Paclitaxel Ifosfamide

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. 

IEP = ifosfamide, etoposide, cisplatin PEP = cisplatin, etoposide, paclitaxel EP = etoposide + cisplatin TP = topotecan+ paclitaxel E Carbo = etoposide + carboplatin. 

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,... 

Marked increments in response were observed with the incorporation of cisplatin into combination regimens response rates greater that 50% were reported in Phase-Ill studies of cisplatin/ifosfamide, cisplatin/ifosfamide/ bleomycin, and cisplatin/5-FU [188-190]. Randomized trials of these combinations administered prior to radiotherapy in locally advanced disease have not shown a survival advantage however, a recent GOG trial of concurrent cisplatin or cisplatin/5-FU/hydroxyurea and radiation was associated with significantly improved progression-free survival versus concurrent hydroxyurea and radiation in patients with Stage IIB-IVA cervical cancers [191]. Combined cisplatin and paclitaxel produced responses in 9 of 11 patients in a recent GOG study [192] and will be the focus of larger trials in the future. 

In several studies, intravenous amifostine (910 mg/m ) preserved glomerular filtration rate when it was co-administered with cisplatin-containing regimens (213). Even after two cycles containing intravenous cisplatin 50 mg/m plus intravenous ifosfamide and etoposide or paclitaxel, glomerular filtration rate can fall by more than 30%, but concomitant use of amifostine prevented this. Even lower dosages of intravenous amifostine (for example 740 mg/m ) may be effective (220,221). 

Shin DM, Khurr FR, Glisson BS, et al Phase II study of paclitaxel, ifosfamide, and carboplatin in patients... 

Cisplatin, in combination with bleomycin, etoposide, ifosfamide, or vinblastine, cures 90% of patients with testicular cancer. Used with paclitaxel, cisplatin induces complete response in most patients with carcinoma of the ovary. Cisplatin produces responses in cancers of the bladder, head and neck, cervix, and endometrium all forms of carcinoma of the lung anal and rectal carcinomas and neoplasms of childhood. The drug sensitizes cells to radiation therapy and enhances control of locally advanced lung, esophageal, and head and neck tumors when given with irradiation. 

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. 

A study in patients given paclitaxel as a 24-hour infusion and cyclophosphamide as an infusion over 1 hour found that neutropenia and thrombocytopenia were more severe when paclitaxel preceded cyclophosphamide. Similarly, in another study, concurrent use of a continuous 72-hour infusion of paclitaxel and a daily bolus of cyclophosphamide had acceptable toxicity. However, when the cyclophosphamide was given as a single intravenous dose after the end of the 72-hour paelitaxel infusion, severe haematological and gastrointestinal toxieity occurred. Whether the clinical efficacy of this combination is also altered by the schedule and sequence has not been determined. See also 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... 

Buda A, Fossati R, Colombo N, et al (2005) Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifos-famide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma the SNAPOl Italian Collaborative Study. J Clin Oncol 23 4137-4145... 

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