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

Brochot A, Kakuda TN, Van De Casteele T, Opsomer M, Tomaka FL, Vermeulen A, Vis P - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research & Development Beerse, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig01: 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.

Mentions: There were minimal differences between the observed and expected trend of the data, with no noticeable structural bias (Figure1). Distributions for individual estimates for the random effects of CLint/F, Q/F, and KA are shown in Figure2. Minimal shrinkage was detected for CLint/F, while shrinkage was more substantial for population estimates of Q/F and KA. This shrinkage was likely due to Q/F and KA being estimated at steady-state, which yields little information on these parameters. However, this had no impact on the exposure simulations and therefore the model was fit for purpose.


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

Brochot A, Kakuda TN, Van De Casteele T, Opsomer M, Tomaka FL, Vermeulen A, Vis P - CPT Pharmacometrics Syst Pharmacol (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544054&req=5

fig01: 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.
Mentions: There were minimal differences between the observed and expected trend of the data, with no noticeable structural bias (Figure1). Distributions for individual estimates for the random effects of CLint/F, Q/F, and KA are shown in Figure2. Minimal shrinkage was detected for CLint/F, while shrinkage was more substantial for population estimates of Q/F and KA. This shrinkage was likely due to Q/F and KA being estimated at steady-state, which yields little information on these parameters. However, this had no impact on the exposure simulations and therefore the model was fit for purpose.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research & Development Beerse, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus