title: Population pharmacokinetic modelling of the changes in atazanavir plasma clearance caused by ritonavir plasma concentrations in HIV-1 infected patients.
abstract: The aim of the present study was to develop a simultaneous population pharmacokinetic model for atazanavir (ATV) incorporating the effect of ritonavir (RTV) on clearance to predict ATV concentrations under different dosing regimens in HIV-1-infected patients.
  
  
  
  A Cross-sectional study was carried out in 83 HIV-1-infected adults taking ATV 400 mg or ATV 300 mg/RTV 100 mg once daily. Demographic and clinical characteristics were registered and blood samples collected to measure drug concentrations. A population pharmacokinetic model was constructed using nonlinear mixed-effects modelling and used to simulate six dosing scenarios.
  
  
  
  The selected one-compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to the RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63 mg l-1predicted an 18% decrease in ATV clearance. The percentages of patients with an end-of-dose-interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15 mg l-1and 0.85 mg l-1favoured the selection of the simulated ATV/RTV once-daily regimens (ATV 400 mg, ATV 300 mg/RTV 100 mg, ATV 300 mg/RTV 50 mg, ATV 200/RTV 100 mg) over the unboosted twice-daily regimens (ATV 300 mg, ATV 200 mg).
  
  
  
  A one-compartment simultaneous model can describe the pharmacokinetics of RTV and ATV, including the effect of RTV plasma concentrations on ATV clearance. This model is promising for predicting individuals' ATV concentrations in clinical scenarios, and supports further clinical trials of once-daily doses of ATV 300 mg/RTV 50 mg or ATV 200 mg/RTV 100 mg to confirm efficacy and safety.
authors.affiliation: 'Lluita contra la Sida' Foundation, HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.|Department de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Moltó
authors.affiliation: Pharmacokinetic/Pharmacodynamic Modeling and Simulation CIM-St Pau., Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Barcelona, Spain.|Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Estévez
authors.affiliation: 'Lluita contra la Sida' Foundation, HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.|Department de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Miranda
authors.affiliation: 'IrsiCaixa' Foundation, HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors.forename: Samandhy
authors.initials: S
authors.lastname: Cedeño
authors.affiliation: 'Lluita contra la Sida' Foundation, HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.|Department de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.|'IrsiCaixa' Foundation, HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Pharmacokinetic/Pharmacodynamic Modeling and Simulation CIM-St Pau., Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Barcelona, Spain.|Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Valle
mesh_terms: D000328:Adult; D000368:Aged; D000069446:Atazanavir Sulfate / Q000097:blood* / Q000627:therapeutic use; D003198:Computer Simulation; D003430:Cross-Sectional Studies; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000627:therapeutic use; D015497:HIV-1; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests
chemical_list: D017320:HIV Protease Inhibitors; D000069446:Atazanavir Sulfate
keywords: HIV-1-infected patients; atazanavir; dose reduction; interaction; population pharmacokinetics; ritonavir