title: Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients.
abstract: OBJECTIVE
  The aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics.
  
  
  METHODS
  Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir-containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero-order and first-order absorption, with and without absorption lag-time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored.
  
  
  RESULTS
  From 186 patients 505 ritonavir plasma concentrations at a single time-point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one-compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h(-1) (95% prediction interval (95% PI) 9.38-11.7), 96.6 l (95% PI 67.2-121) and 0.871 h(-1) (95% PI 0.429-1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7-fold increase in the clearance of ritonavir (P value < 0.001). No patients characteristics influenced the pharmacokinetics of ritonavir.
  
  
  CONCLUSIONS
  The pharmacokinetic parameters of ritonavir were adequately described by our population pharmacokinetic model. Concomitant use of the protease inhibitor lopinavir strongly influenced the pharmacokinetics of ritonavir. The model has been validated and can be used for further investigation of the interaction between ritonavir and other protease inhibitors.
authors.affiliation: Slotervaart Hospital, Department of Pharmacy and Pharmacology, Amsterdam, the Netherlands. apbkp@slz.nl
authors.forename: Bregt S
authors.initials: BS
authors.lastname: Kappelhoff
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Kristel M L
authors.initials: KM
authors.lastname: Crommentuyn
authors.forename: Jan W
authors.initials: JW
authors.lastname: Mulder
authors.forename: Pieter L
authors.initials: PL
authors.lastname: Meenhorst
authors.forename: Eric C M
authors.initials: EC
authors.lastname: van Gorp
authors.forename: Albert T A
authors.initials: AT
authors.lastname: Mairuhu
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D019438:Ritonavir / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019438:Ritonavir