Abstract
For infants and very young children with brain tumors, chemotherapy after surgical resection is the main treatment due to neurological and neuroendocrine adverse effects from whole brain irradiation. Topotecan, an anticancer drug with antitumor activity against pediatric brain tumors, can be given intravenous or orally. However, high inter-patient variability in oral drug bioavailability is common in children less than 3 years. Therefore, this study aimed to determine the population pharmacokinetics of oral topotecan in infants and very young children, specifically evaluating the effects of age and ABCG2 and ABCB1 on the absorption rate constant (Ka), as well as other covariate effects on all pharmacokinetic parameters. A nonlinear mixed effects model was implemented in Monolix 4.3.2. A one-compartment model with first-order input and first-order elimination was found to adequately characterize topotecan lactone concentrations with population estimates as (mean (s.e.)); Ka = 0.61 (0.11) h-1, apparent volume of distribution (V/F) = 40.2 (7.0) L, and apparent clearance (CL/F) = 40.0 (2.9) L/h. After including body surface area on V/F and CL/F as a power model centered on the population median, the ABCG2 rs4148157 allele was found to play a significant role on Ka. Patients homozygous or heterozygous for G>A demonstrated a Ka 2-fold higher than their GG counterparts, complemented with a 2-fold higher maximal concentration as well. These results demonstrate a possible role for the ABCG2 rs4148157 allele in the pharmacokinetics of oral topotecan in infants and very young children, and warrants further investigation.
- clinical pharmacology
- drug absorption
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- HPLC
- human/clinical
- mass spectrometry/MS
- modeling and simulation
- pharmacogenetics/pharmacogenomics
- pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics