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.