title: Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland.
authors.forename: Catalina
authors.initials: C
authors.lastname: Barceló
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gaspar
authors.affiliation: Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland.
authors.forename: Manel
authors.initials: M
authors.lastname: Aouri
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Alice
authors.initials: A
authors.lastname: Panchaud
authors.affiliation: 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.
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.affiliation: 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.
authors.forename: Monia
authors.initials: M
authors.lastname: Guidi
authors.affiliation: Service of Infectious Diseases, University Hospital Centre and University of Lausanne, Lausanne, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.affiliation: Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.affiliation: Innovation & Development, Laboratory of Clinical Pharmacology, Service of Biomedicine, University Hospital Centre and University of Lausanne, Lausanne, Switzerland.
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
authors.affiliation: 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.
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000069547:Cobicistat / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003198:Computer Simulation; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D015363:Quinolones; C509700:elvitegravir; D000069547:Cobicistat