Therapeutic drug monitoring (TDM) is a cost-effective tool to increase treatments’ efficacy and safety. Analyses of pharmacokinetics proprieties of tyrosine kinase inhibitors (TKI) used for chronic myeloid leukemia (CML) can contribute towards effective TDM, development of tailored treatments and new dosing regimens. We aimed to synthesize the available evidence on pharmacokinetic parameters of imatinib, nilotinib, bosutinib, ponatinib in healthy individuals vs. CML patients.

Systematic searches were conducted in PubMed, Scopus and Web of Science. We included in vivo studies addressing TKIs’ pharmacokinetics, including maximum observed concentration (Cmax), time of maximum observed concentration (Tmax) and half-life (t1/2). Meta-analyses of event rates (mixed-effect models) were performed for the parameters of interest: area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) and from time zero to infinity (AUC 0-∞). Results were presented as event rates with 95 percent confidence intervals. Heterogeneity was assessed using chi-square and I2 statistical tests and considered significant when p<0.05 and high when I2>75 percent (Comprehensive Meta-Analysis v.2 Biostat-Englewood, NJ).

Overall, 50 articles were included for analyses (n=26 imatinib, n=11 nilotinib, n=8 bosutinib, n=5 ponatinib). Most studies were performed in the United States (46.0%), designed as open-label trials (70.0%). Several significant interactions between TKI with enzyme inhibitors (ketoconazole, midazolam, aprepitant, metoprolol, grapefruit juice), proton pump inhibitors (esomeprazole, lanzoprazole, omeprazole), antacids, H2 antagonists (famotidine) and enzyme inducers (St. John’s, rifampicin) were found (p<0.001). Given the significant increase in AUC and Cmax in patients with hepatic/liver impairments currently using TKI, strict therapeutic monitoring is paramount to maintain safety. The between study heterogeneity was rated as moderate to high (I2=75-90%) due the limited number of trials for some drugs, different study design, and populations.

The co-administration of TKI with hepatic enzyme inducers or inhibitors, proton pump inhibitors, antacids, H2 antagonists, as well as in patients with hepatic/liver failures requires caution and additional monitoring. Further well-designed trials are needed to strengthen this evidence for some TKIs, namely bosutinib and ponatinib.