Objective Mitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1–6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring (TDM). Methods Appropriate dosing information, plasma concentrations (1137 data points) and covariates were available from TDM of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed-effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules. Results A one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. BMI was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high-dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity. Conclusion The proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

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