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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

Random effects for (a) CLint/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. CLint/F, population estimate of apparent intrinsic clearance; Q/F, intercompartmental clearance; KA, first-order absorption rate constant.
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fig02: Random effects for (a) CLint/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. CLint/F, population estimate of apparent intrinsic clearance; Q/F, intercompartmental clearance; KA, first-order absorption rate constant.

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)

Random effects for (a) CLint/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. CLint/F, population estimate of apparent intrinsic clearance; Q/F, intercompartmental clearance; KA, first-order absorption rate constant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Random effects for (a) CLint/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. CLint/F, population estimate of apparent intrinsic clearance; Q/F, intercompartmental clearance; KA, first-order absorption rate constant.
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