Is there a clinically significant interaction between fenbendazole and cabozantinib, and can they be safely co‑administered?

Fenbendazole and Cabozantinib Drug Interaction Assessment

There is no documented clinically significant pharmacokinetic or pharmacodynamic interaction between fenbendazole and cabozantinib, and they can be co-administered with standard monitoring for cabozantinib-related adverse events.

Metabolic Pathway Analysis

Fenbendazole Metabolism

• Fenbendazole undergoes hydroxylation primarily via CYP2J2 and CYP2C19 enzymes to form hydroxyfenbendazole, with CYP2C19 showing the highest activity (2.68 μl/min/pmol P450) 1
• CYP2J2 contributes secondarily to fenbendazole metabolism (1.94 μl/min/pmol P450), with rates 8.4-fold higher than CYP2D6 1
• Fenbendazole is not a strong inhibitor or inducer of CYP3A4, the primary metabolic pathway for cabozantinib 2

Cabozantinib Metabolism

• Cabozantinib is metabolized predominantly by CYP3A4 3
• Cabozantinib does not significantly inhibit or induce CYP2J2 or CYP2C19, the enzymes responsible for fenbendazole metabolism 2
• The lack of overlapping metabolic pathways indicates minimal risk of pharmacokinetic interaction 2

Practical Management Strategy

Pre-Administration Assessment

• Verify hepatic function (AST, ALT, bilirubin) before initiating fenbendazole in patients on cabozantinib, as both agents can affect liver function 2
• Review current cabozantinib dose and tolerability; if the patient has required dose reductions (which occurs in 56-79% of patients), consider timing fenbendazole during stable cabozantinib dosing 4, 2

Monitoring During Concurrent Use

• Continue established cabozantinib monitoring without alteration: thyroid function (TSH), blood pressure, complete blood count, and liver enzymes 2
• Monitor for additive gastrointestinal toxicity, as diarrhea occurs in >30% of cabozantinib patients and may be exacerbated by fenbendazole 2
• Implement prophylactic antidiarrheal therapy if baseline GI symptoms are present 2
• Maintain hydration and monitor electrolytes if diarrhea develops 2

Cabozantinib-Specific Adverse Event Management

• The most common grade 3+ adverse events with cabozantinib are palmar-plantar erythrodysesthesia (17%), hypertension (16%), elevated AST (12%), fatigue (10%), and diarrhea (10%) 3, 5
• Dose reductions are frequently required (56-62% of patients) but treatment discontinuation due to adverse events remains low (10-16%) 3, 5
• Formulation warning: Cabozantinib tablets (60 mg) and capsules (140 mg) are not bioequivalent and must not be interchanged 4, 2

Important Clinical Caveats

Safety Considerations

• The absence of documented interactions does not guarantee absolute safety, as post-marketing surveillance data for this specific combination are limited 2
• Fenbendazole is not FDA-approved for human use, and its pharmacokinetics and safety profile in humans remain incompletely characterized 6
• Clinical trials are needed to establish optimal fenbendazole dosing, therapeutic regimens, and tolerance profiles in humans 6

High-Risk Scenarios

• Exercise caution in patients with severe hepatic impairment, as both agents may increase hepatotoxicity risk 2
• Patients already experiencing significant cabozantinib adverse events should have fenbendazole initiated only after stabilization of symptoms 2
• If overlapping GI toxicity occurs, promptly evaluate for dehydration and electrolyte abnormalities requiring supportive care 2