Abstract
Early repeated dose-range finding (DRF) toxicology studies, usually conducted in rodent and non-rodent animal species, seek to provide the earliest assessment of the toxicity profile of new chemical entities (NCE) using well-designed and validated nonclinical study designs. Thus, the DRF study provides the toxicologist with a means to expose any potential adverse effect liability of an NCE. The conduct of this study is critical as it provides important safety information to drug discovery research groups in their decision to develop or terminate costly development programs without sufficient safety margins. Establishment of the safety profile of a drug is a key responsibility in the conduct of DRF studies as it provides acute toxicological information on NCEs and an early overview of the toxicokinetic (TK) profile of the NCE following repeated dosing in rodents and non-rodent nonclinical species selected for use in the developing toxicology program. Any potential resolution for drug safety issues that arise in the early safety profiling of a compound requires the utilization of highly skilled drug safety scientists. These individuals have a broad understanding of essential toxicological principles and can distinguish adverse event development and subsequent mitigation and insight into clinical translational relevance.
References and Further Reading
Apple FS, Murakami MM, Ler R, Walker D, York M, HESI Technical Committee of Biomarkers Working Group on Cardiac Troponins (2008) Analytical characteristics of commercial cardiac troponin I and T immunoassays in serum from rats, dogs, and monkeys with induced acute myocardial injury. Clin Chem 54(12):1982–1989
Authier S, Pugsley MK, Troncy E, Curtis MJ (2010) Arrhythmogenic liability screening in cardiovascular safety pharmacology: commonality between non-clinical safety pharmacology and clinical thorough QT (TQT) studies. J Pharmacol Toxicol Methods 62:83–88
Authier S, Delatte M, Redfern WS, Markgraf C, Kallman MJ, Pugsley MK, Stevens J, Arezzo J, Vargas HM, Valentin JP, Curtis MJ (2016) Central nervous system safety pharmacology investigations: an industry survey. J Pharmacol Toxicol Methods 81:31–46
Bleavins MR (2014) Effective incorporation and utilization of biomarkers in nonclinical studies. In: Brock WJ, Mounho B, Fu L (eds) The role of the study director in nonclinical studies. Wiley, Hoboken, pp 245–257
Bolon B, Garman RH, Pardo ID, Jensen K, Sills RC, Roulois A, Radovsky A, Bradley A, Andrews-Jones L, Butt M, Gumprecht L (2013) STP position paper: recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies. Toxicol Pathol 41(7):1028–1048
Corton JC, Peters JM, Klaunig JE (2018) The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions. Arch Toxicol 92(1):83–119
Curtis MJ, Bond RA, Spina D et al (2015) Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol 172(14):3461–3471
Dorato MA, Engelhardt JA (2005) The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and definition(s). Regul Toxicol Pharmacol 42:265–274
Fonck C, Easter A, Pietras MR, Bialecki RA (2015) CNS adverse effects: from functional observation battery/Irwin tests to electrophysiology. Handb Exp Pharmacol 229:83–113
Gad SC, Spainhour CB, Shoemaker C, Pallman DRS, Stricker-Krongrad A, Downing PA, Seals RE, Eagle LA, Polhamus K, Daly J (2016) Tolerable levels of nonclinical vehicles and formulations used in studies by multiple routes in multiple species with notes on methods to improve utility. Int J Toxicol 35(2):95–178
Gopinathan S, O’Neill E, Rodriguez LA et al (2013) In vivo toxicology of excipients commonly employed in drug discovery in rats. J Pharmacol Toxicol Methods 68(2):284–295. https://doi.org/10.1016/j.vascn.2013.02.009
