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 min is highly challenging in outpatients, in whom there is typically a variability in sample collection time after dosing. Various methods are used to estimate C min from the collected samples. This simulation study aimed to evaluate the performance of 3 different methods in estimating the C min of 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,obs and C min,sim,obs ) by adding a residual error. From C t, sim,obs , C min was predicted (C min,pred ) by the Bayesian estimation (method 1), taking the ratio of the C t,sim,obs and 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,pred with 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,pred values. However, method 2 was easier to implement than method 1 to guide individual dose adjustments in TDM programs.