Model-Based Once-Daily Darunavir/Ritonavir Dosing Recommendations in Pediatric HIV-1-Infected Patients Aged ≥3 to <12 Years

Abstract

An existing population pharmacokinetic model of darunavir in adults was updated using pediatric data from two studies evaluating weight-based, once-daily dosing of darunavir/ritonavir (ARIEL, NCT00919854 and DIONE, NCT00915655). The model was then used to provide once-daily dosing recommendations for darunavir/ritonavir in pediatric patients aged ≥3 to <12 years. The final model comprised two compartments with first-order absorption and apparent clearance dependent on the concentration of α1-acid glycoprotein. The recommended darunavir/ritonavir once-daily dosing regimens in children aged ≥3 to <12 years are: 35/7 mg/kg from 10 to <15 kg, 600/100 mg from 15 to <30 kg, 675/100 mg from 30 to <40 kg, and 800/100 mg for ≥40 kg. These doses should result in exposures similar to the adult exposure after treatment with darunavir/ritonavir 800/100 mg once daily, while minimizing pill burden and allowing a switch from suspension to tablet(s) as early as possible.

Figure 1

Basic goodness-of-fit plots for the model adjustment. (a) Observed vs. population prediction; (b) observed vs. individual prediction; (c) conditional weighted residuals vs. population prediction; (d) conditional weighted residuals vs. time after dose. Black dots represent adult DUET data, red dots DELPHI data, green dots ARIEL data, blue dots ARIEL QD substudy data, and pink dots DIONE data. Opacity is applied so that if points overlap, the overlapping area is darker.

Figure 2

Random effects for (a) CL_int/F, (b) Q/F, and (c) KA. The blue line represents the expected individual parameter distribution, and the red line the density line of the observed individual parameter distributions. CL_int/F, population estimate of apparent intrinsic clearance; Q/F, intercompartmental clearance; KA, first-order absorption rate constant.

Figure 3

Visual predictive checks of CL/F vs. (a) α₁-acid glycoprotein concentration (AAG); (b) bodyweight; (c) total daily darunavir dose; and (d) age. The dots represent the observed parameters determined by a noncompartmental analysis, the black lines represent the 5^th, 50^th (median), and 95^th percentile (with smoothing applied) of the parameters based on simulated values. Black dots represent adult DUET data, red dots DELPHI data, green dots ARIEL data, blue dots ARIEL QD substudy data, and pink dots DIONE data.

Figure 4

Expected darunavir exposures in children aged ≥3 to <18 years, weighing 10 to 65 kg at selected once-daily darunavir/ ritonavir regimens, given for the 5th, 50th (median), and 95th percentile of AAG concentrations, and compared to 80%, 100%, and 130% of the target exposure in adults (89.7 µg·h/ml, blue lines).