Carbamazepine induces bioactivation of cyclophosphamide and thiotepa

Abstract

Purpose We report a patient with metastatic breast cancer who received three cycles of high-dose chemotherapy with cyclophosphamide [1,000 mg/(m 2 day)], thiotepa (80 mg/ (m 2 day) and carboplatin (dose calculated based on modiWed Calvert formula with 3.25 mg min/ml as daily target AUC) over 4 days, followed by peripheral blood progenitor cell support. During the Wrst two cycles the patient concomitantly used carbamazepine for the treatment of epilepsy. Due to severe nausea and vomiting the patient was unable to ingest carbamazepine; therefore, this was discontinued after the second cycle. Methods Blood samples were drawn on 2 days (day 1 and 2, 3 or 4) of each cycle and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined. Results Exposure to 4-hydroxycyclophosphamide and tepa on day 1 was increased in the presence of carbamazepine (58 and 75%, respectively), while exposure to cyclophosphamide and thiotepa was reduced (40 and 43%, respectively). ConclusionSince increased exposure to the active metabolites is associated with an increased risk of toxicity, it is important to be aware of this drug-drug interaction.

Psychopharmacological Treatment in Older People: Avoiding Drug Interactions and Polypharmacy

“…Carbamazepine and St. John's wort are both potent inductors of multiple CYP isoenzymes (e.g., 1A2, 2C9, 2C19, 3A4) (26)(27)(28)(29). Thus, the concomitant administration of either of these drugs can markedly lower the plasma level of quetiapine through the induction of isoenzyme 3A4 (19,20).…”

Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids

“…23,57 Concurrent therapy with the enzyme inducers carbamazepine or phenytoin yields smaller peak concentrations, increased clearance, and diminished AUC of cyclophosphamide, alongside higher peak concentrations and larger AUC of 4-hydroxycyclophosphamide. 23,25 These observations illustrate that in case of coenzyme-dependent conversion of a parent drug into the active metabolite, a concurrently administered enzyme inducer produces enhanced effects of the parent drug despite acceleration of its own metabolism.…”

“…24 Concurrent thiotepa and carbamazepine or phenytoin result in accelerated clearance of the primary drug, and organ exposure to tepa is increased by a factor of 2. 24,25 The use of vincristine with carbamazepine or phenytoin results in a substantially shorter elimination half-life and smaller AUC. 27 Methotrexate, particularly high-dose methotrexate, is an essential part of chemotherapy for leukemia and non-Hodgkin's lymphoma, including CNS lymphoma.…”

Drug Interactions Between Anti‐Epileptics and Chemotherapeutic Drugs: Value of a Pre‐Treatment Pharmaceutical Review

“…Cyclophosphamide is converted to the active metabolite, 4-hydroxy cyclophosphamide, via activation by CYP2B6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5. 3 CYP3A4 also catalyses the inactivation of cyclophosphamide. A pharmacokinetic study of the concurrent administration of cyclophosphamide and carbamazepine demonstrated increased clearance of cyclophosphamide and increased area under the concentration time curve of 4-hydroxy cyclophosphamide, possibly due to CYP3A4 and CYP2B6 induction.…”

“…There is a risk the increased exposure to 4-hydroxycyclophosphamide could increase toxicity. 3 Ifosfamide is activated via CYP3A but no data could be found about the effect of carbamazepine on ifosfamide metabolism.…”