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. 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) mg!h/l respectively PZ0.001) 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) mg!h/l, PZ0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 mg!h/l versus 1344 (1079-1609) (mean (95% CI)) mg!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.

Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

“…This hypothesis awaits further confirmation at the clinical level (Hermsen et al 2011). At variance with the hepatic microsomal transformation of mitotane by CYP3A4 (van Erp et al 2011, Kroiss et al 2011, which is likely responsible for the pharmacokinetic interaction whereby mitotane reduces plasma levels of sunitinib (Fassnacht et al 2012, Kroiss et al 2012, it has been suggested that CYPc11 or CYP11B1 could be involved in tissue-specific and compartment-selective mitotane metabolism (Lund & Lund 1995, Lindhe et al 2002. Although CYP11B1 may catalyze the initial hydroxylation step of mitotane (Cai et al 1995, Lund & Lund 1995, Lindhe et al 2002, its direct involvement in mt dysfunction is very unlikely given that SW13 cells, which do no express CYP11B1, were similarly affected by mitotane treatment.…”

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

“…Sorafenib did not show an anti-tumor effect in patients, whereas sunitinib and axitinib showed a partial response in 14 and 62% of the patients respectively (Table 5). The mitotane-induced CYP3A4 increase may limit the therapeutic efficacy of tyrosine kinase inhibitors via enhanced drug metabolism (van Erp et al 2011). As previously mentioned, there is evidence that monotherapy with tyrosine kinase inhibitors causes compensatory hyperactivation of other signaling pathways, explaining the lack of efficacy in many patients (Stommel et al 2007).…”

EJE PRIZE 2014: Current and evolving treatment options in adrenocortical carcinoma: where do we stand and where do we want to go?

“…Thus, it has become clear by thorough investigation of a fortuitous finding, namely reduced plasma concentrations of sunitinib and its active metabolite during concomitant mitotane treatment (42), that mitotane is one of the strongest inducers of CYP3A4 -the major drug-metabolizing enzyme in humans leading to multiple drug interactions (for review see (43)). Till date, it is unclear whether mitotane itself is metabolized by CYP3A4 and which other P450 enzymes are altered in their activity, although there is first evidence that CYP2B6 might be involved (44).…”