Extrapolation of PK of selected dose to pediatric ALL: Monte Carlo simulations in paediatric acute leukaemia patients using literature model
The PK established in healthy adults may not always reflect the PK profile in pediatrics with ALL. Thus, to confirm safe exposures of the 6MP test formulation in pediatrics, a simulation of 6MP and its metabolite exposures in children was performed by incorporating the formulation specific parameters derived from the healthy volunteer study and the available literature model. A literature search was performed using the search strategy; Mercaptopurine [MeSH] OR Mercaptopurine [tiab] OR ”6-mercaptopurine” [tiab] AND Leukemia [MeSH] OR Leukemia [tiab] OR ”Acute lymphoblastic leukaemia” [tiab] AND Pharmacokinetics [MeSH] OR Pharmacokinetic* [tiab] OR ”Population pharmacokinetic*”[tiab] AND Pediatrics [MeSH] OR Pediatric* [tiab] OR Children [tiab]in ‘PubMed’. Similar search was carried out on ‘Embase’, ‘Web of Science’ and ‘Google Scholar’ databases. The studies published in English before November 2022 that reported the PK of 6MP in paediatric patients with ALL were considered satisfactory. One population pharmacokinetic model for 6MP and its metabolites in pediatrics that evaluated the PopPK in 19 children with ALL with 150 plasma concentrations was identified and used for carrying out the simulations [12].
Monte Carlo simulation of 6MP and 6 thioguanine (6TGN) exposures in children was performed with a fixed absorption rate constant from the dissolution compartment of the developed Poppk model. The model was parameterised using allometrically scaled apparent clearance and weight normalized apparent volume of distribution derived from the non-compartmental analysis. Other relevant model parameters for the formation of 6TGN were used from the literature as the changes in 6MP concentrations after the introduction of the test drug disposition parameters shall ultimately reflect in the metabolite levels. The body weight for allometric scaling and the height for calculating the body surface area were randomly generated from the CDC growth charts. The BSA corresponding to the body weight and height of an individual that was included by the author as a covariate for 6TGN clearance was calculated using the Dubois formula. A per m2 dosing equivalent to the standard 6MP dose of 50mg/m2 that is routinely initiated in pediatrics which happened to be close to the median doses of the identified pharmacokinetic studies was scaled down as per the previous model recommendation on dose reduction and used for the simulations. TPMT mutation that was included in the literature model was not included as the adult study excluded TPMT polymorphism and the relatively rare incidence of it [13]. Pumas® version 2.0 (Maryland, USA) was used to perform the simulations for 100 paediatric patients aged between 2-18 years of age with the body weight and height randomly sampled from the CDC growth charts, using the parameters (Supplementary table1). The interindividual variability of 40% was used for the parameters obtained from the healthy volunteer study due to the expectation of high variability in the clinical context and 33% for 6TGN clearance that was reported in the literature study. 6-TGN exposures were simulated for 30 days and the recommended dose was verified and considered optimal based on the attainment of concentrations within similar ranges published in the literature.