Academic Journal
Population Pharmacokinetic Model of Platinum Disposition in Cancer Patients Receiving Cisplatin and Randomized to 5‐HT3 Antagonist Antiemetic Drugs.
| Title: | Population Pharmacokinetic Model of Platinum Disposition in Cancer Patients Receiving Cisplatin and Randomized to 5‐HT |
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| Authors: | Thompson, Lauren E., Ghimire, Avisek, Wen, Xia, Kim, Christine, Doherty, Cathleen L., Buckley, Brian T., Bowles, Daniel W., O'Bryant, Cindy L., Jaimes, Edgar A., Aleksunes, Lauren M., Joy, Melanie S. |
| Source: | Journal of Clinical Pharmacology; Jun2025, Vol. 65 Issue 6, p763-778, 16p |
| Subject Terms: | Biological models, Pearson correlation (Statistics), Cisplatin, Research funding, Blood chemical analysis, T-test (Statistics), Antiemetics, Statistical sampling, Kruskal-Wallis Test, Cancer patients, Randomized controlled trials, Descriptive statistics, Mann Whitney U Test, Cancer chemotherapy, Longitudinal method, Mass spectrometry, One-way analysis of variance, Comparative studies, Platinum, Serotonin antagonists, Regression analysis |
| Geographic Terms: | United States |
| Abstract: | Cisplatin is a platinum‐based chemotherapeutic drug used to treat many types of cancer. The aim of this study was to develop a population pharmacokinetic model that incorporates plasma unbound and bound platinum levels. Cancer patients undergoing their first or second cycle of cisplatin‐containing chemotherapy (n = 33) were prospectively randomized to receive a 5‐hydroxytryptamine (5‐HT3) antagonist (5‐HT3A) antiemetic (ondansetron, granisetron, or palonosetron) followed by blood collection over 10 days. Total and unbound platinum levels were quantified using inductively coupled plasma mass spectrometry. Plasma concentrations of bound and unbound platinum were used to develop a nonlinear mixed‐effect pharmacokinetic model in Phoenix NLME (v8.3, Certara Inc.). A stepwise search was used to screen covariates that influenced pharmacokinetic parameters. A compartment for bound platinum was added to a two‐compartment unbound platinum model to create a combined platinum model. The volume of the central compartment for unbound platinum (V1_u) was significantly impacted by previous cisplatin exposure and the intercompartmental clearance of unbound platinum (CL2_u) was significantly influenced by concomitant lorazepam use. The models also suggested ondansetron‐ and granisetron‐treated subjects had a 331% and 114% increase, respectively, in circulating exposures to unbound platinum than palonosetron‐treated subjects. The results suggest platinum pharmacokinetics are altered by concomitant 5‐HT3A antiemetic use, concomitant lorazepam use, and previous exposure to cisplatin. Ondansetron and granisetron co‐treatment increased unbound platinum exposure compared to palonosetron co‐treatment, suggesting that palonosetron may be a preferred 5‐HT3A to reduce the risk of cisplatin‐induced kidney injury. [ABSTRACT FROM AUTHOR] |
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| Database: | Complementary Index |
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