Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of oxaliplatin for hematological toxicity in rats.

Oxaliplatin (L-OHP) is a platinum (Pt)-based anticancer agent and is widely used for treating gastroenterological cancer. However, L-OHP-induced hematological toxicity is a critical undesirable effect that limits the dose of L-OHP. An ideal chemotherapeutic strategy that avoids severe hematological toxicity while maintaining positive chemotherapeutic outcomes has not been established for L-OHP. In this study, a pharmacokinetic-pharmacodynamic (PK-PD) model was developed that can link the associations between L-OHP administration regimens and the risk of hematological toxicity.The plasma concentration of L-OHP and neutrophil, lymphocyte and platelet counts after L-OHP (3, 5, and 8 mg/kg) administration to rats were used to develop the PK-PD model. The mechanism-based PK-PD model comprised a semi-physiological PD model that adequately described and simulated the entire time-course of alterations in blood cell counts.The model-based simulation proposed that a combination of the PK-PD model and monitoring of platelet counts throughout L-OHP-based chemotherapy is a valuable approach to determine an individualized optimal dosing strategy including the washout period.The current results might provide a framework for population PK-PD model analysis using hematological data of patients receiving L-OHP and investigations of chemotherapeutic strategies that are difficult to address in patients.

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

PURPOSE: 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. METHODS: Rats were administered intravenous L-OHP, once a week for 4 weeks, at doses of 3, 5, or 8 mg/kg. Pharmacokinetic profiles were observed on Day 1 and Day 22. Acute and chronic neuropathies were evaluated over 4 weeks; 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. RESULTS: The mean AUC0-∞ values for L-OHP were 0.4 ± 0.2, 2.4 ± 0.4, and 3.5 ± 0.9 ng h/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 8 mg/kg groups, and the extent of this response was dose-dependent. Mechanical allodynia was also observed from Day 10 in the 5 and 8 mg/kg groups. Moreover, the platelet count was the most sensitive among the hematological parameters. CONCLUSION: 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.