Universität zu Köln

Arshad, U., Taubert, M., Kurlbaum, M., Frechen, S., Herterich, S., Megerle, F., Hamacher, S., Fassnacht, M., Fuhr, U. and Kroiss, M. (2018). Enzyme autoinduction by mitotane supported by population pharmacokinetic modeling in a large cohort of adrenocortical carcinoma patients. Eur. J. Endocrinol., 179 (5). S. 287 - 298. BRISTOL: BIOSCIENTIFICA LTD. ISSN 1479-683X

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Arshad, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurlbaum, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frechen, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herterich, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Megerle, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamacher, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fassnacht, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroiss, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-167551
DOI:	10.1530/EJE-18-0342
Journal or Publication Title:	Eur. J. Endocrinol.
Volume:	179
Number:	5
Page Range:	S. 287 - 298
Date:	2018
Publisher:	BIOSCIENTIFICA LTD
Place of Publication:	BRISTOL
ISSN:	1479-683X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SERUM-LIPOPROTEINS; O,P'-DDD MITOTANE; CYP3A4; PLASMA; CHEMOTHERAPY; METABOLISM; ACTIVATION; INDUCTION; THERAPY; O,P'DDD Multiple languages Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16755