title: Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.
abstract: OBJECTIVE
  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.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Arab-Alameddine
authors.affiliation: Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Lubomirov
authors.affiliation: Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Fayet-Mello
authors.affiliation: Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Aouri
authors.affiliation: Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Rotger
authors.affiliation: Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Buclin
authors.affiliation: Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Widmer
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Gatri
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Ledergerber
authors.affiliation: Clinical Chemistry, University Hospital Basel, Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Rentsch
authors.affiliation: Division of Infectious Diseases, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Cavassini
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Panchaud
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Guidi
authors.affiliation: Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Telenti
authors.affiliation: Clinical Pharmacology Laboratory, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: L A
authors.initials: LA
authors.lastname: Décosterd
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland chantal.csajka@chuv.ch.
authors.forename: C
authors.initials: C
authors.lastname: Csajka
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000069454:Darunavir; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir
keywords: NONMEM; pharmacogenetics; simulations