title: Population pharmacokinetics of indinavir alone and in combination with ritonavir in HIV-1-infected patients.
abstract: OBJECTIVE
  The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir.
  
  
  METHODS
  HIV-1-infected patients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM).
  
  
  RESULTS
  The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h(-1) (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h(-1), respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100-400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males.
  
  
  CONCLUSIONS
  The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.
authors.affiliation: Slotervaart Hospital, Department of Pharmacy & 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: Sanjay U C
authors.initials: SU
authors.lastname: Sankatsing
authors.forename: Pieter L
authors.initials: PL
authors.lastname: Meenhorst
authors.forename: Eric C M
authors.initials: EC
authors.lastname: Van Gorp
authors.forename: Jan W
authors.initials: JW
authors.lastname: Mulder
authors.forename: Jan M
authors.initials: JM
authors.lastname: Prins
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019469:Indinavir; D019438:Ritonavir