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Higher Maraviroc Levels With HCV Agents Boceprevir and Telaprevir
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14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
Boceprevir and telaprevir, the HCV protease inhibitors, greatly boosted exposure of the CCR5 antagonist maraviroc in a study of healthy volunteers [1]. Pfizer investigators concluded that maraviroc can be dosed at 150 mg twice daily with these anti-HCV agents, as it is with other potent CYP3A inhibitors. And they determined that no boceprevir or telaprevir dose adjustments are needed with maraviroc. The findings may be clinically relevant because some work suggests maraviroc could have benefits in people with compromised liver function [2,3].
Boceprevir and telaprevir are substrates and potent inhibitors of CYP3A, and telaprevir is a P-glycoprotein substrate [4,5]. Serious interactions between these agents, efavirenz, and certain ritonavir-boosted protease inhibitors have been identified [6].
Pfizer investigators conducted this open-label, single-center, fixed-sequence study of maraviroc with boceprevir or telaprevir in 14 healthy men, 12 of them white, with an average age of 33.3 and an average weight of 79.3 kg (175 lb). All participants took 150 mg of maraviroc twice daily for 5 days in Period 1 then added 800 mg of boceprevir 3 times daily in Period 2. After at least a 10-day drug washout, participants took 750 mg of telaprevir 3 times daily plus the same maraviroc dose for 10 days in Period 3. At the end of each period, the investigators measured relevant drug concentrations: area under the concentration-time curve after 12 hours for maraviroc (AUC12h) and 8 hours for boceprevir and telaprevir (AUC8h), maximum concentration (Cmax), 12-hour concentration for maraviroc (C12), and 8-hour concentration for the anti-HCV agents (C8).
Thirteen people completed all three treatment periods. There was only one severe adverse event, an asthmatic crisis in a volunteer with preexisting asthma. The crisis followed completion of maraviroc codosing with boceprevir and was judged unrelated to study drugs, but the volunteer dropped out of the study at that point.
All other adverse events were mild or moderate, with overall incidences of 43% in Period 1, 100% in Period 2, and 92% in Period 3. With maraviroc plus boceprevir the most frequent adverse events were a distorted sense of taste in 50% and pruritus (itchiness) in 29%. With maraviroc plus telaprevir the most frequent problems were fatigue in 46% and headache in 31%.
Codosing maraviroc with boceprevir tripled maraviroc concentrations, as indicated by the following geometric means for maraviroc/boceprevir versus maraviroc alone:
Geometric mean (and 90% confidence interval) for MVC/BOC vs MVC alone:
Maraviroc AUC12: 3.02 (2.53 to 3.59)
Maraviroc Cmax: 3.33 (2.54 to 4.36)
Maraviroc C12: 2.78 (2.40 to 3.23)
Codosing maraviroc with telaprevir raised maraviroc concentrations 8 to 10 times:
Geometric mean (and 90% confidence interval) for MVC/TPV vs MVC alone:
Maraviroc AUC12: 9.49 (7.94 to 11.34)
Maraviroc Cmax: 7.81 (5.92 to 10.32)
Maraviroc C12: 10.17 (8.73 to 11.85)
Geometric mean maraviroc average exposure with maraviroc/boceprevir was 151 ng/mL and with maraviroc/telaprevir 465 ng/mL. Boceprevir and telaprevir concentrations with maraviroc were consistent with historical data for these HCV protease inhibitors:
Boceprevir AUC8: 5404 ng x h/mL
Boceprevir Cmax: 192 ng/mL
Boceprevir C8: 80.7 ng/mL
Telaprevir AUC8: 21,980 ng x h/mL
Telaprevir Cmax: 3533 ng/mL
Telaprevir C8: 1943 ng/mL
The Pfizer team concluded that higher maraviroc exposure with boceprevir and telaprevir is consistent with CYP3A inhibition by the HCV protease inhibitors. They recommended that maraviroc should be dosed at 150 mg twice daily with boceprevir or telaprevir, as with other potent CYP3A inhibitors, pending regulatory review. They proposed that boceprevir and telaprevir doses need no adjustment with maraviroc. Twice-daily telaprevir dosing, now being considered, could change these recommendations.
A pharmacokinetic trial is testing maraviroc in a once-daily dose with darunavir/ritonavir (150/800/100 mg) [7]. Darunavir/ritonavir triples maraviroc exposure. The much bigger maraviroc boost with telaprevir raises the question whether once-daily maraviroc may be an option with telaprevir.
References
1. Vourvahis M, Plotka A, Kantaridis C, Fang A, Heera J. The effect of boceprevir and telaprevir on the pharmacokinetics of maraviroc: an open-label, fixed-sequence study in healthy volunteers. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_17.
2. Macias J, Viloria MM, Rivero A, et al. Lack of short-term increase in serum mediators of fibrogenesis and in non-invasive markers of liver fibrosis in HIV/hepatitis C virus-coinfected patients starting maraviroc-based antiretroviral therapy. Eur J Clin Microbiol Infect Dis. 2012;31:2083-2088.
3. Ochoa-Callejero L, Perez-Martinez L, Rubio-Mediavilla S, et al. Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model. PLoS One. 2013;8:e53992.
4. Seden K, Back D. Directly acting antivirals for hepatitis C and antiretrovirals: potential for drug-drug interactions. Curr Opin HIV AIDS. 2011;6:514-526.
5. Wilby KJ, Greanya ED, Ford JA, Yoshida EM, Partovi N. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol. 2012;11:179-185.
6. Hulskotte E, Feng HP, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 771LB. http://www.natap.org/2012/CROI/croi_20.htm
7. The maraviroc darunavir/ritonavir once daily pharmacokinetic study. http://www.clinicaltrials.gov/ct2/show/NCT01348763
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