Kidney Week

Abstract: FR-OR67

Pharmacokinetic/Toxicodynamic Approach to Evaluate Platinum Nephrotoxicity Using the Kidney Injury Molecule-1 Biomarker

Session Information

• Innovative AKI Strategies and Drug Discoveries
  October 25, 2024 | Location: Room 7, Convention Center
  Abstract Time: 05:00 PM - 05:10 PM

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

• 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Asby, Sarah C., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Sarah C. Asby

• Thompson, Lauren E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Lauren E. Thompson, PhD

• Ghimire, Avisek, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Avisek Ghimire, MS

• Wen, Xia, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Xia Wen

• Kim, Christine, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Christine Kim, PharmD

• Doherty, Cathleen, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Cathleen Doherty, MS, PhD

• Buckley, Brian, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Brian Buckley, PhD

• Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States

Edgar A. Jaimes, MD

• Aleksunes, Lauren, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States

Lauren Aleksunes, PharmD, PhD

• Joy, Melanie S., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Melanie S. Joy, PharmD, PhD, FASN

Background

Cisplatin is a platinum-based chemotherapeutic drug that causes acute kidney injury (AKI), as assessed by serum creatinine (SCr) in over 30% of patients. Urinary kidney injury molecule-1 (KIM-1) is an excellent biomarker to detect subclinical and clinical kidney injury secondary to cisplatin. The aim of this study was to develop a predictive population pharmacokinetic/toxicodynamic (PKTD) model of cisplatin-induced kidney injury that incorporates total platinum concentrations in plasma and structural kidney injury changes, as measured by KIM-1.

Methods

As part of study NCT03817970, cancer patients undergoing their first or second round of cisplatin chemotherapy (n=39) were prospectively randomized to one of three 5-HT₃A antiemetics (ondansetron, granisetron, or palonosetron) and had blood and urine collected for 10 days following cisplatin administration. Plasma total platinum concentrations were quantified using ICP/MS (LOQ 0.48-2.40 ng/mL). Urinary KIM-1 concentrations were measured using a commercial ELISA kit (R&D Systems) and normalized to urinary creatinine (UCr). Plasma concentrations of total platinum and urinary concentrations of KIM-1 were used in the development of a nonlinear mixed effect population PKTD model using Phoenix® NLME (v8.3, Certara Inc.). Covariates were screened by stepwise search to determine influence on PKTD parameters.

Results

A two-compartment pharmacokinetic model for total platinum concentrations in plasma was expanded to an effect compartment Emax PKTD model using urinary KIM-1 concentrations as the toxicodynamic marker. Significant covariate effects for the PKTD model included 1) prior exposure to cisplatin on volume of distribution 1 (V1), 2) 5-HT₃A antiemetic treatment on V2, and 3) baseline urinary KIM-1 levels on Emax. Additional analyses demonstrated that treatment with the 5-HT₃A ondansetron resulted in a 163% increase in exposure to plasma total platinum, a 94% increase in urinary KIM-1 maximum concentrations, and a 235% increase in total urinary KIM-1 excretion compared to palonosetron treatment.

Conclusion

Inclusion of urinary biomarkers such as KIM-1 in PKTD modeling can reveal novel predictors of total plasma platinum PK and subclinical and clinical kidney injury as the TD response.

Funding

• NIDDK Support