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

Julie M. Janssen, Thomas P.C. Dorlo, Jos H. Beijnen, Alwin D.R. Huitema

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

16 Citaten (Scopus)


Background:For oral anticancer drugs, trough concentration (Cmin) is usually used as a target in therapeutic drug monitoring (TDM). Recording of Cminis highly challenging in outpatients, in whom there is typically a variability in sample collection time after dosing. Various methods are used to estimate Cminfrom the collected samples. This simulation study aimed to evaluate the performance of 3 different methods in estimating the Cminof 4 oral anticancer drugs for which TDM is regularly performed.Methods:Plasma concentrations of abiraterone, dabrafenib, imatinib, and pazopanib at a random time (Ct,sim) and at the end of the dosing interval (Cmin,sim) were simulated from population pharmacokinetic models including 1000 patients, and the values were converted into simulated observed concentrations (Ct,sim,obsand Cmin,sim,obs) by adding a residual error. From Ct, sim,obs, Cminwas predicted (Cmin,pred) by the Bayesian estimation (method 1), taking the ratio of the Ct,sim,obsand typical population concentration and multiplying this ratio with the typical population value of Cmin,sim(method 2), and log-linear extrapolation (method 3). Target attainment was assessed by comparing Cmin,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 Cmin,predvalues. However, method 2 was easier to implement than method 1 to guide individual dose adjustments in TDM programs.

Originele taal-2Engels
Pagina's (van-tot)532-539
Aantal pagina's8
TijdschriftTherapeutic Drug Monitoring
Nummer van het tijdschrift4
StatusGepubliceerd - 1 aug. 2020
Extern gepubliceerdJa


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