title: Simultaneous population pharmacokinetic modelling of atazanavir and ritonavir in HIV-infected adults and assessment of different dose reduction strategies.
abstract: OBJECTIVE
  The objective of this study was to develop a simultaneous population pharmacokinetic (PK) model to describe atazanavir/ritonavir (ATV/RTV) PK (300/100 mg) and to assess the effect of RTV dose reduction on ATV PK. Simulations of ATV concentration-time profiles were performed at doses of ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily.
  
  
  METHODS
  A total of 288 ATV and 312 RTV plasma concentrations from 30 patients were included to build a population PK model using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.2 software.
  
  
  RESULTS
  A one-compartment model with first-order absorption and lag-time best described the data for both drugs in the final simultaneous model. A maximum-effect model in which RTV inhibited the elimination of ATV was used to describe the relationship between RTV concentrations and ATV clearance (CL/F). An RTV concentration of 0.22 mg/L was associated with 50% maximum inhibition of ATV CL/F. The population prediction of ATV CL/F in the absence of RTV was 16.6 L/h (relative standard error, 7.0%), and the apparent volume of distribution and absorption rate constant were 106 L (relative standard error, 8%) and 0.87 per hour (fixed), respectively. Simulated average ATV trough concentrations at ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily were 45%, 63%, and 33% lower, respectively, than that of the standard dose.
  
  
  CONCLUSIONS
  Although simulated median ATV trough concentrations after dose reductions were still more than the ATV minimum effective concentration (2.9-, 1.9-, and 3.6-fold for ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg, respectively); our modeling predicted a high proportion of individuals with subtherapeutic trough concentrations on the 200/50 mg dose. This suggests that 300/50 mg and 200/100 mg dosing are preferred candidate regimens in future clinical studies.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom. a.schipani@liv.ac.uk
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.forename: Laura
authors.initials: L
authors.lastname: Dickinson
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.forename: Rupert
authors.initials: R
authors.lastname: Austin
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.forename: Gerry
authors.initials: G
authors.lastname: Davies
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir