Is there any risk of interaction between aprepitant (Emend) and ifosfamide (Holoxan)?/nThis is a ge

Fråga: Is there any risk of interaction between aprepitant (Emend) and ifosfamide (Holoxan)?

This is a general question, concerning guidelines for antiemetic treatment.

Sammanfattning: There is a theoretical possibility of an interaction and the effect of ifosfamide is unpredictable when administered concomitantly with aprepitant, even though no reports have been found in the literature or in relevant databases. Other antiemetic options should be considered.

Svar: The data is limited and no documentation of interactions has been found searching the literature and relevant databases. In one study, ketoconazole, a potent CYP3A4-inhibitor, decreased the activation of ifosfamide (1). Emend has only been approved since November 2003 and there is a theoretical possibility of an interaction as discussed below.

Ifosfamide is an oxazaphosphorine, and chemically related to nitrogen mustard derivatives that were used during World War I. The cytotoxic effect is due to inhibition of DNA replication. Using it as chemotherapy, the main side-effect was initially haemorrhagic cystitis but after addition of mesna this problem was prevented. Overdosing may result in neurotoxicity, myelosuppression and cystitis (3). It is usually given as infusions for five consecutive days (2). Ifosfamide is an inactive prodrug, which is both activated and then deactivated mainly by CYP3A4. Ifosfamide also induces CYP3A4-activity, probably by preventing the degradation of the enzyme. Rifampicin and other CYP3A4-inducers may possibly interact with ifosfamide to a clinically relevant degree, causing both increased effect and toxicity. Inhibitors of CYP3A4, such as erythromycin, may probably decrease the therapeutic effect (3). Ifosfamide, which is activated in the liver, may have a limited ability to reach extrahepatic tumours and CYP3A-activity for example in lungtumours may be of importance for the therapeutic effect (4). With decreased liver function, the metabolism is slowed and advanced hepatic failure results in almost no measurable activation and only renal elimination of the parent compund. The elimination via the kidneys is normally low. In high-dose treatment, the dose is often close to the maximum dose tolerated and variations in pharmacokinetics is therefore of importance. Therapeutic drug monitoring may be useful, but would need to include analysis of the active metabolite and is not done in Sweden (3).

In the summary of product characteristics for Emend, the manufacturer has written that aprepitant is a substrate, an inhibitor and an inducer of CYP3A4. Plasma concentrations of CYP3A-substrates have been increased during treatment with Emend. The AUC of oral midazolam, a CYP3A4-substrate, was two times higher day one of concomitant treatment with Emend and three times higher on the fifth day of concomitant treatment with Emend. The effect is less pronounced on parenterally administered drugs, but the manufacturer recommends caution when Emend is combined with a few intravenously administered cytostatics. Ifosfamide is not included on this list, though. There is also an induction of CYP3A4, which peaked 3-5 days after a three-day treatment period with Emend was terminated, and continued for a few days (5). Taken together, the findings suggest that CYP3A4 is inhibited by aprepitant during ongoing treatment with Emend and that increased CYP3A4-activity is observed after elimination of aprepitant during a few days after cessation of treatment with Emend. The effect of concomitantly administered ifosfamide is therefore somewhat unpredictable. Kerbusch T, Jansen RL, Mathot RA, Huitema AD, Jansen M, van Rijswijk RE et al. Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin. Clin Pharmacol Ther 2001;70(2):132-41. Fass 2006 Kerbusch T, de KJ, Keizer HJ, van Putten JW, Groen HJ, Jansen RL et al. Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites. Clin Pharmacokinet 2001;40(1):41-62 Kivisto KT, Fritz P, Linder A, Friedel G, Beaune P, Kroemer HK. Immunohistochemical localization of cytochrome P450 3A in human pulmonary carcinomas and normal bronchial tissue. Histochem Cell Biol 1995;103(1):25-29 Emend. Summary of product characteristics (SPC) (MSD)