Population Pharmacokinetics of Oral Topotecan in Infants and Very Young Children with Brain Tumors Demonstrates a Role of ABCG2 rs4148157 on the Absorption Rate Constant

Abstract

For infants and very young children with brain tumors, chemotherapy after surgical resection is the main treatment due to neurologic 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 interpatient variability in oral drug bioavailability is common in children less than 3 years old. 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 (K a ), as well as other covariate effects on all pharmacokinetic parameters. A nonlinear mixed effects model was implemented in Monolix 4.3.2 (Lixoft, Orsay, France). 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.)]; K a = 0.61 (0.11) h 21, apparent volume of distribution (V/F) = 40.2 (7.0) l, and apparent clearance (CL/F) = 40.0 (2.9) l/h. After including the body surface area in the 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 in the value of K a . Patients homozygous or heterozygous for G>A demonstrated a K a value 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.

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

“…16) However, both of them are commonly administered intravenously due to their low oral bioavailabilities and dose limiting toxicity. 17,18) Various strategies have been explored to improve the oral bioavailability and alleviate the side-effect of CPT derivatives, which can be mainly divided into two classes of ways: structural modification and nanomedicines. 19) Structural modification is a strategy of introducing different groups on the CPT molecule by chemical bonding.…”

Pharmacokinetics and population pharmacokinetics in pediatric oncology

“…studied the PopPK of oral topotecan in infants and young children focusing on the effects of age and drug efflux transporters on absorption. Polymorphism of the efflux transporter ABCG2 showed to have a significant effect on absorption, resulting in an almost twofold difference in maximum concentration . PK analysis provides a useful tool in studying these effects and make better predictions.…”

Pheophorbide A: Fluorescent Bcrp Substrate to Measure Oral Drug-Drug Interactions in Real-Time In Vivo

“…The xenobiotic efflux transporter breast cancer resistance protein (BCRP), encoded by ABCG2, is well characterized for its effect on the pharmacokinetics and pharmacodynamics of multiple drugs (Schwabedissen and Kroemer, 2011). Intestinal BCRP/ABCG2 has a significant effect limiting the oral bioavailability of its substrates (Roberts et al, 2016), which include drugs such as the nucleoside reverse-transcriptase inhibitor antiretroviral drugs, calcium channel blockers, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, and topoisomerase I inhibitors, but also includes endogenous dietary substances such as the chlorophyll metabolite pheophorbide A (PhA) (Krishnamurthy and Schuetz, 2006;Robey et al, 2009;Schwabedissen and Kroemer, 2011). Moreover, multiple clinically used drugs, such as the tyrosine kinase inhibitor lapatinib (LPB), HIV protease inhibitor ritonavir, proton pump inhibitor pantoprazole (PPZ), as well as the dietary constituent curcumin (CCM), are known inhibitors of this transporter (Mao and Unadkat, 2015).…”