Abstract: TH-PO0820
Pharmacokinetics of Immune Checkpoint Inhibitors Are Best Recapitulated in Human Immune System Mice
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1900 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Huang, Yuxin, Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States
- Ghimire, Avisek, 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
- Kostka-Newman, Zander C., Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado, United States
- Garcia, John Rhey Mhar G., Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado, United States
- Lang, Julie, Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado, 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
Immune checkpoint inhibitors (ICIs) including anti-PD1 (Nivolumab) and CTLA-4 (Ipilimumab) treat a wide variety of cancers. However, ICIs cause immune mediated organ toxicities including nephrotoxicity. The aim of this study was to assess the pharmacokinetics (PK) of nivolumab and ipilimumab across mouse models and explore covariates to fill significant gaps in translating preclinical models that best inform human exposure and kidney toxicity responses.
Methods
Three different mouse models – PBMC (n=30), humanized (n=24) and non-humanized (n=12) mice were treated with nivolumab (20 mg/kg; n=15), or nivolumab/ipilimumab (20/10 mg/kg; n=15) by a single i.p. injection. Blood samples were collected at 0.5, 12, 24, 48, 56, 72, 168 h and unbound ICI concentrations in plasma were measured by LC-MS/MS. PK modeling was conducted to explore 1- and 2-compartmental models using additive, multiplicative and combined error assessments using Phoenix NLME (v8.6.1.6, Certara Inc.). Mouse model, ICI treatment, and sex were evaluated as covariates using a stepwise covariate search, with a threshold p-value of 0.01 for forward addition and 0.001 for backward deletion.
Results
Nivolumab concentration data was described by a 2-compartment multiplicative model: absorption rate constant (Ka) 0.34 1/h, volume 1 (V1) 1.10 mL, volume 2 (V2) 1.27 mL, clearance 1 (CL1) 0.0049 mL/h, clearance 2 (CL2) 6.07 mL/h. Covariate model analysis showed that PBMC mice had 1.18 fold higher CL1, non-humanized mice had 0.045 fold higher CL1, both compared to humanized mice; and females had 0.924 fold higher Ka compared to male. Ipilimumab was described by a 2-compartment additive model: Ka 0.44 1/h, V1 1.26 mL, CL1 0.0094 mL/h, V2=1.55 mL, CL2 0.387 mL/h. No significant covariate effects were found with the ipilimumab model.
Conclusion
The specific preclinical mouse model impact nivolumab PK. The PBMC mice exhibited 227% increases in clearance compared to humanized mice and may not recapitulate human nivolumab PK. The humanized mouse model improves the translational application of ICI PK and associated toxicity outcomes compared to conventional preclinical mouse models.
Acknowledgment
The authors would like to thank University of Colorado Animal care facilities for support in conducting animal studies, Pre-clinical Human System Mice Shared Resource (PHSM) for humanized mouse model and performing flow cytometry and analysis, and mass spectrometry facility at University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences for sample preparation, LC/MS and analysis.
Funding
- Other NIH Support