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Longitudinal Studies of Cardiac Troponin-I Concentrations in Serum from Male Sprague Dawley Rats: Baseline Reference Ranges and Effects of Handling and Placebo Dosing on Biological Variability
1 Department of Pathology, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA Correspondence: A. Eric Schultze, D.V.M., Ph.D., Diplomate, A.C.V.P., Fellow, I.A.T.P., Research Advisor—Pathologist, Lilly Research Laboratories, 355 East Merrill Street (Dock 48), Drop Code 0424, Indianapolis, IN 46225, USA; e-mail:aes{at}lilly.com. Serum cardiac troponin-I has been validated as a biomarker for cardiotoxicity in numerous animal models; however, baseline reference ranges for cTnI concentration in a healthy population of laboratory rats, as well as an investigation of biological cTnI variability in rats with respect to time, handling, and placebo dosing methods, have not been reported. In this study, we used an ultrasensitive cTnI immunoassay to quantify hourly concentrations of cTnI in live rats handled under standard laboratory conditions using 15 µL of serum per determination. The baseline reference range (mean 4.94 pg/mL, range 1–15 pg/mL, 99% confidence interval [CI]) of cTnI concentration in rats was consistent with previously reported reference ranges for cTnI in humans (1–12 pg/mL) and with preliminary studies in dogs (1–4 pg/mL) and monkeys (4–5 pg/mL) using the same cTnI assay method. In addition, cTnI concentrations in individual rat serum samples show minimal biological variability over a twenty-four-hour interval when compared to a meaningful reference change value of 193% to 206%. Furthermore, measurements of cTnI concentration were consistent within the reference limits in individual rats over long periods and under three different standard laboratory handling conditions. Thus, using this new method, rats can be followed longitudinally at hourly intervals, and a doubling of cTnI concentration would be significant above biological variability. This is a new paradigm for preclinical testing, which allows transient changes in cTnI concentration to be accurately quantified. This understanding of baseline and biological variability in rats will be fundamental for designing and analyzing future studies that assess potential cardiotoxicity in drug development.
Key Words: cardiac troponin concentration • cardiotoxicity • cTnI • rat • toxicology studies • rat husbandry • reference ranges Abbreviations: CI, confidence interval • cTnI, cardiac troponin-I • CV, coefficient of variance • LLoQ, lower limit of quantification • LoD, limit of detection • MP, micro-particle • n.s., not significant • OD, oral dosing • RCV, reference change values • RR, resting rats • SD, standard deviation • ST, simulated transport • ULoQ, upper limit of quantification
This version was published on October
1, 2009 Toxicologic Pathology, Vol. 37, No. 6,
754-760 (2009) |
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