DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



Mitotane has a strong and a durable inducing effect on CYP3A4 activity.

Author(s): van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H

Affiliation(s): 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

Publication date & source: 2011-04, Eur J Endocrinol., 164(4):621-6. Epub 2011 Jan 10.

Publication type: Clinical Trial

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. DESIGN: 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) mugxh/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) mugxh/l, P=0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 mugxh/l versus 1344 (1079-1609) (mean (95% CI)) mugxh/l). CONCLUSION: 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.

Page last updated: 2011-12-09

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017