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Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals

Barceló, Catalina ; Gaspar, Frédéric ; Aouri, Manel ; Panchaud, Alice ; Rotger, Margalida ; Guidi, Monia ; Cavassini, Matthias ; Buclin, Thierry ; Decosterd, Laurent A. ; Csajka, Chantal ; Aubert, V. ; Battegay, M. ; Bernasconi, E. ; Böni, J. ; Braun, DL ; Bucher, HC ; Burton-Jeangros, C. ; Calmy, A. ; Cavassini, M. ; Dollenmaier, G. ; Egger, M. ; Elzi, L. ; Fehr, J. ; Fellay, J. ; Furrer, H. ; Fux, CA ; Gorgievski, M. ; Günthard, H. ; Haerry, D. ; Hasse, B. ; Hirsch, HH ; Hoffmann, M. ; Hösli, I. ; Kahlert, C. ; Kaiser, L. ; Keiser, O. ; Klimkait, T. ; Kouyos, R. ; Kovari, H. ; Ledergerber, B. ; Martinetti, G. ; Martinez de Tejada, B. ; Marzolini, C. ; Metzner, K. ; Müller, N. ; Nadal, D. ; Nicca, D. ; Pantaleo, G. ; Rauch, A. ; Regenass, S. ; Rudin, C. ; Schöni-Affolter, F. ; Schmid, P. ; Speck, R. ; Stöckle, M. ; Tarr, P. ; Trkola, A. ; Vernazza, P. ; Weber, R. ; Yerly, S. ; Aubert, V. ; Battegay, M. ; Bernasconi, E. ; Böni, J. ; Braun, DL ; Bucher, HC ; Burton-Jeangros, C. ; Calmy, A. ; Cavassini, M. ; Dollenmaier, G. ; Egger, M. ; Elzi, L. ; Fehr, J. ; Fellay, J. ; Furrer, H. ; Fux, CA ; Gorgievski, M. ; Günthard, H. ; Haerry, D. ; Hasse, B. ; Hirsch, HH ; Hoffmann, M. ; Hösli, I. ; Kahlert, C. ; Kaiser, L. ; Keiser, O. ; Klimkait, T. ; Kouyos, R. ; Kovari, H. ; Ledergerber, B. ; Martinetti, G. ; Martinez de Tejada, B. ; Marzolini, C. ; Metzner, K. ; Müller, N. ; Nadal, D. ; Nicca, D. ; Pantaleo, G. ; Rauch, A. ; Regenass, S. ; Rudin, C. ; Schöni-Affolter, F. ; Schmid, P. ; Speck, R. ; Stöckle, M. ; Tarr, P. ; Trkola, A. ; Vernazza, P. ; Weber, R. ; Yerly, S.

In: Journal of Antimicrobial Chemotherapy, 2016, vol. 71, no. 7, p. 1933-1942

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    Titre
    • Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals
    Auteur
    • Barceló, Catalina. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Gaspar, Frédéric. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
    • Aouri, Manel. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Panchaud, Alice. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
    • Rotger, Margalida. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Guidi, Monia. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Cavassini, Matthias. Service of Infectious Diseases, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Buclin, Thierry. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Decosterd, Laurent A.. Innovation & Development, Laboratory of Clinical Pharmacology, Service of Biomedicine, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Csajka, Chantal. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Aubert, V.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Battegay, M.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Bernasconi, E.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Böni, J.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Braun, DL. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Bucher, HC. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Burton-Jeangros, C.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Calmy, A.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Cavassini, M.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Dollenmaier, G.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Egger, M.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Elzi, L.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Fehr, J.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Fellay, J.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Furrer, H.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Fux, CA. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Gorgievski, M.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Günthard, H.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Haerry, D.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Hasse, B.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Hirsch, HH. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Hoffmann, M.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Hösli, I.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Kahlert, C.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Kaiser, L.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Keiser, O.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Klimkait, T.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Kouyos, R.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Kovari, H.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Ledergerber, B.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Martinetti, G.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Martinez de Tejada, B.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Marzolini, C.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Metzner, K.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Müller, N.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Nadal, D.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Nicca, D.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Pantaleo, G.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Rauch, A.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Regenass, S.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Rudin, C.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Schöni-Affolter, F.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Schmid, P.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Speck, R.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Stöckle, M.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Tarr, P.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Trkola, A.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Vernazza, P.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Weber, R.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Yerly, S.. 1 Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland
    • Aubert, V.
    • Battegay, M.
    • Bernasconi, E.
    • Böni, J.
    • Braun, DL
    • Bucher, HC
    • Burton-Jeangros, C.
    • Calmy, A.
    • Cavassini, M.
    • Dollenmaier, G.
    • Egger, M.
    • Elzi, L.
    • Fehr, J.
    • Fellay, J.
    • Furrer, H.
    • Fux, CA
    • Gorgievski, M.
    • Günthard, H.
    • Haerry, D.
    • Hasse, B.
    • Hirsch, HH
    • Hoffmann, M.
    • Hösli, I.
    • Kahlert, C.
    • Kaiser, L.
    • Keiser, O.
    • Klimkait, T.
    • Kouyos, R.
    • Kovari, H.
    • Ledergerber, B.
    • Martinetti, G.
    • Martinez de Tejada, B.
    • Marzolini, C.
    • Metzner, K.
    • Müller, N.
    • Nadal, D.
    • Nicca, D.
    • Pantaleo, G.
    • Rauch, A.
    • Regenass, S.
    • Rudin, C.
    • Schöni-Affolter, F.
    • Schmid, P.
    • Speck, R.
    • Stöckle, M.
    • Tarr, P.
    • Trkola, A.
    • Vernazza, P.
    • Weber, R.
    • Yerly, S.
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Journal of Antimicrobial Chemotherapy, 2016, vol. 71, no. 7, p. 1933-1942. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:331084
    Summary
    Abstract Objectives Co-formulated elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine is among the preferred regimens for first-line ART. A population approach was used to characterize the pharmacokinetics of elvitegravir and cobicistat and identify individual factors and co-medications influencing their disposition, taking into consideration the interaction between the two compounds. Methods The study population included 144 HIV-infected individuals who provided 186 and 167 elvitegravir and cobicistat plasma concentrations, respectively. First, distinct NONMEM® analyses were conducted for elvitegravir and cobicistat, including individual demographic, clinical and genetic factors as potential covariates. Elvitegravir and cobicistat interaction was then assessed through different inhibitory models. Simulations based on the final model served to compare expected drug concentrations under standard and alternative dosage regimens. Results Clearance with between-subject variability was 7.6 L/h [coefficient of variation (CV) 16.6%] and volume of distribution 61 L for elvitegravir and 16.0 L/h (CV 41.9%) and 88.3 L, respectively, for cobicistat. Concomitant administration of non-ritonavir-boosted atazanavir decreased elvitegravir clearance by 35%, likely due to UDP-glucuronosyl transferase (UGT) 1A1 inhibition. Concomitant administration of non-ritonavir-boosted atazanavir and ritonavir-boosted darunavir decreased cobicistat clearance by 47% and 27%, respectively. The final interaction model included cobicistat exposure (AUC0-24) on elvitegravir clearance. Simulations confirmed that a reduced elvitegravir dose of 85 mg co-administered with cobicistat and atazanavir produces a concentration-time course comparable to the standard regimen without atazanavir. Conclusions Elvitegravir and cobicistat pharmacokinetic variability appears to be mainly explained by drug-drug interactions that may be encountered in routine clinical practice. In these cases, therapeutic drug monitoring and surveillance for potential toxicities would be justified.