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Population Pharmacokinetic Modeling of the Changes in Atazanavir Plasma Clearance Caused by Ritonavir Plasma Concentrations in HIV-1 Infected Patients.

Population Pharmacokinetic Modeling of the Changes in Atazanavir Plasma Clearance Caused by Ritonavir Plasma Concentrations in HIV-1 Infected Patients.
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Moltó J, Estévez JA, Miranda C, Cedeño S, Clotet B, Valle M,


Moltó J, Estévez JA, Miranda C, Cedeño S, Clotet B, Valle M, (click to view)

Moltó J, Estévez JA, Miranda C, Cedeño S, Clotet B, Valle M,

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British journal of clinical pharmacology 2016 7 22() doi 10.1111/bcp.13072

Abstract
AIMS
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.

METHODS
Cross-sectional study 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 NONMEM and used to simulate six dosing scenarios.

RESULTS
The selected one-compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63 mg/L predicted a 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 and 0.85 mg/L favored 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).

CONCLUSIONS
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.

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