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

ABSTRACT: 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.

SUBMITTER: Cazaubon Y

PROVIDER: S-EPMC6920765 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Project description:BackgroundMitotane is the only approved treatment for patients with adrenocortical carcinoma (ACC). A better explanation for the variability in the pharmacokinetics (PK) of mitotane, and the optimization and individualization of mitotane treatment, is desirable for patients.ObjectivesThis study aims to develop a population PK (PopPK) model to characterize and predict the PK profiles of mitotane in patients with ACC, as well as to explore the effect of genetic variation on mitotane clearance. Ultimately, we aimed to facilitate mitotane dose optimization and individualization for patients with ACC.MethodsMitotane concentration and dosing data were collected retrospectively from the medical records of patients with ACC taking mitotane orally and participating in the Dutch Adrenal Network. PopPK modelling analysis was performed using NONMEM (version 7.4.1). Genotypes of drug enzymes and transporters, patient demographic information, and clinical characteristics were investigated as covariates. Subsequently, simulations were performed for optimizing treatment regimens.ResultsA two-compartment model with first-order absorption and elimination best described the PK data of mitotane collected from 48 patients. Lean body weight (LBW) and genotypes of CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to significantly affect mitotane clearance (CL/F), which decreased the coefficient of variation (CV%) of the random inter-individual variability of CL/F from 67.0 to 43.0%. Fat amount (i.e. body weight - LBW) was found to significantly affect the central distribution volume. Simulation results indicated that determining the starting dose using the developed model is beneficial in terms of shortening the period to reach the therapeutic target and limit the risk of toxicity. A regimen that can effectively maintain mitotane concentration within 14-20 mg/L was established.ConclusionsA two-compartment PopPK model well-characterized mitotane PK profiles in patients with ACC. The CYP2C19 enzyme and SLCO1B1 and SLCO1B3 transporters may play roles in mitotane disposition. The developed model is beneficial in terms of optimizing mitotane treatment schedules and individualizing the initial dose for patients with ACC. Further validation of these findings is still required.

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

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