title: 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 (Ka), 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.)]; 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 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 Ka Patients homozygous or heterozygous for G>A demonstrated a Ka 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.
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Roberts
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Birg
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Tong
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Vinay M
authors.initials: VM
authors.lastname: Daryani
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Giles W
authors.initials: GW
authors.lastname: Robinson
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Amar J
authors.initials: AJ
authors.lastname: Gajjar
authors.affiliation: Department of Pharmaceutical Sciences (J.K.R., A.V.B., V.M.D., J.C.P., C.F.S.), Department of Biostatistics (T.L.), and Department of Oncology (A.B., G.W.R., A.J.G.), St. Jude Children's Research Hospital, Memphis, Tennessee Clinton.stewart@stjude.org.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000367:Age Factors; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D065569:Gastrointestinal Absorption; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019772:Topotecan / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D019772:Topotecan