Related Experiment Video
Updated: Jun 21, 2025
Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats
Published on: March 11, 2016
Qualified kidney injury biomarkers demonstrate value during early clinical drug development
Kodihalli C Ravindra1, Kelly A Fader2, David Potter3
1Department of Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, United States.
Abstract:
Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.
Insights
This study demonstrates the FDA-qualified kidney biomarker panel effectively identifies drug-induced kidney injury (DIKI) in early trials. The panel aids risk assessment and clinical decisions for novel therapeutics in healthy volunteers and patient populations.
Area of Science:
- Pharmacology and Toxicology
- Nephrology
- Biomarker Discovery
Background:
- Drug-induced kidney injury (DIKI) poses significant risks during drug development and clinical use.
- Early identification of DIKI is crucial for patient safety and therapeutic success.
- FDA-qualified kidney safety biomarker panels offer a promising approach for DIKI assessment.
Purpose of the Study:
- To implement and evaluate an FDA-qualified kidney safety biomarker panel in Phase 1 and 2 clinical trials.
- To assess the utility of the biomarker panel in detecting DIKI induced by novel therapeutics (PFE-1 and PFE-2).
- To guide risk assessment, dose selection, and clinical decision-making for new drugs.
Main Methods:
- Utilized a panel of six urinary biomarkers: Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN).
- Measured biomarkers in urine samples from healthy volunteers (HVs) and patients in Phase 1 (PFE-1) and Phase 2 (PFE-2) trials, as well as lupus patients and HVs.
- Calculated the FDA-defined composite measure (CM) as the geometric mean response across the six biomarkers.
Main Results:
- The composite measure (CM) increased by approximately 30% in HVs receiving PFE-1, indicating DIKI.
- The CM for rheumatoid arthritis patients receiving PFE-2 was comparable to placebo, de-risking DIKI concerns at clinical doses.
- CLU, KIM-1, NAG, NGAL, and OPN were elevated in RA and lupus patients compared to HVs.
Conclusions:
- The FDA-qualified kidney biomarker panel successfully identified DIKI in a Phase 1 trial.
- The panel helped de-risk a candidate therapeutic (PFE-2) in a Phase 2 trial, demonstrating its value in clinical decision-making.
- The study validates the use of this biomarker panel for assessing kidney safety of novel therapeutics in diverse populations.
Related Concept Videos
01:17Factors Affecting Renal Clearance: Renal Impairment
One condition associated with renal failure is uremia. Uremia is characterized by impaired glomerular filtration and fluid accumulation in the body. This condition hinders the renal clearance of drugs, resulting in drug accumulation and potential...
01:20Blood Studies for Cardiovascular System I: Cardiac Biomarkers
The essential diagnostic tools for detecting myocardial necrosis and monitoring individuals suspected of having acute coronary syndrome (ACS) include:
Troponins
Troponins, particularly cardiac troponins I and T, are the most precise and sensitive markers of myocardial injury. They are detectable within 4-6 hours of myocardial injury and remain...
01:11Renal Failure: Dose Adjustments
Reduced renal clearance and elimination rate are common outcomes of renal impairment. These alterations lead to a prolonged elimination half-life and an altered apparent volume of distribution for drugs. As a result, dosage adjustments are typically necessary to maintain optimal drug levels in the body.
However, dosage adjustments...
01:08Renal Drug Clearance: Comparison Between Renal Excretion Methods
Renal clearance is often associated with the renal glomerular filtration rate (GFR), which represents the rate at which plasma is filtered through the glomeruli in the kidney. When drug reabsorption is minimal and there is no active secretion, renal clearance is closely related to the...
01:06Renal Drug Clearance: Overview
Renal clearance can be calculated using different methods. One approach is to divide the urinary drug excretion rate by the plasma drug concentration. This method directly measures renal clearance, indicating the kidneys' efficiency in...