval, MK-0518 (or matching placebo) was coadministered with ATV after multiple doses of ATV in Period 2 as follows:
Blood samples were collected at specified times up to 12 hours postdose after administration of the single dose of MK-0518 in Period 1 and in Period 2, Day 7, when both MK-0518 and ATV were coadministered for MK-0518 assay.
Analytical and Pharmacokinetic Methods
Plasma samples were analyzed for MK-0518 concentrations using a validated HPLC Ð MS/MS assay with limit of quantitation of 4.5 nM.
Plasma concentrations of MK-0518 were used to calculate pharmacokinetic parameter values: C12 hr, AUC0-∞ (calculated using linear trapezoidal method for ascending concentrations and log trapezoidal method for descending concentrations), Cmax, Tmax, and apparent terminal half-life (t1/2) for each subject in the presence or absence of multiple doses of ATV.
Statistical Analysis
Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for MK-0518 C12 hr, AUC0-∞, and Cmax were constructed using an appropriate mixed-effects linear model, as applied to the log-transformed data.
RESULTS
Pharmacokinetic Results
The pharmacokinetic profile of MK-0518 in the presence and absence of ATV are given in Figure I and Table I.
MK-0518 C12 hr increased by an average of 95% in the presence of ATV (GMR=1.95) and the corresponding 90% CI was (1.30, 2.92).
Higher AUC0-∞ (increased 72%) and Cmax (increased 53%) values were also observed when MK-0518 was coadministered with ATV (GMR= 1.72 [1.47, 2.02] for AUC and 1.53 [1.11, 2.12] for Cmax).
No substantial differences were observed in Tmax or t1/2 of MK-0518 in the presence of ATV. In the current study, the plasma concentrations of MK-0518 resulting from the coadministration with ATV alone were generally similar compared to the coadministration of MK-0518 with ATV and RTV.1
Safety Results
All subjects completed the study and no serious AEs were reported.
Nine (9) subjects reported a total of 12 nonserious clinical AEs in Period 2, 8 of which were considered by the investigator as related to study drug.
No AEs were reported in Period 1 when the subjects received MK-0518 alone.
The most common drug-related AE was hyperbilirubinaemia (7/8 reports), which is a known side effect of ATV, 1 episode of which occurred when the subject received placebo matched to MK-0518 + ATV.
REFERENCE
1. Mistry GC, Wenning LA, Merschman S, Kost JT, Bridson WE, Stone J, Gottesdiener KM, Wagner JA, Iwamoto M. Atazanavir and ritonavir increase plasma levels of MK-0518. Poster presented at: Eighth International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland; 2006. Abstract published in Eighth International Congress on Drug Therapy in HIV Infection: Abstracts. 2006; P291.
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