Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

• Main Authors: Yoann Cazaubon (Author), Yohann Talineau (Author), Catherine Feliu (Author), Céline Konecki (Author), Jennifer Russello (Author), Olivier Mathieu (Author), Zoubir Djerada (Author)
• Format: Book
• Published: MDPI AG, 2019-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1999-4923; 10.3390/pharmaceutics11110566
• Keywords: mitotane; adrenocortical carcinoma; pharmacokinetics; simulation; modelling; optimization; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 11, Iss 11, p 566 (2019)

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2−3 g/day and should be slightly increased to reach the therapeutic index of 14−20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h⁻¹ (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.