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Abstract: TH-PO0837

Pharmacokinetic/Toxicodynamic Model of Platinum Kidney Injury Using Urinary Calbindin and Beta-2-Microglobulin as Biomarkers

Session Information

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

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

Authors

  • Ghimire, Avisek, Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States
  • Thompson, Lauren E., Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States
  • Asby, Sarah C., Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States
  • Wen, Xia, Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, United States
  • Kim, Christine, Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, United States
  • Doherty, Cathleen, Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, United States
  • Buckley, Brian, Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, United States
  • O'Bryant, Cindy L., Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States
  • Jaimes, Edgar A., Renal Division, Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Aleksunes, Lauren, Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, United States
  • Joy, Melanie S., Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States
Background

Cisplatin is a platinum-based alkylating agent associated with clinical acute kidney injury in one-third of patients as assessed by serum creatinine. Urinary calbindin and β-2-microglobulin (B2M) are validated biomarkers that significantly increase after treatment with cisplatin. The aim of this study was to develop a population pharmacokinetic / toxicodynamic (PKTD) model of cisplatin induced nephrotoxicity utilizing total plasma platinum (Pt), urinary calbindin, and B2M.

Methods

Blood and urine samples were collected up to 10 days after cisplatin administration in cancer patients randomized to a 5-HT3A antiemetic (ondansetron, granisetron, palonosetron; NCT03817970). Pt levels were measured using ICP/MS (LOQ 0.48 -2.40 ng/mL) and calbindin and B2M concentrations were quantified in urine samples using an ELISA kit and normalized to urinary creatinine. A nonlinear mixed effect population PKTD model was developed in Phoenix® NLME (v8.6.1.6, Certara Inc.). Stepwise covariate search was used for covariate analysis with a p-value of 0.05 for forward addition and 0.01 for backward deletion.

Results

Pt concentration data was described by a two-compartment model with central volume (V1), 22.79 L; peripheral volume (V2), 52.73 L; central clearance (CL1), 0.47 L/h; and intercompartmental clearance (CL2), 32.67 L/h. Significant covariate effects were first cisplatin dose on V1, 0.70; granisetron vs. ondansetron on V2, 0.49; and palonosetron vs. ondansetron on V2, 0.27. The TD estimates for calbindin were zero order turnover rate of production (Kin), 0.0013 ng/mg/h; first order turnover rate of loss (Kout), 0.00105 1/h; half maximal effective concentration (EC50), 1109.53 ng/mL; maximum calbindin level (Emax), 65.99 ng/mg and a significant covariate effect of baseline urinary calbindin on Kin, 0.63. For B2M, parameters were; Kin, 10.01 ng/mg/h; Kout, 9.67 1/h; EC50, 128.31 ng/mL and Emax, 1018.81 ng/mg. Ondansetron administration resulted in 129% higher Pt AUC, 103% higher urinary calbindin/UCr AUC and 208% higher urinary B2M/UCr AUC as compared to palonosetron.

Conclusion

Development of PKTD models using urinary biomarkers calbindin and B2M can inform the relationship between platinum blood levels, drug-drug interactions and kidney injury responses. Ondansetron treatment with cisplatin resulted in greater Pt AUC and subsequent increases in kidney injury biomarkers.

Acknowledgment

The authors would like to thank Jordan N. Palan (UCCC), Justine Jorgensen (MSKCC), and Arianna Mohan (MSKCC) for their assistance with patients recruitment and sample collection. The University of Colorado is a Certara Center of Excellence. The Center of Excellence program supports leading institutions with Certara’s state-of-the-art model-informed drug development software. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views.

Funding

  • NIDDK Support