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.

Fig. 1.

Concentration-time data for the patients included in the analysis represented as topotecan lactone concentrations (ng/ml) versus time (hour). Patients with wild-type rs4148157 and variant rs4148157 are represented by gray circles and black open circles, respectively. The dashed line at 1 ng/ml represents the lower limit of quantitation for the assay.

Fig. 2.

Observed topotecan lactone concentrations versus population predicted (A) and individual predicted (B) topotecan lactone concentrations for the final topotecan lactone model. The closed circles represent data above the lower limit of quantitation, the open circles represent data below the limit of quantitation or simulated data, the solid line represents the line of identity, and the dashed gray line represents the spline of the model.

Fig. 3.

(A–D) PWRES and the individual weighted residuals (IWRES) versus time and predicted topotecan lactone concentrations. The closed circles represent data above the lower limit of quantitation, the open circles represent data below the limit of quantitation or simulated data, and the solid line is the reference line at zero.

Fig. 4.

The normalized prediction distribution errors (NPDE) plotted against time (A) and population predicted topotecan lactone concentrations (B). The closed circles represent data above the lower limit of quantitation, the open circles represent data below the limit of quantitation or simulated data, and the solid line is the reference line at zero.