title: Renal studies in safety pharmacology and toxicology: A survey conducted in the top 15 pharmaceutical companies.
abstract: BACKGROUND
  With the recent development of more sensitive biomarkers to assess kidney injury preclinically, a survey was designed i) to investigate what strategies are used to investigate renal toxicity in both ICH S7A compliant Safety Pharmacology (SP) studies after a single dose of a compound and within repeat-dose toxicity studies by large pharmaceutical companies today; ii) to understand whether renal SP studies have impact or utility in drug development and/or if it may be more appropriate to assess renal effects after multiple doses of compounds; iii) to ascertain how much mechanistic work is performed by the top 15 largest pharmaceutical companies (as determined by R&D revenue size); iv) to gain an insight into the impact of the validation of DIKI biomarkers and their introduction in the safety evaluation paradigm; and v) to understand the impact of renal/urinary safety study data on progression of projects.
  
  
  METHODS
  Two short anonymous surveys were submitted to SP leaders of the top 15 pharmaceutical companies, as defined by 2012 R&D portfolio size. Fourteen multiple choice questions were designed to explore the strategies used to investigate renal effects in both ICH S7A compliant SP studies and within toxicology studies.
  
  
  RESULTS
  A 67% and 60% response rate was obtained in the first and second surveys, respectively. Nine out of ten respondent companies conduct renal excretory measurements (eg. urine analysis) in toxicology studies whereas only five out of ten conduct specific renal SP studies; and all of those 5 also conduct the renal excretory measurements in toxicology studies. These companies measure and/or calculate a variety of parameters as part of these studies, and also on a case by case basis include regulatory qualified and non-qualified DIKI biomarkers. Finally, only one company has used renal/urinary functional data alone to stop a project, whereas the majority of respondents combine renal data with other target organ assessments to form an integrated decision-making set.
  
  
  CONCLUSIONS
  These short surveys highlighted areas of similarity: a) urinary measurements are most commonly taken on repeat-dose toxicity studies, and b) renal SP studies are less often utilised. The two major differences are a) lack of consistent use of DIKI biomarkers in urinary safety studies and b) the way large pharmaceutical companies assess renal function. Finally, suggestions were made to improve the safety assessment methods for determining the safety of compounds with potential renal liability.
authors: Safety Pharmacology Centre of Excellence, Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Electronic address: amanda.benjamin@astrazeneca.com.
authors: Amanda
authors: A
authors: Benjamin
authors: Center of Excellence for Cardiovascular Safety Research & Mechanistic Pharmacology Janssen, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.
authors: David J
authors: DJ
authors: Gallacher
authors: Safety Pharmacology, Hoffmann-La Roche Inc., Basel, Switzerland.
authors: Andrea
authors: A
authors: Greiter-Wilke
authors: Sanofi R&D, Preclinical Safety, Safety Pharmacology, 13 quai Jules Guesde, 94400 Vitry sur Seine, France.
authors: Jean-Michel
authors: JM
authors: Guillon
authors: Drug Safety Research Labs, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
authors: Cheiko
authors: C
authors: Kasai
authors: Novartis Pharma AG, Preclinical Safety, Basel, Switzerland.
authors: David
authors: D
authors: Ledieu
authors: Bristol Myers Squibb, Princeton, NJ 08534, USA.
authors: Paul
authors: P
authors: Levesque
authors: Safety Pharmacology, Bayer HealthCare, Wuppertal, Germany.
authors: Katja
authors: K
authors: Prelle
authors: Drug Safety Research and Development, Pfizer, Eastern Point Road, Groton, CT 0634, USA.
authors: Sian
authors: S
authors: Ratcliffe
authors: Safety & Exploratory Pharmacology, Merck Research Laboratories, SALAR Division, 770 Sumneytown Pike, P.O. Box 4, West-Point, PA 19486-0004, USA.
authors: Frederick
authors: F
authors: Sannajust
authors: Safety Pharmacology Centre of Excellence, Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Jean-Pierre
authors: JP
authors: Valentin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry / Q000379:methods* / Q000706:statistics & numerical data; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced*; D011795:Surveys and Questionnaires; D018675:Toxicity Tests / Q000379:methods
chemical_list: D015415:Biomarkers
keywords: DIKI biomarkers; ICH S7A; Kidney; Safety pharmacology; Strategy