Abstract
Purpose of studyOnce‐daily ritonavir‐boosted darunavir (DRV/RTV) is a preferred antiretroviral regimen for treatment‐naïve patients. Population pharmacokinetic modelling of the interaction between DRV and RTV allows evaluation of alternative dosing strategies, particularly lower RTV doses (e.g. 800/50 mg once daily) and assessment of factors that may influence DRV/RTV PK.MethodsData were pooled from 3 DRV/RTV PK studies. Fifty‐one HIV‐infected patients (7 female) stable on DRV/RTV (800/100 mg or 900/100 mg once daily; n=32 and 19, respectively) were included. Median age, weight and baseline CD4 cell count were 39 yr (21–63), 74 kg (57–105) and 500 cells/mm3 (227–1129), respectively; 49 had undetectable viral load. Nonlinear mixed effects modelling (Monolix v.4.1.2) was applied simultaneously to DRV and RTV to determine PK parameters, interindividual variability and residual error. Covariates evaluated included: age, weight, sex and study. The model was validated by simulation and visual predictive check. DRV/RTV 800/50 mg once daily was simulated.Summary of resultsRTV and DRV were described by a 1 and 2‐compartment model, respectively with first‐order absorption and lag‐time. A maximum effect model, in which RTV inhibited DRV clearance (CL/F), best described the relationship between the two drugs. A RTV concentration of 0.33 mg/L was associated with 50% maximum inhibition of DRV CL/F with the maximum inhibitory effect fixed at 1. The population CL/F of DRV in the absence of RTV was 13.7L/h. Inclusion of weight on RTV CL/F and volume and age on DRV CL/F and study on DRV CL/F, volume and absorption improved the fit. Based on visual predictive check 93% and 91% of observed RTV and DRV concentrations were within the 95% prediction interval, indicative of an adequate model. Of 1000 simulated DRV troughs, 10% and 0% were below the MEC for treatment‐experienced (<0.55 mg/L) and naïve patients (<0.055 mg/L), respectively. For DRV/RTV 800/50 mg once daily this corresponded to 14% and 0%. Median area under the curve was 17% lower with 50 mg compared to 100 mg RTV (53.5 mg.h/L vs. 64.2 mg.h/L), which is consistent with previous data [1].ConclusionsA population model describing the PK of once‐daily DRV/RTV has been developed and validated and included the influence of RTV concentration on DRV CL/F. The model allowed simulation of DRV/RTV 800/50 mg once daily; concentrations were lower but trough concentrations remained within the therapeutic range for treatment‐naïve patients.
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