Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy
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 effica...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/2/125 |
| _version_ | 1828152975195897856 |
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| author | Shinji Kobuchi Risa Shimizu Yukako Ito |
| author_facet | Shinji Kobuchi Risa Shimizu Yukako Ito |
| author_sort | Shinji Kobuchi |
| collection | DOAJ |
| description | 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<sup>®</sup> 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. |
| first_indexed | 2024-04-11T22:18:53Z |
| format | Article |
| id | doaj.art-2a3c6e6d51734a7ea9992e7d5bd67bb3 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T22:18:53Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2a3c6e6d51734a7ea9992e7d5bd67bb32022-12-22T04:00:15ZengMDPI AGPharmaceutics1999-49232020-02-0112212510.3390/pharmaceutics12020125pharmaceutics12020125Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic NeuropathyShinji Kobuchi0Risa Shimizu1Yukako Ito2Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, JapanDepartment of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, JapanDepartment of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, JapanOxaliplatin (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<sup>®</sup> 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.https://www.mdpi.com/1999-4923/12/2/125pharmacokinetic-toxicodynamic modelingperipheral neuropathycancer chemotherapyplatinum compoundpersonalized therapytoxicology |
| spellingShingle | Shinji Kobuchi Risa Shimizu Yukako Ito Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy Pharmaceutics pharmacokinetic-toxicodynamic modeling peripheral neuropathy cancer chemotherapy platinum compound personalized therapy toxicology |
| title | Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy |
| title_full | Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy |
| title_fullStr | Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy |
| title_full_unstemmed | Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy |
| title_short | Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy |
| title_sort | semi mechanism based pharmacokinetic toxicodynamic model of oxaliplatin induced acute and chronic neuropathy |
| topic | pharmacokinetic-toxicodynamic modeling peripheral neuropathy cancer chemotherapy platinum compound personalized therapy toxicology |
| url | https://www.mdpi.com/1999-4923/12/2/125 |
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