Guth BD, Bass AS, Briscoe R, Chivers S, Markert M, Siegl PKS, Valentin J-P (2009) Comparison of electrocardiographic analysis for risk of QT interval prolongation using safety pharmacology and toxicological studies. J Pharmacol Toxicol Methods 60(2):107–116
Herlich JA, Taggart P, Proctor J, Stahle P, Colis R, Hall L, Pugsley MK (2009) The non-GLP toleration/dose range finding study: design and methodology used in an early toxicology screening program. Proc West Pharmacol Soc 52:94–98
ICH (2001) S7A safety pharmacology studies for human pharmaceuticals. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Federal Register, 86, pp 50363–50365
ICH (2005) ICH S7B: the non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Federal Register, 70, pp 61133–61134
ICH (2008) M3(R2): guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. Retrieved October 2023 from https://www.ema.europa.eu/en/ich-m3-r2-non-clinical-safety-studies-conduct-human-clinical-trials-pharmaceuticals-scientific
ICH (2011) S6(R1): preclinical safety evaluation of biotechnology-derived pharmaceuticals. Retrieved February 2023 from https://database.ich.org/sites/default/files/S6_R1_Guideline_0.pdf
ICH (2017) S3A guidance: note for guidance on toxicokinetics: the assessment of systemic exposure in toxicity studies: focus on microsampling questions and answers. Retrieved October 2023 from https://www.fda.gov/files/drugs/published/S3A-Guidance%2D%2DNote-for-Guidance-on-Toxicokinetics%2D%2DThe-Assessment-of-Systemic-Exposure-in-Toxicity-Studies%2D%2DFocus-on-Microsampling.pdf
ICH (2022) ICH E14/S7B implementation working group: clinical and nonclinical evaluation of QT/QTc interval prolongation an proarrhythmic potantial questions and answers. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Federal Register, 85, pp 61753–61755
Irwin S (1968) Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berlin) 13:222–257
Kale VP, Bebenek I, Ghantous H, Kapeghian J, Singh BP, Thomas LJ (2022) Practical considerations in determining adversity and the no-observed-adverse-effect-level (NOAEL) in nonclinical safety studies: challenges, perspectives and case studies. Int J Toxicol 41(2):143–162
Koshman Y, Winters BR, Ryans J, Authier S, Pugsley MK (2024) Maximum tolerated dose (MTD) studies in drug toxicology assessments. In: Hock FJ, Pugsley MK (eds) Drug discovery and evaluation: safety and pharmacokinetic assays, 3rd edn. Springer Nature Press, Berlin
Kuwahara K (2021) The natriuretic peptide system in heart failure: diagnostic and therapeutic implications. Pharmacol Ther 227:107863
Lord PG, Nie A, McMillian M (2006) Application of genomics in preclinical drug safety evaluation. Basic Clin Pharmacol Toxicol 98(6):537–546
Moye L (2016) Statistical methods for cardiovascular researchers. Circ Res 118:439–453
Navarro VJ, Senior JR (2006) Drug-related hepatotoxicity. N Engl J Med 354:731–739
O’Brien PJ (2008) Cardiac troponin is the most effective translational safety biomarker for myocardial injury in cardiotoxicity. Toxicology 245(3):206–218
OECD Test Guideline No. 407 (2008) OECD guideline for the testing of chemicals – repeated dose 28-day oral toxicity study in Rodents. Retrieved March 2023 from https://read.oecd-ilibrary.org/environment/test-no-407-repeated-dose-28-day-oral-toxicity-study-in-rodents_9789264070684-en#page1
Okamoto F, Sohmiya K, Ohkaru Y, Kawamura K, Asayama K, Kimura H, Nishimura S, Ishii H, Sunahara N, Tanaka T (2000) Human heart-type cytoplasmic fatty acid-binding protein (H-FABP) for the diagnosis of acute myocardial infarction. Clinical evaluation of H-FABP in comparison with myoglobin and creatine kinase isoenzyme MB. Clin Chem Lab Med 38(3):231–238
