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Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1.

ABSTRACT: The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex.Sirolimus concentration-time data were collected from an ongoing prospective trial in children with NF1. An iterative 2-stage Bayesian method was used for the PK parameter analyses.Data from 44 patients with NF1 were included in the analyses. Mean age was 8.4 years (SD 4.5, range 3-18), and mean weight was 29.8 kg (SD 16.7, range 12-85.8). Mean sirolimus clearance was 11.8 L/h (SD 4.6, range 2.2-24.1), and the mean dose to obtain a target trough concentration of 10-15 ng/mL was 2.0 mg/m administered twice daily (SD 0.72, range 0.77-3.85). A nonlinear relationship between age and clearance was observed. Total body weight and BSA were strong predictors of sirolimus clearance (r = 0.67 and 0.65, respectively).Sirolimus clearance in children with NF1 is comparable with that in pediatric transplant patients. Clearance was most associated with body size parameters (BSA and total body weight) in children with NF1. When normalized for size, an age effect on clearance was observed in the youngest patients, most likely because of the maturational changes in drug absorption and metabolism. A mean dose of 2.0 mg/m twice a day was required for attainment of target trough concentrations of 10-15 ng/mL in children greater than 3 years of age who have NF1. The updated model will allow PK-guided individualized dosing of sirolimus in patients with NF1.

SUBMITTER: Scott JR

PROVIDER: S-EPMC3660960 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1.

Scott Jeffrey R JR Courter Joshua D JD Saldaña Shannon N SN Widemann Brigitte C BC Fisher Michael M Weiss Brian B Perentesis John J Vinks Alexander A AA

Therapeutic drug monitoring 20130601 3

<h4>Purpose</h4>The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of tr ...[more]

PMID: 23666574

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Project description:Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day(-1), respectively. Covariate model building conducted using forward addition (P < 0.05) followed by backward elimination (P < 0.001) yielded two significant covariate-parameter relationships, i.e., age on V2/F and formulation on Ka. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and NCT00541385, NCT00403260, NCT00422084, and NCT00440999 [phase III studies]. The most recent phase III study was registered at pactr.org under registration no. PACTR201105000286876.).

Dataset Information

Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1.

Publications

Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1.

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