Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors

Buoyed by the discovery of small-molecule tyrosine kinase inhibitors (smTKIs), significant impact has been made in cancer chemotherapeutics. However, some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties. Almost all of these molecules exhibit significant inter- and intra-patient variations in plasma concentration-time profiles. Thus, therapeutic drug monitoring, dose adjustments and precision medicine are being contemplated by clinicians. Complex formulations or nanoformulation-based drug delivery systems offer promising approaches to provide drug encapsulation or spatiotemporal control over the release, overcoming the biopharmaceutical and pharmacokinetic limitations and improving the therapeutic outcomes. In this context, the present review comprehensively tabulates and critically analyzes all the relevant properties (T1/2 , solubility, pKa , therapeutic index, IC50 , metabolism etc.) of the approved smTKIs. A detailed appraisal is conducted on the advancements made in complex formulations of smTKIs, with a focus on strategies to enhance their pharmacokinetic profile, tumor targeting ability, and therapeutic efficacy. Various nanocarrier platforms, have been discussed, highlighting their unique features and potential applications in cancer therapy. Nanoformulations have been shown to improve area under the curve and peak plasma concentration, and reduce dosing frequency for several smTKIs in animal models. It is inferred that extensive efforts will be made in developing complex formulations of smTKIs in near future. There, the review concludes with key recommendations for the developing of smTKIs to facilitate early clinical translation.