title: Mitotane has a strong and a durable inducing effect on CYP3A4 activity.
abstract: OBJECTIVE
  The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib.
  
  
  METHODS
  A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study. Both patients were diagnosed with adrenocortical carcinoma (ACC) and were exposed to mitotane. The sunitinib PK study was designed to determine the relationship between CYP3A4 activity and sunitinib exposure using 7.5 mg midazolam orally as a phenotypic probe. Patient and methods Serial blood samples for PK analysis of midazolam, 1-hydroxy-midazolam, and sunitinib were collected at steady-state sunitinib PK (between days 14 and 20). To confirm this observation in the mitotane-exposed patients, midazolam PK was evaluated in two additional patients with ACC and mitotane treatment.
  
  
  RESULTS
  The four mitotane-treated patients showed highly induced CYP3A4 activity, even after interrupting mitotane therapy months before study entry, reflected by decreased midazolam exposure compared with the other seven patients (mean AUC(0)(-)(12 h) (95% CI): 7.6 (5.5-9.7) vs 139.0 (95.1-182.9) μg×h/l respectively P=0.001) and increased 1-hydroxy-midazolam exposure (mean AUC(0)(-)(12 h) (95% CI): 409.6 (290.5-528.7) vs 35.0 (26.4-43.6) μg×h/l, P=0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 μg×h/l versus 1344 (1079-1609) (mean (95% CI)) μg×h/l).
  
  
  CONCLUSIONS
  Mitotane has a strong and long-lasting inducing effect on CYP3A4 activity, which will result in clinically relevant interactions with multiple drugs since many drugs are metabolized by this enzyme.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, PO Box 9600, Postal zone L0-P, 2300 RC Leiden, The Netherlands. p.h.van_erp@lumc.nl
authors.forename: Nielka P
authors.initials: NP
authors.lastname: van Erp
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ploeger
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.forename: Jan den
authors.initials: Jd
authors.lastname: Hartigh
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D008939:Mitotane; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077210:Sunitinib