Md Amin Hossain1, Timothy Tran1, Tianmeng Chen1, Gerd Mikus2, David J Greenblatt1,3. 1. Graduate Program in Pharmacology and Drug Development, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA. 2. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. 3. Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.
Abstract
OBJECTIVES: Ritonavir and cobicistat are strong inhibitors of human cytochrome P450-3A (CYP3A) isoforms, and are used clinically as pharmacokinetic boosting agents for other antiretroviral drugs. Data reported by the manufacturer suggest that cobicistat is a more selective inhibitor of CYP3A than ritonavir. However, this claim has not been validated in clinical studies. This study evaluated the in-vitro inhibitory potency of ritonavir and cobicistat vs a series of human CYP isoforms. METHOD: The model system utilized human liver microsomes and isoform-selective index substrates. KEY FINDINGS: Ritonavir and cobicistat both were strong inhibitors of CYP3A4, with IC50 values of 0.014 and 0.032 μm, respectively. A component of inhibition was time-dependent (mechanism-based). Neither drug meaningfully inhibited CYP1A2 (IC50 > 150 μm). CYP2B6, CYP2C9, CYP2C19 and CYP2D6 were inhibited by both drugs, but with IC50 values exceeding 6 μm. CONCLUSIONS: Consistent with previous reports, both ritonavir and cobicistat were highly potent inhibitors of CYP3A. Both drugs were weaker inhibitors of other human CYPs, with IC50 values at least two orders of magnitude higher. There was no evidence of a meaningful difference in selectivity between the two drugs.
OBJECTIVES:Ritonavir and cobicistat are strong inhibitors of humancytochrome P450-3A (CYP3A) isoforms, and are used clinically as pharmacokinetic boosting agents for other antiretroviral drugs. Data reported by the manufacturer suggest that cobicistat is a more selective inhibitor of CYP3A than ritonavir. However, this claim has not been validated in clinical studies. This study evaluated the in-vitro inhibitory potency of ritonavir and cobicistat vs a series of human CYP isoforms. METHOD: The model system utilized human liver microsomes and isoform-selective index substrates. KEY FINDINGS:Ritonavir and cobicistat both were strong inhibitors of CYP3A4, with IC50 values of 0.014 and 0.032 μm, respectively. A component of inhibition was time-dependent (mechanism-based). Neither drug meaningfully inhibited CYP1A2 (IC50 > 150 μm). CYP2B6, CYP2C9, CYP2C19 and CYP2D6 were inhibited by both drugs, but with IC50 values exceeding 6 μm. CONCLUSIONS: Consistent with previous reports, both ritonavir and cobicistat were highly potent inhibitors of CYP3A. Both drugs were weaker inhibitors of other human CYPs, with IC50 values at least two orders of magnitude higher. There was no evidence of a meaningful difference in selectivity between the two drugs.
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Authors: Augusto Di Castelnuovo; Simona Costanzo; Andrea Antinori; Nausicaa Berselli; Lorenzo Blandi; Marialaura Bonaccio; Raffaele Bruno; Roberto Cauda; Alessandro Gialluisi; Giovanni Guaraldi; Lorenzo Menicanti; Marco Mennuni; Ilaria My; Agostino Parruti; Giuseppe Patti; Stefano Perlini; Francesca Santilli; Carlo Signorelli; Giulio G Stefanini; Alessandra Vergori; Walter Ageno; Luca Aiello; Piergiuseppe Agostoni; Samir Al Moghazi; Rosa Arboretti; Filippo Aucella; Greta Barbieri; Martina Barchitta; Alessandro Bartoloni; Carolina Bologna; Paolo Bonfanti; Lucia Caiano; Laura Carrozzi; Antonio Cascio; Giacomo Castiglione; Mauro Chiarito; Arturo Ciccullo; Antonella Cingolani; Francesco Cipollone; Claudia Colomba; Crizia Colombo; Francesco Crosta; Giovanni Dalena; Chiara Dal Pra; Gian Battista Danzi; Damiano D'Ardes; Katleen de Gaetano Donati; Francesco Di Gennaro; Giuseppe Di Tano; Gianpiero D'Offizi; Tommaso Filippini; Francesco Maria Fusco; Carlo Gaudiosi; Ivan Gentile; Giancarlo Gini; Elvira Grandone; Gabriella Guarnieri; Gennaro L F Lamanna; Giovanni Larizza; Armando Leone; Veronica Lio; Angela Raffaella Losito; Gloria Maccagni; Stefano Maitan; Sandro Mancarella; Rosa Manuele; Massimo Mapelli; Riccardo Maragna; Lorenzo Marra; Giulio Maresca; Claudia Marotta; Franco Mastroianni; Maria Mazzitelli; Alessandro Mengozzi; Francesco Menichetti; Jovana Milic; Filippo Minutolo; Beatrice Molena; R Mussinelli; Cristina Mussini; Maria Musso; Anna Odone; Marco Olivieri; Emanuela Pasi; Annalisa Perroni; Francesco Petri; Biagio Pinchera; Carlo A Pivato; Venerino Poletti; Claudia Ravaglia; Marco Rossato; Marianna Rossi; Anna Sabena; Francesco Salinaro; Vincenzo Sangiovanni; Carlo Sanrocco; Laura Scorzolini; Raffaella Sgariglia; Paola Giustina Simeone; Michele Spinicci; Enrico Maria Trecarichi; Giovanni Veronesi; Roberto Vettor; Andrea Vianello; Marco Vinceti; Elena Visconti; Laura Vocciante; Raffaele De Caterina; Licia Iacoviello Journal: Front Med (Lausanne) Date: 2021-06-09