Cyclophosphamide (CY) is a prodrug metabolized primarily via CYP2B6, CYP3A4/5, CYP2C9, and CYP2A6; it is widely used in chemotherapy regimens, which may necessitate antifungal prophylaxis in immunocompromised patients. Inhibition of CYP3A4 and CYP2C9 by triazoles raises concerns about potential drug-drug interactions (DDIs) that could alter cyclophosphamide metabolism, leading to increased toxicity. Ketoconazole, known for its robust inhibitory effects on CYP3A4 and CYP3A5, notably increases the plasma exposure of cyclophosphamide by dampening its CYP3A-mediated metabolism, more so than itraconazole, which has a milder inhibitory effect on CYP3A4. Fluconazole, a potent competitive inhibitor of CYP2C9 and CYP2C19 but a weak inhibitor of CYP3A4, exhibits limited influence on the pharmacokinetics of cyclophosphamide compared to the other two triazoles. Additionally, cyclophosphamide's altered plasma exposure may be further complicated by its interaction with P-glycoprotein (P-gp), an efflux transporter that affects drug absorption, distribution, metabolism, and excretion, and is implicated in cancer multidrug resistance. Inhibition of P-gp by ketoconazole could contribute to increased cyclophosphamide accumulation. [1], [2], [3]
A 2004 trial (Table 1) randomized patients undergoing allogeneic stem cell transplantation (SCT) to either itraconazole (200 mg IV daily or 2.5 mg/kg PO TID) or fluconazole (400 mg IV or PO daily), starting with conditioning therapy and continuing for at least 120 days post-transplant. After an interim review by a data and safety monitoring board, patients receiving itraconazole demonstrated higher serum bilirubin and creatinine levels, particularly within the first 20 days post-SCT, and most notably in those also receiving CY-based conditioning. Subsequent pharmacokinetic analyses assessed a subset of patients, revealing that itraconazole recipients had increased exposure to the active CY metabolite 4-hydroxycyclophosphamide (HCY) and its downstream products, including keto-cyclophosphamide (ketoCY) and carboxyethylphosphoramide mustard (CEPM). In contrast, fluconazole recipients exhibited increased exposure to CY and deschloroethyl-cyclophosphamide (DCCY), suggesting differential modulation of CY metabolism by these azole antifungals. A concurrent analysis of 149 patients showed patients receiving fluconazole had significantly higher CY (p=0.0065) and DCCY (p=0.007) exposure, whereas those given itraconazole exhibited a 20% increase in CY clearance (p=0.007) and markedly elevated HCY (p<0.001) and ketoCY (p<0.001) exposure. The pattern of metabolite alterations corresponded with early hepatic and renal toxicities primarily observed in itraconazole recipients. These findings indicated that itraconazole, a potent inhibitor of CYP3A4, alters CY metabolism in a manner that increases HCY and its toxic downstream metabolites, potentially exacerbating conditioning-related toxicities. Conversely, fluconazole's inhibition of CYP2C9 may reduce HCY formation, offering a relative protective effect. [1], [2]
Voriconazole, posaconazole, and isavuconazole are important broad antifungal spectrum in hematology/oncology patients, which may present problems when co-administered with antineoplastic agents, primarily due to inhibition of CYP450 enzymes and transport proteins (i.e., P-gp and breast cancer resistance protein). Among the notable interactions, voriconazole and posaconazole were associated with increased plasma concentrations of substrates metabolized by CYP3A4, thereby elevating the risk of toxicity and QT prolongation. In contrast, isavuconazole exhibited a milder inhibitory effect on CYP3A4 and a unique QT-shortening profile, suggesting a potentially safer alternative in patients receiving concomitant cardiotoxic agents. Impaired cylophosphamide metabolism and resultant increased exposure have been noted in patients co-treated with azole antifungals like itraconazole, fluconazole, and ketoconazole, potentially due to CYP2B6 inhibition; however, data on isavuconazole as a CYP2B6 inducer suggest it might reduce cyclophosphamide levels, but is not conclusively confirmed. Treatment with cyclophosphamide has been associated with cardiac arrhythmias such as supraventricular arrhythmias, including atrial fibrillation, and ventricular arrhythmias, including severe QT prolongation. [3], [4]
A pharmacokinetic study (Table 1) investigated interactions between cyclophosphamide and three triazole antifungals (fluconazole, itraconazole, and ketoconazole) using physiologically based pharmacokinetic (PBPK) modeling. To assess interactions, simulations were conducted using Simcyp software, evaluating single and multiple-dose regimens of orally administered triazoles with intravenous cyclophosphamide in virtual cancer populations. Model validation was performed by comparing simulated results with existing clinical pharmacokinetic data, ensuring reliability with fold-error values below two for key pharmacokinetic parameters. The 2019 PBPK modeling study demonstrated that all three triazole antifungals increased cyclophosphamide plasma exposure, but with varying extents of interaction. After a single dose, coadministration with fluconazole, itraconazole, or ketoconazole increased the area under the concentration-time curve (AUC) of cyclophosphamide by 10%, 17%, and 76%, respectively. With multiple doses, these increases were more pronounced, reaching 29% for fluconazole, 63% for itraconazole, and 102% for ketoconazole. Ketoconazole exhibited the strongest inhibitory effect due to its potent CYP3A4 inhibition, whereas fluconazole, a weaker inhibitor of CYP3A4, had the least impact. These findings suggest that concurrent use of triazole antifungals, particularly ketoconazole, necessitates close monitoring for potential cyclophosphamide toxicity, reinforcing the need for careful antifungal selection in oncology settings. [1]
A 2021 study investigated the potential drug interaction between cyclophosphamide and voriconazole via CYP2B6 inhibition using a combination of in vitro, in vivo, and database-driven pharmacovigilance approaches. The inhibitory potential of voriconazole on CYP2B6 was assessed through an in vitro cocktail incubation method, demonstrating an IC50 of 0.12 µM, indicating potent inhibition. In mouse liver microsomes, voriconazole suppressed the formation of 4-hydroxycyclophosphamide, the active metabolite of cyclophosphamide, by over 90% at concentrations of 10 µM and above. A pharmacokinetic study in mice co-administered with cyclophosphamide and voriconazole revealed a 2.3-fold increase in cyclophosphamide blood concentrations, confirming the inhibition of its metabolic activation. Additionally, cyclophosphamide-induced toxicities, including alopecia and leukopenia, were significantly attenuated when administered with voriconazole, supporting a clinically relevant interaction. An analysis of adverse event reporting systems, including data from FAERS and JADER, further corroborated this interaction. The proportional reporting ratio for cyclophosphamide-associated neutropenia, hemorrhagic cystitis, and alopecia was significantly reduced when cyclophosphamide was co-prescribed with voriconazole, fluconazole, or itraconazole. Notably, in the FDA Adverse Events Reporting System, the proportional reporting ratio for alopecia with voriconazole was reduced approximately 30-fold, removing the adverse event signal entirely. These findings suggest that the inhibition of CYP2B6-mediated cyclophosphamide activation by voriconazole alters both pharmacokinetics and therapeutic outcomes, highlighting the need for clinical awareness of potential drug interactions that may compromise efficacy in chemotherapy regimens. [5]