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Once-Daily 150-mg Maraviroc Explored in People Taking Atazanavir/Ritonavir
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12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
HIV-positive people taking standard-dose atazanavir/ritonavir plus 150 mg of maraviroc once daily had lower maraviroc maximum concentrations (Cmax) and average concentrations (Cavg) than HIV-negative people taking 300 mg of maraviroc twice daily without atazanavir/ritonavir. But in this pharmacokinetic modeling study, maraviroc minimum concentration (Cmin) and effective constant concentration (ECC) were similar in the two groups.
Clinical researchers are interested in a regimen combining the CCR5 antagonist maraviroc with atazanavir/ritonavir and excluding reverse transcriptase inhibitors. But finding the appropriate maraviroc dose is complicated because atazanavir/ritonavir raises maraviroc concentrations through inhibition of the CYP3A4 enzyme and drug transporters. And modeling maraviroc pharmacokinetics has proved difficult because of interpatient and intrapatient variability in rate and extent of maraviroc absorption.
Pharmacokinetic data from antiretroviral-experienced people suggested lower maraviroc exposure than predicted by a drug interaction study in healthy volunteers taking 300 mg of maraviroc twice daily with atazanavir/ritonavir (study A4001025) [2].
To further assess maraviroc's interaction with atazanavir/ritonavir, Pfizer researchers used a semiphysiologic maraviroc PK model to analyze maraviroc concentrations in two groups: (1) 12 healthy volunteers who took 300 mg of maraviroc twice daily without atazanavir/ritonavir in study A4001025 [2], and (2) 58 HIV-positive antiretroviral-naive people who took 150 mg of maraviroc plus 300/100 mg of atazanavir/ritonavir, both once daily, in study A4001078.
The Pfizer team used data from the volunteers to estimate the impact of atazanavir/ritonavir on intrinsic maraviroc clearance and extent of absorption. Then they applied these values to a "rich" set of data involving 145 samples from 15 people with HIV and a "sparse" data set involving 138 samples from 57 people with HIV. The Pfizer investigators used a nonlinear mixed model with two absorption compartments and four disposition compartments. The model introduced absorbed maraviroc into a liver compartment in which atazanavir/ritonavir inhibited metabolic clearance and absorption transporters. The model scaled renal clearance at a baseline creatinine clearance of 120 mL/min.
In the 12 HIV-negative volunteers taking 300 mg of maraviroc twice daily, atazanavir/ritonavir reduced population intrinsic clearance of maraviroc from 90 to 14 L/h, while maraviroc absorption rose from 83.3% to 98.5%. These changes led to the following predicted changes: (1) a 2.5-fold increase in maraviroc Cmax, (2) a 4.6-fold increase in 12-hours maraviroc area under the concentration-time curve, and (3) a 10-fold increase in Cmin.
At the same intrinsic clearance, the 150-mg once-daily maraviroc dose in HIV-positive people resulted in 93.5% absorption. Compared with the healthy volunteers taking 300 mg of maraviroc twice daily without atazanavir/ritonavir, the sparse-data 57-person HIV group taking 150 mg once daily with the protease inhibitors had a lower maraviroc Cmax (591 versus 933 ng/mL) and a lower Cavg (170 versus 213 ng/mL). But Cmin was higher in the HIV group than in HIV-negative volunteers (43 versus 38 ng/mL), as was ECC (95 versus 89 ng/mL).
Analysis of maraviroc concentrations in the 15-person rich-data HIV sample yielded similar results: Cmax 614 ng/mL, Cavg 170 ng/mL, Cmin 44 ng/mL, and ECC 96 ng/mL. However, intrinsic maraviroc clearance in the rich-data analysis was 9 L/h and absorption 69%.
Compared with a maraviroc dose of 300 mg twice daily without atazanavir/ritonavir, the Pfizer researchers concluded that in HIV-positive people a dose of 150 mg once daily with atazanavir/ritonavir "produced less peak-trough fluctuation with very similar Cmin and ECC values." The investigators believe this result "implies similar efficacy for the maraviroc component of any such combination."
References
1. Weatherley B, Vourvahis M, McFadyen L. Modeling of maraviroc pharmacokinetics in the presence of atazanavir/ritonavir in healthy volunteers and HIV-1-infected patients. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract P_05.
2. Abel S, Jenkins TM, Whitlock LA, Ridgway CE, Muirhead GJ. Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers. Br J Clin Pharmacol. 2008;65 Suppl 1:38-46. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2311406/?tool=pubmed.
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