Drug-drug interactions with tyrosine-kinase inhibitors

In their Review, Roelof van Leeuwen and colleagues1 recommend various dose adjustments during concomitant use of tyrosine-kinase inhibitors and drugs that inhibit or induce cytochrome P450 3A4 (CYP3A4).1 Most information is taken from the US Food and Drug Administration (FDA)'s drug label or the European Medicines Agency (EMA)'s Summary of Product Characteristics. However, we could not find support for their advice regarding concomitant use of pazopanib and strong CYP3A4 inducers such as carbamazepine. They suggested to gradually increase the pazopanib dose in 200 mg steps depending on patient's tolerance,1 whereas both the FDA and EMA recommend that concomitant use should be avoided, and that the dose of pazopanib should not exceed 800 mg.2 and 3 We are unaware of clinical evidence for safety and efficacy of dose enhancement. By contrast, concomitant use and enhancement might result in carbamazepine toxic effects, because pazopanib can also act as a CYP3A4 inhibitor,2, 3 and 4 whereas carbamazepine is not only a CYP3A4 inducer, but also a CYP3A4 substrate with a narrow therapeutic index. We wonder which evidence supports the dosing guidelines that have been recommended by the authors.1

The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (employers of FV) has received unrestricted research funding from the Netherlands Organisation for Health Research and Development, the Dutch Health Insurance Board, the Royal Dutch Association for the Advancement of Pharmacy, the private–public funded Top Institute Pharma (EU Innovative Medicines Initiative, EU 7th Framework Program), the Dutch Medicines Evaluation Board, the Dutch Ministry of Health, and industry (GlaxoSmithKline, Pfizer, and others).