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Population pharmacokinetics of prednisolone in children with acute lymphoblastic leukemia
Kamilla B Petersen1, William J Jusko, Mette Rasmussen
1Department of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
Insights
This study found that prednisolone has complete oral bioavailability in children with acute lymphoblastic leukemia (ALL). Body surface area dosing ensures consistent systemic exposure, with lower clearance and longer half-life than previously reported.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Clinical Pharmacokinetics
Background:
- Prednisolone is a crucial corticosteroid in treating acute lymphoblastic leukemia (ALL) in children.
- Understanding its pharmacokinetics and protein binding is vital for optimizing therapeutic outcomes.
- Previous studies have indicated variability in prednisolone disposition in this population.
Purpose of the Study:
- To evaluate plasma protein binding and pharmacokinetics of prednisolone in pediatric ALL patients.
- To utilize a population approach for a comprehensive pharmacokinetic analysis.
- To assess the impact of therapeutic use on prednisolone disposition.
Main Methods:
- Employed a two-compartment pharmacokinetic model for 23 children with ALL (aged 2-15 years).
- Administered prednisolone orally and intravenously, collecting samples over 5 weeks of remission induction.
- Utilized nonlinear mixed-effects modeling to analyze unbound plasma concentrations and estimate pharmacokinetic and protein binding parameters.
Main Results:
- Prednisolone demonstrated complete oral bioavailability with lower unbound clearance and a longer half-life than previously reported in pediatric ALL.
- Body weight significantly influenced distribution volumes, while body surface area effectively reduced clearance variability.
- Plasma protein binding was found to be independent of albumin concentration, showing minimal inter- and intraindividual variation.
Conclusions:
- Prednisolone exhibits complete oral bioavailability in pediatric ALL, with pharmacokinetic parameters supporting consistent systemic exposure.
- Body surface area-based dosing is recommended for achieving uniform therapeutic effects among patients.
- The observed lower clearance and longer half-life necessitate consideration in treatment protocols for pediatric ALL.
Purpose:
To evaluate the plasma protein binding and pharmacokinetics of prednisolone during therapeutic use in children with acute lymphoblastic leukemia (ALL) using the population approach.
Methods:
A two-compartment pharmacokinetic model was used to describe data from 23 children with ALL (aged 2-15 years). Prednisolone (60 mg/m(2) per day in three divided doses) was administered both orally and intravenously, and samples were obtained on several days during the initial 5 weeks of remission induction therapy. Unbound plasma concentrations ( n=288) were determined by HPLC and ultrafiltration. Nonlinear mixed-effects modeling (WinNonMix version 2.0.1) was used to estimate the pharmacokinetic parameters, to identify significant covariates, and to estimate the protein binding parameters.
Results:
Prednisolone showed complete oral bioavailability. The median unbound clearance (32 l/h per m(2)) was lower, and the half-life (3.6 h) longer than previously reported in childhood ALL. Body weight was a significant covariate for the central and peripheral volumes of distribution resulting in interindividual variabilities of 50% and 42%. Including body surface area as a covariate for clearance decreased the interindividual variability to 14%. The estimated areas under the unbound plasma concentration-time curves showed less than twofold variation among patients, and a residual variability of 20% indicated that the pharmacokinetic parameters remained stable during induction therapy. The estimated protein binding parameters were comparable to, but slightly lower than, previously published values and independent of the albumin concentration.
Conclusions:
The study showed complete oral bioavailability, a lower unbound clearance and a longer half-life for prednisolone than previously reported in childhood ALL. Plasma protein binding was independent of the albumin concentration. Due to the small inter- and intraindividual variations in the pharmacokinetic parameters, body surface area-based dosing is sufficient to obtain similar systemic exposure among patients.
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