Background <p>Granisetron, a selective 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist, is widely used for the prevention and treatment of chemotherapy-induced nausea-vomiting in patients with cancer. However, quantitative data describing differences in in vivo pharmacokinetics (PK) among available formulations, including intravenous, oral, subcutaneous, and transdermal patches, and comparative drug concentrations at pharmacological target tissues, such as the central chemoreceptor trigger zone and enterovagal nerve terminals, remain limited.</p> Purpose <p>This study aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to predict systemic and pharmacological target tissue concentrations of granisetron across multiple routes of administration and to elucidate route-specific PK and target-tissue exposure characteristics to support optimization of antiemetic therapy.</p> Methods <p>A PBPK model was developed using literature-derived clinical PK data integrated with human physiological parameters and relevant in vitro data. The model was calibrated and validated against single-dose and multiple-dose clinical datasets. Predictive performance was evaluated using the ratio of model-predicted values ​​to observed values ​​and the proportion of observed data captured within prediction intervals. Subsequently, granisetron concentrations in pharmacological target tissues were simulated at clinically relevant doses for each route of administration.</p> Results <p>The PBPK model accurately reproduced plasma concentration-time profiles for all administration routes and demonstrated acceptable predictive accuracy for key PK parameters. Tissue-level simulations showed that intravenous and oral administration produced rapid and high central exposure, with oral administration reflecting rapid gastrointestinal absorption into the systemic circulation. In contrast, the transdermal patch provided sustained and stable central and peripheral exposure, whereas subcutaneous administration yielded prolonged systemic exposure compared with intravenous and oral dosing, resulting in intermediate systemic and target-tissue exposure. Distinct tissue exposure profiles and exposure durations were observed for each formulation.</p> Conclusion <p>This study provides the first PBPK-based quantitative characterization of granisetron PK and target-tissue exposure across clinically relevant routes of administration. The findings support route-specific optimization of antiemetic therapy according to patient characteristics and clinical context. Furthermore, the developed model may facilitate personalized supportive care in oncology, including applications in vulnerable populations (e.g., older adults, individuals with hepatic impairment, pregnant patients), as well as formulation development research.</p>