title: Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring.
abstract: OBJECTIVE
  Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose.
  
  
  METHODS
  A prospective case-control study was conducted to investigate the variation in plasma mitotane levels.
  
  
  METHODS
  Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose.
  
  
  RESULTS
  Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (n=7) and 17.0 mg/l (13.7-23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at t=4 after morning dose and a change of 13% (range -14 to 33%) at t=4 without morning dose (P=0.02).
  
  
  CONCLUSIONS
  A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands T.Kerkhofs@mmc.nl.
authors.forename: T M A
authors.initials: TM
authors.lastname: Kerkhofs
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: L J J
authors.initials: LJ
authors.lastname: Derijks
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: M H T
authors.initials: MH
authors.lastname: Ettaieb
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: E M W
authors.initials: EM
authors.lastname: Eekhoff
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Neef
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: den Hartigh
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Cent
authors.forename: H R
authors.initials: HR
authors.lastname: Haak
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D018268:Adrenocortical Carcinoma / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008939:Mitotane / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008939:Mitotane