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

Abstract

1. 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.

2. 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.

3. 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.

4. 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.

Keywords:

• Oxaliplatin
• PK–PD modeling
• myelosuppression
• cancer chemotherapy

Acknowledgments

All authors would like to acknowledge Professor Toshiyuki Sakaeda of the Department of Pharmacokinetics, Kyoto Pharmaceutical University (Kyoto, Japan) for his research guidance and suggestions. This description has been submitted to the journal in the review process of the manuscript as not review-blind file.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was supported in part by Grants-in-Aid for Scientific Research (C) (Grant No. 15K08085 and 18K06765) and Grants-in-Aid for Young Scientists (B) (Grant No. 15K18937 and 18K14963) from JSPS KAKENHI.