Simultaneous population pharmacokinetic modelling of atazanavir and ritonavir in HIV-infected adults and assessment of different dose reduction strategies

J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):60-6. doi: 10.1097/QAI.0b013e3182737231.


Objectives: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / pharmacokinetics*
  • Atazanavir Sulfate
  • Female
  • HIV Infections / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Models, Statistical
  • Oligopeptides / administration & dosage*
  • Oligopeptides / pharmacokinetics*
  • Plasma / chemistry
  • Pyridines / administration & dosage*
  • Pyridines / pharmacokinetics*
  • Ritonavir / administration & dosage*
  • Ritonavir / pharmacokinetics*
  • Young Adult


  • Anti-HIV Agents
  • Oligopeptides
  • Pyridines
  • Atazanavir Sulfate
  • Ritonavir