Ifosfamide Docetaxel

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... 

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Use aprepitant with caution in patients receiving concomitant medicinal products, including chemotherapy agents that are primarily metabolized through CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine). 

Aprepitant may be affected by paroxetine, CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin), CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine), and oral contraceptives. 

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,... 

Clinically important, potentially hazardous interactions with altretamine, amikacin, aminoglycosides, antineoplastics, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, corticosteroids, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, estramustine, etoposide, fludarabine, fluorouracil, gemcitabine, gentamicin, hydroxyurea, idarubicin, ifosfamide, indomethacin, kanamycin, levamisole, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, neomycin, pentostatin, plicamycin, procarbazine, streptomycin, streptozocin, thioguanine, thiotepa, tobramycin, tretinoin, uracil, vinblastine, vincristine, vinorelbine... 

Aprepitant had no effect on the pharmacokinetics of a single dose of docetaxeL The activation of cyclophosphamide and thiotepa was slightly lower in patients receiving aprepitant, but this was not clinically relevant. However, because of the possibility of increased toxicity the manufacturer recommends caution with antineoplastics principally metabolised by the cytochrome P450 isoenzyme CYP3A4, particularly irinotecan, and also etoposide, vinorelbine, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, although there appears to be some limited evidence of safe concurrent use. 

The UK manufacturer of aprepitant recommends caution when it is used with antineoplastics that are metabolised by CYP3A4, particularly irinotecan, because of the possibility of increased toxicity with this drug. They also mention that etoposide, vinoreibine, docetaxel, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, were given without dosage adjustment for potential interactions, but as this was not a formal interaction study they recommend caution. However, with intravenous docetaxel, it appears that no important changes in pharmacokinetics occur, and therefore dosage adjustments are unlikely to be needed for this drug,... 

The clearance of ifosfamide is higher when it is given after do-cetaxel. This results in less toxicity, but the effect on efficacy is unknown. Ifosfamide did not aiter the pharmacokinetics of docetaxel. The sequence of ifosfamide followed by paclitaxel was antagonistic in vitro. 

The AUCs of ifosfamide and its metabolites were lower when ifosfamide was given immediately after docetaxel than when it was given 24 hours before docetaxel, due to increased clearance. Docetaxel pharmacokinetics were unaltered by ifosfamide. This supports the evidence that the maximum tolerated dose is greater when ifosfamide is given after docetaxel. The mechanism is unknown, but it has been suggested that docetaxel may competitively inhibit the activation of ifosfamide by the cytochrome P450 isoenzyme CYP3A4. These results showthat the toxicity, and possibly efficacy, of the combination are schedule dependent. More study is needed. Cyclophosphamide does not appear to alter doeetaxel pharmacokinetics. For full details see also Taxanes + Cyclophosphamide , p.661. 

Schrijvers D, Pronk L, Highley H Bruno R, Locci-Tonelli D, De Bruijn E, Van Oosterom AT, Verweij J. Pharmacokinetics of ifosfamide are changed by combination widi docetaxel. AmJ Clin Oncol (2000) 23, 358-63,... 

Pronk L, Schrijvers D, Schellens JHM, De Bruijn EA Planting ASTh, Locci-Tonelli D, Groult V, Verweij J, Van Oosterom AT. Phase I study on docetaxel and ifosfamide in patients widi advanced solid tumours. BrJ Cancer (1998) 77, 153-8. 

Ando Y, Possible metabolic interaction between docetaxel and ifosfamide, BrJ Ca c r(2000) 82, 497,... 

The pharmacokinetics of docetaxel were not altered by pretreatment with an intravenous bolus dose of cyclophosphamide in a phase I study. For a report that the pharmacokinetics of docetaxel are not affected by ifosfa-mide, see Cyclophosphamide or Ifosfamide + Taxanes , p.628. 

Crommentuyn KML, Schellens JHM, Van Den Berg JD, Beijnen JH (1998) In-vitro Metabolism of Anticancer Drugs, Methods and Applications Paclitaxel, Docetaxel, Tamoxifen and Ifosfamide. Cancer Treat Rev 24 345... 

Fossella, FV., DeVore, R., Kerr, R.N., et al. (2000). Randomized phase III trial of docetaxel versus vinorelbine of ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J. Clin. Oncol. 18, 2354-2362. 

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