Abstract
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.
Highlights
The platinum (Pt)-based anticancer agent oxaliplatin (L-OHP) is a key drug used for the treatment of advanced or metastatic colorectal cancer in some chemotherapy regimens, including CapOX (L-OHP and capecitabine), SOX (L-OHP and S-1), and FOLFOX (L-OHP and 5-fluorouracil/leucovorin) [1,2,3,4]
These results indicated that selection of an appropriate PK model for L-OHP would be needed when extending the range of applications of the current PK-TD model to clinical data analysis
We successfully developed a PK-TD model for prediction of L-OHP-induced acute and chronic neuropathy and determined the quantitative relationship between dosing regimen and magnitude of neuropathy
Summary
The platinum (Pt)-based anticancer agent oxaliplatin (L-OHP) is a key drug used for the treatment of advanced or metastatic colorectal cancer in some chemotherapy regimens, including CapOX (L-OHP and capecitabine), SOX (L-OHP and S-1), and FOLFOX (L-OHP and 5-fluorouracil/leucovorin) [1,2,3,4]. Despite favorable antitumor effects of L-OHP, undesirable adverse effects such as nausea, vomiting, myelosuppression, and peripheral neuropathy contribute to treatment failure. Acute and chronic peripheral neuropathy are well-known frequent and serious toxic effects of L-OHP, resulting in discontinuation of chemotherapy and poor prognosis [7,8]. A challenge to improving clinical outcomes in L-OHP-based chemotherapy is to elucidate mechanisms of drug-induced peripheral neuropathy and to develop alternative dosing strategies that do not induce severe peripheral neuropathy
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