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Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy

Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
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Pharmaceutics 2020, 12(2), 125; https://doi.org/10.3390/pharmaceutics12020125
Received: 4 December 2019 / Revised: 21 January 2020 / Accepted: 28 January 2020 / Published: 3 February 2020
Oxaliplatin (L-OHP) is widely prescribed for treating gastroenterological cancer. L-OHP-induced peripheral neuropathy is a critical toxic effect that limits the dosage of L-OHP. An ideal chemotherapeutic strategy that does not result in severe peripheral neuropathy but confers high anticancer efficacy has not been established. To establish an optimal evidence-based dosing regimen, a pharmacokinetic-toxicodynamic (PK-TD) model that can characterize the relationship between drug administration regimen and L-OHP-induced peripheral neuropathy is required. We developed a PK-TD model of L-OHP for peripheral neuropathy using Phoenix® NLME™ Version 8.1. Plasma concentration of L-OHP, the number of withdrawal responses in the acetone test, and the threshold value in the von Frey test following 3, 5, or 8 mg/kg L-OHP administration were used. The PK-TD model consisting of an indirect response model and a transit compartment model adequately described and simulated time-course alterations of onset and grade of L-OHP-induced cold and mechanical allodynia. The results of model analysis suggested that individual fluctuation of plasma L-OHP concentration might be a more important factor for individual variability of neuropathy than cell sensitivity to L-OHP. The current PK-TD model might contribute to investigation and establishment of an optimal dosing strategy that can reduce L-OHP-induced neuropathy. View Full-Text
Keywords: pharmacokinetic-toxicodynamic modeling; peripheral neuropathy; cancer chemotherapy; platinum compound; personalized therapy; toxicology pharmacokinetic-toxicodynamic modeling; peripheral neuropathy; cancer chemotherapy; platinum compound; personalized therapy; toxicology
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MDPI and ACS Style

Kobuchi, S.; Shimizu, R.; Ito, Y. Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy. Pharmaceutics 2020, 12, 125. https://doi.org/10.3390/pharmaceutics12020125

AMA Style

Kobuchi S, Shimizu R, Ito Y. Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy. Pharmaceutics. 2020; 12(2):125. https://doi.org/10.3390/pharmaceutics12020125

Chicago/Turabian Style

Kobuchi, Shinji, Risa Shimizu, and Yukako Ito. 2020. "Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy" Pharmaceutics 12, no. 2: 125. https://doi.org/10.3390/pharmaceutics12020125

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