Optimizing intermittent dosing of oral small molecule inhibitors

Abstract

Introduction

With recent expansion of oral small molecule inhibitors, the drug development studies need to provide insight into optimal dose selection for these agents with vastly different mechanism and pharmacokinetic considerations compared to our traditional chemotherapy agents. Currently there is one published meta-analysis that examines intermittent and alternative dosing of oral small molecule inhibitors and it is unclear what guidance is available for treatment personalization beyond package insert labeling for patients undergoing toxicities from treatment.

Methods

A systematic review of oral small molecule inhibitors with intermittent dosing was conducted in the National Library of Medicine PubMed database. Studies were selected based on predefined inclusion/exclusion criteria. Data was extracted to summarize findings on available guidance for intermittent or alternative dosing of oral small molecule inhibitors. Studies were categorized based on food and drug administration (FDA) approved or non-FDA approved agents, and further characterized by comparison of different dosing schemas.

Results

Fifty-five trials were included in the final review and data analysis. Thirty-three trials were phase 1 trials, 26 trials for FDA approved agents and 29 non-FDA approved agents. Most trials reported on agents used in solid tumors, particularly renal cell carcinoma, with most trials examining sunitinib. Of the 55 trials, 28 compared different dosing strategies with 26 of the 28 trials examining efficacy outcomes with 27 of the 28 trials examining safety outcomes.

Conclusions

This systematic review found limited guidance for clinicians in optimizing dosing for intermittently dosed oral small molecule inhibitors.