Pharmacokinetics of darunavir at 900 milligrams and ritonavir at 100 milligrams once daily when coadministered with efavirenz at 600 milligrams once daily in healthy volunteers

Abstract

Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC(50)) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC(0-24) (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC(0-24) when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC(50) for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

Figures

FIG. 1.

Schematic of the dosing regimen and the times of collection of samples for pharmacokinetic (PK) analysis.

FIG. 2.

(A) Arithmetic mean darunavir (DRV) plasma concentrations at steady state after the administration of 900 mg darunavir with 100 mg ritonavir (RTV) once daily with or without 2 weeks of treatment with 600 mg efavirenz (EFV) once daily in healthy male and female subjects (inset, semilogarithmic scale). The EC50 of 55 ng/ml is indicated by the dashed line. (B) Individual darunavir 24-h trough concentrations before and after efavirenz treatment.

FIG. 3.

Arithmetic mean plasma ritonavir concentrations at steady state after the administration of 100 mg ritonavir once daily with 900 mg darunavir with or without 2 weeks of treatment with 600 mg efavirenz once daily in healthy male and female subjects (inset, semilogarithmic scale).

FIG. 4.

Arithmetic mean plasma efavirenz concentrations at steady state after the administration of 600 mg of efavirenz with or without 2 weeks of treatment with 900 mg darunavir once daily and 100 mg ritonavir once daily in healthy male and female subjects (inset, semilogarithmic scale). The therapeutic range of 1,000 to 4,000 ng/ml is indicated by the dashed lines.