Qualified kidney injury biomarkers demonstrate value during early clinical drug development

医学 生物标志物 狼疮性肾炎 急性肾损伤 内科学 凝集素 肾脏疾病 胱抑素C 系统性红斑狼疮 类风湿性关节炎 药品 脂质运载蛋白 肌酐 胃肠病学 药理学 疾病 细胞凋亡 生物化学 化学
作者
Kodihalli C. Ravindra,Kelly A. Fader,David M. Potter,Zaher A. Radi,Gary S. Friedman,Karrie A. Brenneman,Neeta B. Amin,Roberta C. Weiss,Spencer I. Danto,Karen Page,Shashi K. Ramaiah,Vishal S. Vaidya
出处
期刊:Toxicological Sciences [Oxford University Press]
卷期号:201 (2): 206-215 被引量:3
标识
DOI:10.1093/toxsci/kfae088
摘要

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.

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