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Abstract: FR-PO223

5-HT3 Antagonist Antiemetic Drugs Alter Cisplatin Pharmacokinetics and Risk of Nephrotoxicity

Session Information

  • Pharmacology
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)

  • 1900 Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)

Authors

  • Thompson, Lauren E., University of Colorado Health, Aurora, Colorado, United States
  • Wen, Xia, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
  • Jorgensen, Justine, Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Palan, Jordan, University of Colorado Health, Aurora, Colorado, United States
  • Doherty, Cathleen, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
  • Buckley, Brian, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
  • Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Aleksunes, Lauren, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
  • Joy, Melanie S., University of Colorado Health, Aurora, Colorado, United States
Background

Cisplatin, a common chemotherapeutic, causes acute kidney injury (AKI) in up to one-third of patients. Previous reports have indicated that maximum plasma concentration (Cmax) or area under the plasma concentration vs time curve (AUC) of platinum increase risk of AKI. Ondansetron, a commonly co-prescribed 5-HT3 antagonist antiemetic drug in patients receiving cisplatin-containing chemotherapy, has been associated with enhanced risk of AKI in rodents and retrospective clinical studies. However, to date, there has been no prospective evaluation of AKI risk in patients randomized to different 5-HT3 antagonist drugs.

Methods

As part of study NCT03817970, an initial group of patients (n=23) undergoing their first or second round of cisplatin chemotherapy (≥25 mg/m2) were prospectively randomized to one of three antiemetic drugs (ondansetron 8 mg p.o., granisetron 2 mg p.o., or palonosetron 0.25 mg i.v.). Total platinum plasma concentrations were quantified using inductively coupled plasma-mass-spectrometry (ICP/MS). Pharmacokinetic analyses were performed, and parameters were compared based on 5-HT3A treatment using one-way ANOVAs with Tukey-Kramer post-hoc tests. All analyses were performed using R and Certara Phoenix™.

Results

Patients randomized to receive ondansetron had significantly increased total platinum plasma Cmax levels (normalized by cisplatin dose) compared to patients receiving granisetron (102% increase) or palonosetron (81% increase) (p=0.005). Moreover, ondansetron-treated patients had the highest AUC from 0-2 hours (normalized by cisplatin dose) (granisetron: 83% increase; palonosetron: 40% increase; p=0.147) and the largest average decrease in estimated glomerular filtration rate (eGFR) following cisplatin treatment compared to granisetron (408% decrease) and palonosetron-treated (173% decrease) patients (p=0.170).

Conclusion

Cisplatin-treated cancer patients prescribed ondansetron for the prevention of emesis exhibited decreased kidney function when compared to patients receiving granisetron or palonosetron. Future work will expand analyses to include additional patients, urinary excretion of cisplatin, and urinary biomarkers of kidney injury.

Funding

  • NIDDK Support