Pandher K, Leach MW, Burns-Naas LA (2012) Appropriate use of recovery groups in nonclinical toxicity studies: value in a science-driven case-by-case approach. Vet Pathol 49(2):357–361
Pugsley MK, Authier S, Curtis MJ (2008) Principles of safety pharmacology. Br J Pharmacol 154(7):1382–1399
Rossman EI, Wisialowski TA, Vargas HM, Valentin J-P, Rolf MG, Roche BM, Riley S, Pugsley MK, Nichols J, Li D, Leishman DJ, Kleiman RB, Greiter-Wilke A, Gintant GA, Engwall MJ, Delaunois A, Authier S (2023) Best practice considerations for nonclinical in vivo cardiovascular telemetry studies in non-rodent species: delivering high quality QTc data to support ICH E14/S7B Q&As. J Pharmacol Toxicol Methods 121:107270. https://doi.org/10.1016/j.vascn.2023.107270
Sellers RS, Morton D, Michael B, Roome N, Johnson JK, Yano BL, Perry R, Schafer K (2007) Society of toxicologic pathology position paper: organ weight recommendations for toxicology studies. Toxicol Pathol 35(5):751–755
Sewell F, Chapman K, Baldrick P et al (2014) Recommendations from a global cross-company data sharing initiative on the incorporation of recovery phase animals in safety assessment studies to support first-in-human clinical trials. Regul Toxicol Pharmacol 70(1):413–429
Smith D, Combes R, Depelchin O, Jacobsen SD, Hack R, Luft J, Lammens L, Landenberg FV, Phillips B, Pfister R, Rabemampianina Y, Sparrow S, Stark C, Stephan-Gueldner M (2005) Optimising the design of preliminary toxicity studies for pharmaceutical safety testing in the dog. Regul Toxicol Pharmacol 41(2):95–101
Spied LH, Lumley CE, Walker SR (1990) Harmonization of guidelines for toxicity testing of pharmaceuticals by 1992. Regul Toxicol Pharmacol 12:179–211
Star RA (1998) Treatment of acute renal failure. Kidney Int 54(6):1817–1831
Takahashi K, Hattori N, Yokoyama H, Jinno F, Ohtsuka H, Nakai K, Takumi A, Shibui Y, Yamaguchi K, Shimazaki T, Tanaka T, Saito K, Kobayashi A, Saito Y (2023) Impact of microsampling on toxicological evaluation in rodent safety studies. J Appl Toxicol 44(1):118–128. https://doi.org/10.1002/jat.4523
Tanaka T, Hirota Y, Sohmiya K, Nishimura S, Kawamura K (1991) Serum and urinary human heart fatty acid-binding protein in acute myocardial infarction. Clin Biochem 24(2):195–201
U.S. Food & Drug Administration (2005) Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. U.S. Food and Drug Administration (U.S. FDA), Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER), Rockville. Retrieved October 2023 from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers
U.S. Food & Drug Administration (2011) E16 biomarkers related to drug or biotechnology product development: context, structure, and format of qualification submissions. Fed Regist 76:49773–49774
Vargas HM, Rossman EI, Wisialowski TA, Nichols J, Pugsley MK, Roche B, Gintant GA, Greiter-Wilke A, Kleiman RB, Valentin J-P, Leishman DJ (2023) Improving the in vivo QTc assay: the value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute. J Pharmacol Toxicol Methods 121:107265. https://doi.org/10.1016/j.vascn.2023.107265
Whitmire ML, Bryan P, Henry TR, Holbrook J, Lehmann P, Mollitor T, Ohorodnik S, Reed D, Wietgrefe HD (2010) Nonclinical dose formulation analysis method validation and sample analysis. AAPS J 12(4):628–634
Wilson NH, Hardisty JF, Hayes JR (2001) Short-term, subchronic, and chronic toxicology studies. In: Hayes AW (ed) Principles and methods of toxicology. Taylor & Francis, Philadelphia
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Miller, L., Winters, B.R., Authier, S., Ryans, J., Pugsley, M.K. (2024). Dose Range Finding (DRF) Studies in Drug Toxicology Assessments. In: Hock, F.J., Pugsley, M.K. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_116-1
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