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

Abstract

Buoyed by the discovery of small-molecule tyrosine kinase inhibitors (smTKI), significant impact has been made in cancer chemotherapeutics. However, off-target toxicities and suboptimal efficacies are still encountered with some of these agents due to their inferior biopharmaceutical and/or pharmacokinetic properties. Almost all of these molecules exhibit significant inter- and intra-patient differences 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 a promising approach in providing drug encapsulation or spatiotemporal control over the release to overcome the biopharmaceutical and pharmacokinetic limitations and improve the therapeutic outcomes. In this context, the present review comprehensively tabulates and critically analyses all the relevant properties (T1/2, solubility, pKa, therapeutic index, IC50, metabolism etc.) of the approved smTKIs, which should enable an informed selection of a drug amongst this class of therapeutics for development into complex formulations. Detailed appraisal of the advances made in complex formulations of smTKIs, focusing on strategies to enhance their pharmacokinetic profile, tumor targeting ability, and therapeutic efficacy. Various nanocarrier platforms, including micelles, polymeric nanoparticles, liposomes, nanosponges, nanocrystals, nanocapsules, and carbon nanotubes (CNTs), 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 complex formulations of smTKIs in near future thus, the paper concludes with key recommendations for developing complex formulations of smTKI so that early clinical translation is realized.