Abstract
<title>Abstract</title> <p> <bold>Background:</bold> Oral tyrosine kinase inhibitors (TKIs) have converted the management of numerous malignancies, but many are Biopharmaceutics Classification System (BCS) class II or IV compounds whose absorption is highly sensitive to co-administration with food. Reported food effects on maximum plasma concentration (Cmax) and area under the curve (AUC) range from negligible to several-fold changes, with direct implications for efficacy, toxicity, and dosing guidance. <bold>Objectives:</bold> To quantify, for each FDA-approved oral anti-cancer TKI individually, the effect of food (and of meal fat/caloric content) on AUC and Cmax relative to the fasted state, and to explore population, dosing-condition, and physicochemical determinants of this effect. <bold>Methods:</bold> This protocol was developed in accordance with the PRISMA-P 2015 statement and registered with PROSPERO. PubMed, Scopus, Embase, Web of Science, Google Scholar, and the FDA regulatory review databases will be searched from January 2000 to the end of 2025 for randomized or fixed-sequence crossover trials reporting AUC and/or Cmax under fed and fasted conditions. Two reviewers will independently screen studies, extract data in duplicate, and assess risk of bias with the extended Cochrane RoB 2 tool for crossover trials. Pharmacokinetic parameters will be analyzed on the log-transformed scale; where only arithmetic means and standard deviations are reported, Taylor-series approximations will be used to derive the corresponding log-scale statistics, and the standard error of the within-subject difference will be computed incorporating an imputed or reported within-subject correlation coefficient. Drug-specific random-effects and, where sufficient conditions are reported, network meta-analyses will pool the ratio of geometric means (RoGM) for AUC and Cmax; meta-regression will examine physicochemical and pharmacokinetic moderators. <bold>Ethics and dissemination:</bold> No original patient data will be collected and formal ethics approval is not required. Findings will be disseminated through peer-reviewed publication and conference presentation and are intended to inform evidence-based food-intake recommendations for oral TKI administration. </p>