Could aprepitant (Emend) interact pharmacologically with dacarbazine?

Fråga: Could aprepitant (Emend) interact pharmacologically with dacarbazine?

Sammanfattning: There is no evidence of a pharmacologic interaction between aprepitant and dacarbazine.

Svar: Dacarbazine is a alkylating cytostatic used for treatment metastasizing malignant melanoma (1). Aprepitant is an NK1-antagonist used in the treatment of cytostatic-induced nausea (2).

No reports of an interaction between the two drugs were identified in Drugline, Medline or standard pharmacological literature. Aprepitant is primarily metabolised by cytochrome P450 3A4 (CYP3A4), and possibly to a smaller extent by CYP1A2 and CYP2C19 (2-4). In addition to being a CYP3A4 substrate, apretpitant is an inducer and inhibitor of this enzyme. During aprepitant treatment, the net effect on CYP3A4 activity is inhibitory, but following withdrawal of aprepitant, the CYP3A4 activity is elevated above baseline levels for up to two weeks. Aprepitant also induces CYP2C9 to some extent (2).

Dacarbazine is a prodrug that is activated by demethylation via three cytochrome P450 enzymes, CYP1A1, CYP1A2 and CYP2E1 (1,5). In addition, 20-50% of an intravenously administered dose is eliminated in unchanged form via the urine. No dose adjustment is necessary in mild to moderate renal impairment (1).

The metabolic pathways involved in the elimination of the two drugs are not suggestive of any obvious interactions risks on the pharmacokinetic level. Likewise, the drugs mechanisms of action do not indicate a substantial risk of pharmacodynamic interactions. SPC Dacarbazine (2007-02-01) SPC Emend (2009-07-29) Drugline no 23603 (year 2008) Sanchez RI, Wang RW, Newton DJ, Bakhtiar R, Lu P, Chiu SH et al. Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos 2004;32(11):1287-1292 Reid JM, Kuffel MJ, Miller JK, Rios R, Ames MM. Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res 1999;5(8):2192-2197