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  14th International Workshop on Clinical Pharmacology of HIV Therapy
April 22-24, 2013
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Protease Inhibitors Boost Levels of Cenicriviroc, a CCR5/CCR2 Antagonist
  14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
Ritonavir, darunavir/ritonavir, and atazanavir/ritonavir all more than tripled exposure of cenicriviroc, an investigational CCR5 and CCR2 receptor antagonist, in 60 healthy volunteers [1]. There were no serious or unexpected adverse events in these 20-day studies.
Cenicriviroc, which thwarts HIV binding to CCR5 and CCR2 receptors on CD4 cells, controlled viral replication as well as efavirenz through 24 weeks of a 48-week trial that enrolled antiretroviral-naive people [2]. A higher virologic nonresponse rate with cenicriviroc than efavirenz in that trial appeared to reflect dropouts rather than actual virologic failure. Blocking CCR2 could limit immune activation.
Researchers from Tobira Therapeutics and collaborators conducted three phase 1 open-label crossover studies to determine pharmacokinetics of cenicriviroc when given with standard doses of ritonavir, atazanavir/ritonavir, or darunavir/ritonavir [1]. Sixty healthy volunteers (20 in each arm) took cenicriviroc alone at a dose of 50 mg once daily for 10 days then added either ritonavir at 100 mg once daily, darunavir/ritonavir at 800/100 mg once daily, or atazanavir/ritonavir at 300/100 mg once daily on days 11 through 20. The investigators collected blood samples over 24 hours on days 10 and 20. Cenicriviroc is metabolized via CYP3A4 and CYP2C8 but is not known to be a CYP inducer or inhibitor; ritonavir is a potent CYP3A4 inhibitor.
Everyone completed the darunavir/ritonavir study. Two people in the ritonavir study withdrew consent, and 2 people in the atazanavir/ritonavir study dropped out because of moderate rash. The investigators reported no serious or unexpected adverse events or any clinically relevant lab abnormalities. Hyperbilirubinemia, a frequent occurrence with atazanavir, developed when study participants added atazanavir/ritonavir to cenicriviroc and resolved after they stopped the antiretrovirals. Mild jaundice developed in all 20 volunteers taking cenicriviroc with atazanavir/ritonavir.
Study participants achieved steady-state plasma concentrations of cenicriviroc after 6 days of cenicriviroc monotherapy and after 9, 7, and 7 days of codosing with ritonavir, darunavir/ritonavir, and atazanavir/ritonavir.
Cenicriviroc levels rose substantially when volunteers added any of the protease inhibitors, as indicated by the following least-squares geometric mean ratios for 24-hour area under the concentration-time curve (AUC0-24), maximum concentration (Cmax), and minimum concentration (Cmin) (and 90% confidence intervals) figured as concomitant dosing/cenicriviroc alone:
Cenicriviroc plus ritonavir:
AUC0-24: 3.55 (3.1 to 4.1)
Cmax: 2.39 (2.1 to 2.7)
Cmin: 5.24 (4.4 to 6.2)
Cenicriviroc plus darunavir/ritonavir:
AUC0-24: 3.13 (2.9 to 3.4)
Cmax: 2.17 (2.0 to 2.3)
Cmin: 4.17 (3.7 to 4.7)
Cenicriviroc plus atazanavir/ritonavir:
AUC0-24: 3.89 (3.5 to 4.3)
Cmax: 2.55 (2.3 to 2.8)
Cmin: 5.75 (4.9 to 6.7)
Thus Cmax more than doubled in every study arm, and 24-hour AUC more than tripled.
In a trial combining cenicriviroc with efavirenz in healthy volunteers, reported separately by NATAP, efavirenz sharply lowered exposure of cenicriviroc given at 200 mg daily [3]. Doubling the cenicriviroc dose to 400 mg daily offset that interaction.
Phase 3 trials are being planned to determine the clinical efficacy of cenicriviroc in combination with guideline-recommended antiretrovirals.
1. Lefebvre E, Enejosa J, Chang W, et al. Pharmacokinetics of cenicriviroc when administered with and without ritonavir, darunavir/ritonavir or atazanavir/ritonavir. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_09A.
2. Gathe J, Cade J, DeJesus E, et al. Week-24 primary analysis of cenicriviroc vs efavirenz, in combination with emtricitabine/tenofovir, in treatment-naive HIV-1+ adults with CCR5-tropic virus. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 106LB. http://www.natap.org/2013/CROI/croi_42.htm and http://www.natap.org/2013/CROI/croi_41.htm
3. Lefebvre E, Enejosa J, Chang W, et al. Pharmacokinetic interactions between cenicriviroc and efavirenz. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_09B.