title: Development of a pharmacokinetic model of mitotane: toward personalized dosing in adrenocortical carcinoma.
abstract: BACKGROUND
  Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/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 this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on 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 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients.
  
  
  RESULTS
  The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The 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 seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. 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.
authors.affiliation: Departments of *Internal Medicine; †Clinical Pharmacology, Máxima Medical Center, Eindhoven; ‡Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center; §Department of Clinical Pharmacy and Toxicology; ¶CAPHRI, School for Public Health and Primary Care, Maastricht University Medical Center+; ‖Department of Clinical Oncology, Leiden University Medical Center; and **Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center+, the Netherlands.
authors.forename: Thomas M A
authors.initials: TM
authors.lastname: Kerkhofs
authors.forename: Luc J J
authors.initials: LJ
authors.lastname: Derijks
authors.forename: Hester
authors.initials: H
authors.lastname: Ettaieb
authors.forename: Jan
authors.initials: J
authors.lastname: den Hartigh
authors.forename: Kees
authors.initials: K
authors.lastname: Neef
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Harm R
authors.initials: HR
authors.lastname: Haak
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015233:Models, Statistical; D057285:Precision Medicine; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008939:Mitotane