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Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals

Arab-Alameddine, M. ; Lubomirov, R. ; Fayet-Mello, A. ; Aouri, M. ; Rotger, M. ; Buclin, T. ; Widmer, N. ; Gatri, M. ; Ledergerber, B. ; Rentsch, K. ; Cavassini, M. ; Panchaud, A. ; Guidi, M. ; Telenti, A. ; Décosterd, L. A. ; Csajka, C. ; Battegay, M. ; Bernasconi, E. ; Böni, J. ; Bucher, H. C. ; Bürgisser, P. ; Calmy, A. ; Cattacin, S. ; Cavassini, M. ; Dubs, R. ; Egger, M. ; Elzi, L. ; Fischer, M. ; Flepp, M. ; Fontana, A. ; Francioli, P. ; Furrer, H. ; Fux, C. A. ; Gorgievski, M. ; Günthard, H. ; Hirsch, H. H. ; Hirschel, B. ; Hösli, I. ; Kahlert, C. ; Kaiser, L. ; Karrer, U. ; Kind, C. ; Klimkait, T. ; Ledergerber, B. ; Martinetti, G. ; Müller, N. ; Nadal, D. ; Paccaud, F. ; Pantaleo, G. ; Rauch, A. ; Regenass, S. ; Rickenbach, M. ; Rudin, C. ; Schmid, P. ; Schultze, D. ; Schüpbach, J. ; Speck, R. ; de Tejada, B. M. ; Taffé, P. ; Telenti, A. ; Trkola, A. ; Vernazza, P. ; Weber, R. ; Yerly, S.

In: Journal of Antimicrobial Chemotherapy, 2014, vol. 69, no. 9, p. 2489-2498

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    Title
    • Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals
    Author
    • Arab-Alameddine, M.. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
    • Lubomirov, R.. Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Fayet-Mello, A.. Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Aouri, M.. Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Rotger, M.. Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Buclin, T.. Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Widmer, N.. Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Gatri, M.. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
    • Ledergerber, B.. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
    • Rentsch, K.. Clinical Chemistry, University Hospital Basel, Basel, Switzerland
    • Cavassini, M.. Division of Infectious Diseases, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Panchaud, A.. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
    • Guidi, M.. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
    • Telenti, A.. Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Décosterd, L. A.. Clinical Pharmacology Laboratory, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Csajka, C.. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
    • Battegay, M.
    • Bernasconi, E.
    • Böni, J.
    • Bucher, H. C.
    • Bürgisser, P.
    • Calmy, A.
    • Cattacin, S.
    • Cavassini, M.
    • Dubs, R.
    • Egger, M.
    • Elzi, L.
    • Fischer, M.
    • Flepp, M.
    • Fontana, A.
    • Francioli, P.
    • Furrer, H.
    • Fux, C. A.
    • Gorgievski, M.
    • Günthard, H.
    • Hirsch, H. H.
    • Hirschel, B.
    • Hösli, I.
    • Kahlert, C.
    • Kaiser, L.
    • Karrer, U.
    • Kind, C.
    • Klimkait, T.
    • Ledergerber, B.
    • Martinetti, G.
    • Müller, N.
    • Nadal, D.
    • Paccaud, F.
    • Pantaleo, G.
    • Rauch, A.
    • Regenass, S.
    • Rickenbach, M.
    • Rudin, C.
    • Schmid, P.
    • Schultze, D.
    • Schüpbach, J.
    • Speck, R.
    • de Tejada, B. M.
    • Taffé, P.
    • Telenti, A.
    • Trkola, A.
    • Vernazza, P.
    • Weber, R.
    • Yerly, S.
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Journal of Antimicrobial Chemotherapy, 2014, vol. 69, no. 9, p. 2489-2498. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:296214
    Summary
    Objectives Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. Methods The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM®). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. Results A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. Conclusions The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed