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Renal Safety Pharmacology in Drug Discovery and Development

  • Chapter
Principles of Safety Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 229))

Abstract

The kidney is a complex excretory organ playing a crucial role in various physiological processes such as fluid and electrolyte balance, control of blood pressure, removal of waste products, and drug disposition. Drug-induced kidney injury (DIKI) remains a significant cause of candidate drug attrition during drug development. However, the incidence of renal toxicities in preclinical studies is low, and the mechanisms by which drugs induce kidney injury are still poorly understood. Although some in vitro investigational tools have been developed, the in vivo assessment of renal function remains the most widely used methodology to identify DIKI. Stand-alone safety pharmacology studies usually include assessment of glomerular and hemodynamic function, coupled with urine and plasma analyses. However, as renal function is not part of the ICH S7A core battery, such studies are not routinely conducted by pharmaceutical companies. The most common approach consists in integrating renal/urinary measurements in repeat-dose toxicity studies. In addition to the standard analyses and histopathological examination of kidneys, novel promising urinary biomarkers have emerged over the last decade, offering greater sensitivity and specificity than traditional renal parameters. Seven of these biomarkers have been qualified by regulatory agencies for use in rat toxicity studies.

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Abbreviations

ADH:

Antidiuretic Hormone

ADRs:

Adverse Drug Reactions

ANP:

Atrial Natriuretic Peptide

AKI:

Acute Kidney Injury

BUN:

Blood Urea Nitrogen

CLU:

Clusterin

COX:

Cyclooxygenase

CysC:

Cystatin C

DIAKT:

Drug-Induced Acute Kidney Tubular

DIKI:

Drug-Induced Kidney Injury

EMA:

European Medicines Agency

eRPF:

effective Renal Plasma Flow

FDA:

Food and Drug Administration

FE:

Fractional Excretion

FITC:

Fluorescein Isothiocyanate

FTIM:

First Time In Man

GFR:

Glomerular Filtration Rate

GLP:

Good Laboratory Practice

ICH:

International Conference on Harmonisation

KIM-1:

Kidney Injury Molecule-1

MAP:

Mean Arterial Pressure

2-MPT:

2-(a-Mannopyranosyl)-L-tryptophan

NCE:

New Chemical Entity

NIC:

Noninvasive Clearance

NHP:

Nonhuman Primate

NSAID:

Nonsteroidal Anti-inflammatory Drug

OECD:

Organisation for Economic Co-operation and Development

PAH:

para-Aminohippuric Acid

NCE:

New Chemical Entity

PMDA:

Pharmaceuticals and Medical Devices Agency

RBF:

Renal Blood Flow

RVR:

Renal Vascular Resistance

SCr:

Serum Creatinine

SP:

Safety Pharmacology

TFF:

Trefoil Factor

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Authors and Affiliations

  1. Drug Safety and Metabolism, AstraZeneca, Alderley Park, Cheshire, SK10-4TG, UK

    Amanda Benjamin

  2. Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest, 1420, Braine l’Alleud, Belgium

    Andre Nogueira da Costa, Annie Delaunois, Marie-Luce Rosseels & Jean-Pierre Valentin

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  1. Amanda Benjamin
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  2. Andre Nogueira da Costa
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  3. Annie Delaunois
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  4. Marie-Luce Rosseels
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  5. Jean-Pierre Valentin
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Correspondence to Jean-Pierre Valentin .

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Editors and Affiliations

  1. Drug Safety Sciences, Johnson & Johnson PR&D, Raritan, New Jersey, USA

    Michael K. Pugsley

  2. Cardiovascular Division, Faculty of Life Sciences & Medicine, St Thomas' Hospital, King's College London, Rayne Institute, London, United Kingdom

    Michael J Curtis

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Benjamin, A., da Costa, A.N., Delaunois, A., Rosseels, ML., Valentin, JP. (2015). Renal Safety Pharmacology in Drug Discovery and Development. In: Pugsley, M., Curtis, M. (eds) Principles of Safety Pharmacology. Handbook of Experimental Pharmacology, vol 229. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46943-9_13

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