Evaluation of Extrapolation Methods to Predict Trough Concentrations to Guide Therapeutic Drug Monitoring of Oral Anticancer Drugs

Background:For oral anticancer drugs, trough concentration (C_min) is usually used as a target in therapeutic drug monitoring (TDM). Recording of C_minis highly challenging in outpatients, in whom there is typically a variability in sample collection time after dosing. Various methods are used to estimate C_minfrom the collected samples. This simulation study aimed to evaluate the performance of 3 different methods in estimating the C_minof 4 oral anticancer drugs for which TDM is regularly performed.Methods:Plasma concentrations of abiraterone, dabrafenib, imatinib, and pazopanib at a random time (C_t,sim) and at the end of the dosing interval (C_min,sim) were simulated from population pharmacokinetic models including 1000 patients, and the values were converted into simulated observed concentrations (C_t,sim,obsand C_min,sim,obs) by adding a residual error. From C_{t, sim,obs}, C_minwas predicted (C_min,pred) by the Bayesian estimation (method 1), taking the ratio of the C_t,sim,obsand typical population concentration and multiplying this ratio with the typical population value of C_min,sim(method 2), and log-linear extrapolation (method 3). Target attainment was assessed by comparing C_min,predwith the proposed pharmacokinetic targets related to efficacy and calculating the positive predictive and negative predictive values.Results:The mean relative prediction error and root mean squared relative prediction error results showed that method 3 was out-performed by method 1 and 2. Target attainment was adequately predicted by all 3 methods (the respective positive predictive value of method 1, 2, and 3 was 92.1%, 92.5%, and 93.1% for abiraterone; 87.3%, 86.9%, and 99.1% for dabrafenib; 79.3%, 79.3%, and 75.9% for imatinib; and 72.5%, 73.5%, and 67.6% for pazopanib), indicating that dose adjustments were correctly predicted.Conclusions:Both method 1 and 2 provided accurate and precise individual C_min,predvalues. However, method 2 was easier to implement than method 1 to guide individual dose adjustments in TDM programs.