Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats.

Abstract

Oxaliplatin (L-OHP) is a third-generation, platinum-based chemotherapeutic agent and is widely used in gastroenterological cancer regimens. It is important to complete chemotherapy cycles to improve treatment efficacy for cancer patients. However, undesirable side effects, including acute and chronic neuropathies, and myelosuppression, lead to the discontinuation of chemotherapy in some treatment regimens. To predict and prevent the onset of side effects, and to establish appropriate dose adjustment, pharmacokinetic and toxicodynamic studies were performed to investigate the effects of L-OHP in rats. Rats were administered intravenous L-OHP, once a week for 4weeks, at doses of 3, 5, or 8mg/kg. Pharmacokinetic profiles were observed on Day 1 and Day 22. Acute and chronic neuropathies were evaluated over 4weeks; cold allodynia was evaluated using an acetone test and mechanical allodynia using the von Frey test. Hematological parameters were also investigated during the same period. The mean AUC0-∞ values for L-OHP were 0.4±0.2, 2.4±0.4, and 3.5±0.9ngh/mL, increasing dose-dependently on Day 1. The accumulation of L-OHP on Day 22 was observed after repeated administration of L-OHP, as shown by mean AUC0-∞ values of 0.6±0.2, 4.0±1.0, and 14.1±9.8 ng·h/mL, for the three doses. Cold allodynia was observed from Day 3 in the 5 and 8mg/kg groups, and the extent of this response was dose-dependent. Mechanical allodynia was also observed from Day 10 in the 5 and 8mg/kg groups. Moreover, the platelet count was the most sensitive among the hematological parameters. These results provide useful experimental data for clinical cancer patients undergoing chemotherapy, to establish a pharmacokinetic and toxicodynamic model of L-OHP for adequate dose adjustment.