Pharmacokinetically Based Estimation of Patient Compliance with Oral Anticancer Chemotherapies
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Clin Pharmacokinet 2009; 48 (6): 359-369 0312-5963/09/0006-0359/$49.95/0
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Pharmacokinetically Based Estimation of Patient Compliance with Oral Anticancer Chemotherapies In Silico Evaluation Emilie He´nin,1 Michel Tod,1 Ve´ronique Trillet-Lenoir,1,2 Catherine Rioufol,1,3 Brigitte Tranchand1,4 and Pascal Girard1 1 2 3 4
Universite´ Lyon 1, EA3738, CTO, Faculte´ de Me´decine Lyon Sud, Oullins, France Service d’Oncologie Me´dicale, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Be´nite, France Unite´ de Pharmacie Clinique Oncologique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Be´nite, France Centre Le´on Be´rard, Lyon, France
Abstract
Background and objectives: More and more anticancer chemotherapies are now available as oral formulations. This relatively new route of administration in oncology leads to problems with patient education and non-compliance. The aim of this study was to explore the performances of the ‘inverse problem’, namely, estimation of compliance from pharmacokinetics. For this purpose, we developed and evaluated a method to estimate patient compliance with an oral chemotherapy in silico (i) from an a priori population pharmacokinetic model; (ii) with limited optimal pharmacokinetic information collected on day 1; and (iii) from a single pharmacokinetic sample collected after multiple doses. Methods: Population pharmacokinetic models, including estimation of all fixed and random effects estimated on a prior dataset, and sparse samples taken after the first dose, were combined to provide the individual POSTHOC Bayesian pharmacokinetic parameter estimates. Sampling times on day 1 were chosen according to a D-optimal design. Individual pharmacokinetic profiles were simulated according to various dose-taking scenarios. To characterize compliance over the n previous dosing times (supposedly known without error), 2n different compliance scenarios of doses taken/not taken were considered. The observed concentration value was compared with concentrations predicted from the model and each compliance scenario. To discriminate between different compliance profiles, we used the Euclidean distance between the observed pharmacokinetic values and the predicted values simulated without residual errors. This approach was evaluated in silico and applied to imatinib and capecitabine, the pharmacokinetics of which are described in the literature, and which have quite different pharmacokinetic characteristics (imatinib has an elimination half-life of 17 hours, and a-fluoro-b-alanine [FBAL], the metabolite of capecitabine, has an elimination half-life of 3 hours). 1000 parameter sets were drawn according to population distributions, and concentration values were simulated at several timepoints under various compliance patterns to compare with the predicted ones. In addition, several simulation scenarios were run in order to explore the impact of the quality of the error model, interoccasion variability (IOV), error in the number of
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