Population Pharmacokinetic Model of Platinum Disposition in Cancer Patients Receiving Cisplatin and Randomized to 5‐HT3 Antagonist Antiemetic Drugs
Year: 2024
Type: article
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.
DOI: 10.1002/jcph.6177
Authors: Lauren E. Thompson, Avisek Ghimire, Xia Wen, Christine Kim, Cathleen L. Doherty, Brian T. Buckley, Daniel W. Bowles, Cindy L. O'Bryant, Edgar A. Jaimes, Lauren M. Aleksunes, Melanie S. Joy
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Memorial Sloan-Kettering Cancer Center, Rutgers Cancer Institute of New Jersey, National Institutes of Health, Cancer Center, University of Colorado, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, Colorado Clinical and Translational Sciences Institute
Awards: G1565180698, G1993201387, G2051006376, G2546823016, G259225883, G2803343078, G289723095, G3298087253, G3670273158, G3759531971, G3797236039, Drug Disposition and Nephrotoxicity, G5029337574, G9000003249, G9000009221, G9000039344, G9000049131, G9000113935, G9000148806, Cancer Center Support Grant, Cancer Center Support Grant, Training in Environmental Toxicology, University of Colorado Cancer Center Support Grant, Colorado Clinical and Translational Sciences Institute (CCTSI), G9001225491, G955892510, G979940031
OpenAlex ID: W4405695088