Thiotepa Cyclophosphamide

Modified from Eder jP, Elias A, Shea JC, et al. A phase l-ll study of cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow transplantation in solid tumor patients. Clin Oncol 1990 8 1242. 

The rate of auto-induction of cyclophosphamide was 23% lower and exposure to the active metabolite 4-hydroxycyelophosphamide was 5% lower in 6 patients receiving aprepitant with a 4-day course of high-dose CTC (cyclophosphamide, thiotepa, carboplatin) when compared with 49 patients receiving high-dose CTC without aprepitant. ... 

In the short-term, aprepitant is an inhibitor of the cytochrome P450 isoenzyme CYP3A4, and might therefore reduce the activation of antineoplastics activated by this isoenzyme (cyclophosphamide, thiotepa), or increase the toxicity of antineoplastics metabolised by this enzyme (docetaxel, irinotecan). 

Thiotepa is chemically less reactive than the nitrogen mustards. It has antineoplastic activity against ovarian and breast cancers as well as lymphomas. However, it has been largely supplanted by cyclophosphamide and other nitrogen mustards. 

Aflatoxin Bl, bupropion, cyclophosphamide, dexamethasone, etoposide, ifosfamide, midazolam, phenobarbital, propofol, rifampin, teitiposide, thiotepa, vitamin D, xenobiotics Amitriptyhne, carisoprodol,... 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

CIMETIDINE BUSULFAN, CARMUSTINE, CHLORAMBUCIL CYCLOPHOSPHAMIDE, ESTRAMUSTINE, IFOS-FAMIDE, LOMUSTINE, THIOTEPA, TREOSULFAN T adverse effects of cytotoxic, e.g. myelosuppression Additive toxicity. Possible minor inhibition of cyclophosphamide metabolism via CYP2C9 Monitor more closely monitor FBC regularly. Avoid co-administration of cimetidine with cyclophosphamide... 

Cytoxan - cyclophosphamide Mustargen - mechlorethamine Thioplex - thiotepa... 

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... 

In some preparative regimens, the only drug given is cyclophosphamide, a drug with both immunosuppressive and cytotoxic effects. Because of the inadequate antitumor activity of cyclophosphamide in some types of cancers, other drugs are often added. Examples of drugs that often are included in preparative regimens are cytarabine (ara-C), busulfan, thiotepa, etoposide (VP-16), carboplatin, cisplatin, carmustine (BCNU), melphalan, and ifosfamide. ... 

The toxicities of thiotepa are essentially the same as those of the other alkylating agents, namely myelosuppres-sion and to a lesser extent mucositis. Myelosuppression tends to develop somewhat later than with cyclophosphamide, with leukopenic nadirs at 2 weeks and platelet nadirs at 3 weeks. In high-dose regimens thiotepa produces neurotoxic symptoms, including coma and seizures. 

Simultaneous acetaminophen, aspirin, carmustine, chlorambucil, Qdarabine, dacarba-zine, diclofenac, etoposide, 5-fluorouracil, ifosfamide, indomethadn, lomustine, methotrexate, naproxen, salicylic acid, tegafur, teniposide, thioguanine Noninterfering betamethasone, carboplatin, cyclophosphamide, cyclosporine A, ibuprofen, thiotepa... 

Simultaneous carmustine, 5-fluorouracil, hydrocortisone, teniposide, thiotepa Noninterfering acetaminophen, aspirin, bleomycin, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, hydroi airea, ifosfamide, methotrexate, mitomycin, mi-toxantrone, procarbazine... 

Zimmerman, T. M., Grinblatt, D. L., Malloy, R. and Williams, S. R, A Phase I dose escalation trial of continuous infusion paclitaxel to augment high dose cyclophosphamide and thiotepa plus stem cell rescue for the treatment of patients with advanced breast carcinoma. Cancer, 15 83(8), 1540, 1998. 

Others Ahretamine, BusuKan, Chlorambucil Chlormethine (Mechlorethamine), Cyclophosphamide, Dacarbazine, Estramustine, Ifosfamide, Melphalan, Temorolomide, Thiotepa... 

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. 

Pretreatment with thiotepa may inhibit the metabolism of cyclophosphamide to its active metaboUte and decrease both its efficacy and toxicity. Cyclophosphamide appears not to affect the metabolism of thiotepa. 

In an in vitro study using human microsomes, cyclophosphamide had no effect on the metabolism of thiotepa to TEPA (triethylenephosphamide) by cytochrome P450 at therapeutic concentrations. ... 

Huitema ADR, Kerbusch T, Tibben MM, Rodenhuis S, Beijnen JH. Reduction of cyclophosphamide bioactivation by thioTEPA critical sequence-dependency in high-dose chemother y regimens. Cancer Chemother Pharmacol 2( 0) 46,119-27. 

Poorly selective though it was, chlormethine pointed the way to the discovery of the following nitrogen-mustard drugs, currently used in cancer therapy cyclophosphamide (perhaps the most selective of them all), chlorambucil, melphalan, and uracil mustard also the closely related thiotepa and busulfan also the related nitrosoureas lomustine, carmustine, semustine, and strepto-zocin (an antibiotic). All of these are alkylating agents, linking two strands of DNA (see Section 13.4 for details). 

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