# Exposure–Response Relationships for Toceranib in Dogs with Solid Tumors: A Pilot Study

## TL;DR

This study explores how blood levels of toceranib in dogs with tumors relate to its effectiveness and side effects, suggesting monitoring drug levels could help adjust doses for better safety and outcomes.

## Contribution

The study establishes the feasibility of therapeutic drug monitoring for toceranib in dogs with solid tumors.

## Key findings

- Steady-state plasma concentrations of toceranib were achieved within one week in dogs.
- Higher peak concentrations may increase the risk of adverse events, though not significantly.
- Pharmacokinetic monitoring could help optimize toceranib dosing and reduce toxicity.

## Abstract

Toceranib phosphate, the most commonly used tyrosine kinase inhibitor in veterinary oncology, meets most of the criteria for therapeutic drug monitoring (TDM); however, its exposure–response relationships have not been established. Therefore, we evaluated correlations between plasma toceranib phosphate concentrations and its efficacy and safety in dogs with solid tumors and explored its feasibility for TDM. In this study, we included 10 dogs with seven solid tumors, including hepatocellular carcinoma (n = 4), squamous cell carcinoma (n = 1), soft tissue sarcoma (n = 1), histiocytic sarcoma (n = 1), oral malignant melanoma (n = 1), mammary carcinoma (n = 1), and pulmonary carcinoma (n = 1). A steady-state plasma concentration was achieved within 1 week. A higher steady-state peak plasma concentration may be associated with an increased risk of adverse events. Although large-scale studies are needed, our findings indicate that toceranib phosphate is a suitable candidate for TDM and suggest that adjusting its dose based on drug exposure could prevent toxicity.

The existence of considerable interpatient variability in pharmacokinetic exposure necessitates dose adjustment to avoid potential adverse events and suboptimal efficacy in targeted therapy. Exposure–response relationships for toceranib phosphate (TOC), the most commonly used tyrosine kinase inhibitor in veterinary oncology, remain unclear. Correlations between TOC exposure and efficacy and safety were evaluated in dogs with solid tumors in our study. Plasma TOC was analyzed at 6 and 48 h post-administration. For the 10 dogs in the exposure–response analysis, the mean interpatient variabilities in dose-normalized peak (Cmax) and trough (Cmin) concentrations were 29% and 61%, respectively. Dose-normalized Cmax did not differ among weeks 1, 4, and 12 (p = 0.414), suggesting that steady-state plasma levels can be achieved within 1 week. Pharmacokinetic exposure at steady state was not significantly associated with efficacy (week 1 Cmax, p = 0.941; average Cmax, p = 0.548). Cmax was positively but nonsignificantly associated with the risk of adverse events (week 1 Cmax, p = 0.190; average Cmax, p = 0.109). These findings suggest the value of pharmacokinetic monitoring in optimizing TOC dosage and reducing its adverse effects in dogs with solid tumors. Clinicians should consider plasma TOC when managing TOC treatment in small-animal practice.