Pharmacokinetics of once-daily darunavir/ritonavir in second-line treatment in African children with HIV

Abstract

Background: Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment.

Methods: We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band.

Results: Data from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir.

Conclusions: Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

Figure 1.

Median darunavir plasma concentrations observed in the CHAPAS-4 trial, stratified by weight band and for all children together (total). DRV; darunavir.

Figure 2.

Individual pharmacokinetic parameter of darunavir stratified by weight-band groups. The solid horizontal lines indicate the geometric mean for each group. (a) Individual darunavir (DRV) area under the concentration–time curve (AUC_0–24h); the dashed line indicates the AUC_0–24h adult median (69.4 h mg/L). (b) Individual DRV maximum concentrations (C_max); the dashed line indicates the C_max adult mean (5.5 mg/L). (c) Individual DRV trough concentrations (C_trough); the upper dashed line indicates the C_trough adult mean (1.4 mg/L), the middle dotted line shows the concentration at 50% (EC₅₀) for resistant virus inhibition and the lowest dotted line the EC₅₀ of wild-type virus (0.055 mg/L). DRV, darunavir; WT, wild type.

Figure 3.

Visual predictive check of darunavir concentration versus time after dose, stratified by non-NRTI backbone. The solid and dashed lines represent the fifth, 50th and 95th percentiles of the observed data, while the shaded areas represent the model-predicted 95% confidence intervals for the same percentiles. The dots are the observed concentrations. DRV/r, darunavir/ritonavir; TAF/FTC, tenofovir alafenamide/emtricitabine; ABC/3TC, abacavir/lamivudine; ZDV/3TC, zidovudine/lamivudine.

Figure 4.

Simulated steady-state darunavir area under the curve from 0 to 24 h (AUC_0–24h), maximum concentrations (C_max) and trough concentrations (C_trough) versus weight band, with concentrations achieved after administration of the weight-based dosing used in CHAPAS-4. The box with dashed boundaries shows the WHO-recommended dosing for the weight band where it differs from CHAPAS-4. The black dashed horizontal lines (from left to right) represent the reported adult median AUC_0–24h (69.4 h mg/L), mean C_max (5.5 mg/L) and mean C_trough (1.4 mg/L), respectively. The boxes indicate the interquartile range and the whiskers the 95% range.