Drug-to-drug interactions of tyrosine kinase inhibitors in chronic myeloid leukemia patients. Is it a real problem?

Abstract

With tyrosine kinase inhibitors (TKI), chronic myeloid leukemia (CML) patients are achieving similar rates of survival to the general population and some treatment aspects such as adherence and drug-to-drug interactions (DDI) are becoming increasingly important. Our aim was to investigate the frequency and real clinical consequences of DDI between TKI and concurrent medications in CML. We performed a retrospective multicenter study including 105 patients receiving 134 TKI treatments. Sixty-three patients (60%) had at least one potential DDI. The mean number of concomitant medications was 4.8 (0-19). The mean number of DDI by TKI treatment was 1.2 (0-8); it increased with the number of concomitant medications and age in a significant manner. A total of 159 DDI were detected, involving 55 different drugs. The most common drug classes involved were proton pump inhibitors, statins, and antidepressants. A DDI-related clinical effect (toxicity and/or lack of efficacy) was suspected during the common course of patient follow-up in only five patients (4.7%). This number increased to 20% when data were centrally reviewed. Most of the adverse events (AE) attributed to DDIs were mild. The most common were diarrhea, vomiting, edema, cramps, and transaminitis. Nilotinib and dasatinib showed a tendency towards a higher risk of DDI compared with imatinib. There were no significant differences in AE frequency or in treatment response between patients with or without DDI. Due to their frequency, and their potential to cause clinically relevant effects, DDI are an important aspect of CML management.

Psychotropic drug initiation in patients diagnosed with chronic myeloid leukemia: a population‐based study in France

“…Thus, our study is to our knowledge the first to focus on PD initiation in both previously exposed and unexposed patients. Eventually, investigating comedications of CML patients seems highly relevant, due to the risk of drug–drug interactions .…”

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…Bosutinib, dasatinib, imatinib, nilotinib, and ponatinib are metabolized in the liver by cytochrome P450 (CYP) enzymes, and concomitant use of drugs that induce or inhibit CYP3A4 or CYP3A5 enzymes may alter the therapeutic effect of TKIs. 153,154 Drugs that are CYP3A4 or CYP3A5 inducers may decrease the therapeutic plasma concentration of TKIs, whereas CYP3A4 inhibitors and drugs that are metabolized by the CYP3A4 or CYP3A5 enzyme might result in increased plasma levels of TKIs. In addition, imatinib is also a weak inhibitor of the CYP2D6 and CYP2C9 isoenzymes and nilotinib is a competitive inhibitor of CYP2C8, CYP2C9, CYP2D6, and UGT1A1, potentially increasing the plasma concentrations of drugs eliminated by these enzymes.…”

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