Ketoconazole Ifosfamide

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

IFOSFAMIDE 1. ANTIBIOTICS -clarithromycin, erythromycin 2. ANTIFUNGALS -fluconazole, itraconazole, ketoconazole voriconazole 3. ANTIVIRALS-efavirenz, ritonavir 4. GRAPEFRUIT JUICE 5. H2 RECEPTOR BLOCKERS - cimetidine 1 plasma concentrations of 4-hydroxyifbsfamide, the active metabolite of ifosfamide, and risk of inadequate therapeutic response Due to inhibition of the isoenzymatic conversion to active metabolites Monitor the efficacy of ifosfamide clinically and t dose accordingly... 

The effect of ketoconazole on the CYP-mediated metabolism of ifosfamide to 4-hydroxjdfosfamide and the ultimate cytotoxic ifosforamide mustard, and its deactivation to 2- and 3-dechloroethyhfosfamide has been studied in a randomized, crossover study in 16 patients, who received intravenous ifosfamide 3 g/m /day, either alone or in combination with ketoconazole 200 mg bd 1 day before treatment and during 3 days of concomitant administration (46). Ketoconazole did not affect the fraction metabolized or exposure to the dechloroethylated metabolites and thus did not alter the pharmacokinetics of ifosfamide or its metabolism. 

Kerbusch T, Jansen RL, Mathot RA, Huitema AD, Jansen M, van Rijswijk RE, Beijnen JH. Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin. Clin Pharmacol Ther 2001 70(2) 132-41. 

Clinically important, potentially hazardous interactions with alprazolam, astemizole, carbamazepine, cisapride, clarithromycin, dexamethasone, diltiazem, docetaxel, ifosfamide, imatinib, irinotecan, itraconazole, ketoconazole, methylprednisolone, midazolam, nefazodone, oral contraceptives, paroxetine, phenytoin, pimozide, rifampin, ritonavir, terfenadine, tolbutamide, trabectedin, troleandomycin, vinblastine, vincristine, warfarin... 

Fluconazole and itraconazole inhibit the metabolism of cyclophosphamide. There is some evidence that, compared with fluconazole, itraconazole might increase cyclophosphamide toxicity. Ketoconazole inhibits the metabolism of ifosfamide. This did not improve the ratio of active to inactive-toxic metabolites, and the possibility remains that ifosfamide efficacy could be reduced. 

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