Population pharmacokinetic model of mitotane enzyme autoinduction in adrenocortical carcinoma patients
Usman Arshad (1), Max Taubert (1), Max Kurlbaum (2), Sebastian Frechen (1), Sabine Herterich (3), Julia Wendler (2), Stefanie Hamacher (4), Uwe Fuhr (1), Martin Fassnacht (5), Matthias Kroiss (2, 3, 5)
(1) Department I of Pharmacology, University Hospital Cologne, Germany, (2) Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital Würzburg, Germany, (3) Clinical Chemistry and Laboratory Medicine, University Hospital Würzburg, Germany, (4) Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Germany, (5) Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany
Objectives: Mitotane is the first choice drug for the treatment of adrenocortical carcinoma (ACC). It has a remarkable inter-patient variability, a narrow therapeutic range and is subject to CYP3A4 auto-induction. Although therapeutic drug monitoring (TDM) is commonly used, it remains unclear which loading dose and TDM schedule would be optimal. The objective of this study is to develop a population pharmacokinetic model of mitotane and to investigate model-based optimizations of dosing regimens and TDM schedules.
Methods: Plasma concentrations from TDM of 45 ACC patients (29 females, mean (SD) age 47 (14) years, body weight 75 (14.4) kg) receiving 0.5-10g mitotane per day were analyzed using NONMEM. A hypothetical enzyme compartment with enzyme synthesis depending on mitotane plasma concentrations was introduced to model autoinduction and a covariate model was developed to identify sources of variability. Simulations of different combinations of loading and maintenance doses were performed to identify the optimum dosing regimen.
Results: The suitable base model to describe the data was a one-compartment model with first order absorption (absorption rate constant: 2.08 h-1; volume of distribution (V): 3740L; baseline clearance (CLbaseline): 0.0296 L/h). High interindividual variability (IIV) was associated with both V (105%) and the baseline clearance (88%). An indirect response model with the change in enzyme linearly related to mitotane plasma concentrations described autoinduction appropriately. A 72-fold increase in enzyme synthesis rate was estimated for the median mitotane plasma concentration of 14.6mg/L. Individual body mass index and sex were identified as statistically significant covariates and reduced the IIV for V by 34%. Similarly, 25% of IIV for CLbaseline was explained by individual triglyceride, γ-glutamyltransferase and creatinine plasma concentrations. Preliminary simulation results suggest a high loading dose of 6g daily followed by a first TDM at day 7 to safeguard a high probability of target attainment and an appropriate adjustment of maintenance doses.
Conclusions: Our results support the clinical practice to use a high mitotane loading dose. The model facilitates the optimization of TDM and is a useful tool to establish individualized maintenance doses by forecasting individual plasma concentrations.
