Mitotane has a strong and a durable inducing effect on CYP3A4 activity
Nielka P. van Erp,Henk-Jan Guchelaar,Bart A. Ploeger,Johannes A. Romijn,Jan den Hartigh,Hans Gelderblom +5 more
TL;DR: 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.
read more
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. 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) 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). 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.
read more
Chat with Paper
AI Agents for this Paper
Find similar papers on Google Scholar, PubMed and Arxiv
Write a critical review of this paper
Analyze citations of this paper to find unaddressed research gaps
Citations
Composer-Computer-Interpreter. A Three-way Collaborative Process to the Creation of Two New Works for Multipercussion
01 Jan 2022
TL;DR: In this article , a study of the relationship between the interpreter and the composer is presented in the works "Solo I" for multi-percussion and “Solo for Two" for two multipercussion sets by Dimitris Andrikopoulos.
Сurrent status of adrenocortical cancer therapy
29 Jun 2022
TL;DR: In this article , the authors present a review of the generally accepted adrenocortical carcinoma therapy methods -mitotane alone or in combination with chemotherapeutic agents -and provide perspectives from the novel agents' studies in adrenocarcinoma patients.
Tablet Splitting: Influence of Technique and Tablet Format
01 Jan 2022
TL;DR: In this article , the authors used SPSS to assess significant differences between the two methods and tablet format when analysing loss of mass or splitting accuracy, and concluded that best results can be achieved when splitting tablets if using oblong tablets and splitting them by hand, with splitting by hand being the one to achieve the best results.
References
Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer
Sandrine Faivre,Catherine Delbaldo,Karina Vera,Caroline Robert,Stéphanie Lozahic,Nathalie Lassau,Carlo L. Bello,Samuel E. DePrimo,Nicoletta Brega,Giorgio Massimini,Jean-Pierre Armand,Paul Scigalla,Eric Raymond +12 more
TL;DR: Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neuroendocrine, and stromal tumors and indicates that potentially active target plasma concentrations > or = 50 ng/mL can be achieved with moderate interpatient variability and a long half-life compatible with a single daily dosing.
1.1K
Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.
Richard B. Kim,Christoph Wandel,Brenda F. Leake,Mirjana Cvetkovic,Martin F. Fromm,Peter J. Dempsey,M. M. Roden,F. Belas,A. K. Chaudhary,Dan M. Roden,Alastair J. J. Wood,Grant R. Wilkinson +11 more
TL;DR: The results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.
484
Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the "cocktail" approach.
TL;DR: Phenotyping for drug metabolizing enzymes and transporters is used to assess quantitatively the effect of an intervention or a condition on their activity to obtain results applicable for other substrates of the respective enzyme/transporter.
245
A Population Pharmacokinetic Meta-analysis of Sunitinib Malate (SU11248) and Its Primary Metabolite (SU12662) in Healthy Volunteers and Oncology Patients
TL;DR: The magnitude of the predicted changes in exposure with the covariates studied minimizes the necessity for dose adjustment in any of these subpopulations.
238
Management of adrenocortical carcinoma
TL;DR: Only large prospective multicentre trials comparing different treatment options will allow to make systematic progress in the management of ACC.
180
Related Papers (5)
Martin Fassnacht,Massimo Terzolo,Bruno Allolio,Eric Baudin,Harm R. Haak,Alfredo Berruti,Staffan Welin,Carmen Schade-Brittinger,André Lacroix,Barbara Jarzab,Halfdan Sorbye,David J. Torpy,Vinzenz Stepan,David E. Schteingart,Wiebke Arlt,Matthias Kroiss,Sophie Leboulleux,Paola Sperone,Anders Sundin,I G C Hermsen,Stefanie Hahner,Holger S. Willenberg,Antoine Tabarin,Marcus Quinkler,Christelle De La Fouchardiere,Martin Schlumberger,Franco Mantero,Dirk Weismann,Felix Beuschlein,Hans Gelderblom,Hanneke Wilmink,Monica Sender,Maureen Edgerly,Werner Kenn,Tito Fojo,Hans-Helge Müller,Britt Skogseid +36 more
Massimo Terzolo,Alberto Angeli,Martin Fassnacht,Fulvia Daffara,Libuse Tauchmanovà,Pier Antonio Conton,R. Rossetto,Lisa Buci,Paola Sperone,Erika Grossrubatscher,Giuseppe Reimondo,Enrico Bollito,Mauro Papotti,Wolfgang Saeger,Stefanie Hahner,Ann Cathrin Koschker,Emanuela Arvat,Bruno Ambrosi,Paola Loli,Gaetano Lombardi,Massimo Mannelli,Paolo Bruzzi,Franco Mantero,Bruno Allolio,Luigi Dogliotti,Alfredo Berruti +25 more