BACKGROUND: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma.
The anti-neoplastic effect appears to be correlated with a minimum plasma level of 14mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of the present study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based upon a target drug exposure, which facilitates personalized therapy.
METHODS: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from two hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative two-stage Bayesian fitting (ITSB, MWPharm). The model was validated in an independent sample of 9 patients.
RESULTS: The concentration-time data were best described by a three-compartment model. The model estimated mitotane clearance at 0.94±0.37L/h and volume of distribution in steady state at 161±68L/kg[BULLET OPERATOR]LBM. Mean prediction error was 14% ± 13%.
CONCLUSIONS: A pharmacokinetic model was developed which characterized mitotane by slow clearance and large volume of distribution. The model appears to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables to adapt dosing based on individual plasma level measurements in prospective setting, which improves the prediction's accuracy. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.
Written by:
Kerkhofs T, Derijks L, Ettaieb M, den Hartigh J, Neef C, Gelderblom H, Guchelaar HJ, Haak H. Are you the author?
Department of Internal Medicine, Máxima Medical Center, Eindhoven/Veldhoven, The Netherlands; Department of Clinical Pharmacology, Máxima Medical Center, Eindhoven/Veldhoven, The Netherlands; Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands; Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Center+, Maastricht, The Netherlands; CAPHRI, School for Public Health and Primary Care, Maastricht University Medical Center+, Maastricht, The Netherlands; Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Internal Medicine, Division of General Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.
Reference: Ther Drug Monit. 2014 May 30. Epub ahead of print.
doi: 10.1097/FTD.0000000000000102
PubMed Abstract
PMID: 24887633
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