Catalina Barceló1, Frédéric Gaspar2, Manel Aouri1, Alice Panchaud2, Margalida Rotger3, Monia Guidi4, Matthias Cavassini5, Thierry Buclin1, Laurent A Decosterd6, Chantal Csajka7. 1. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland. 2. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. 3. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland Institute of Microbiology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland. 4. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. 5. Service of Infectious Diseases, University Hospital Centre and University of Lausanne, Lausanne, Switzerland. 6. Innovation & Development, Laboratory of Clinical Pharmacology, Service of Biomedicine, University Hospital Centre and University of Lausanne, Lausanne, Switzerland. 7. Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland chantal.csajka@chuv.ch.
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.
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.
Authors: Jeremiah D Momper; Brookie M Best; Jiajia Wang; Edmund V Capparelli; Alice Stek; Emily Barr; Martina L Badell; Edward P Acosta; Murli Purswani; Elizabeth Smith; Nahida Chakhtoura; Kyunghun Park; Sandra Burchett; David E Shapiro; Mark Mirochnick Journal: AIDS Date: 2018-11-13 Impact factor: 4.177
Authors: Marianne Harris; Bruce Ganase; Birgit Watson; P Richard Harrigan; Julio S G Montaner; Mark W Hull Journal: AIDS Res Ther Date: 2017-11-02 Impact factor: 2.250