Key result
Handling procedures involving a rodent restrainer transiently increased serum cTnI concentrations in rats, with mean maximum values of 53.0 and 7.2 pg/mL in initial and repeat studies.
Handling procedures such as restraint can cause transient increases in serum cTnI in rats, highlighting the need for population pharmacodynamic modeling to account for interindividual differences in preclinical safety studies.
May artifactually elevate cTnI in rat studies; leaves open refined handling protocols and modeling for preclinical cardiac safety assessments.
Serum cardiac troponins are the key biomarkers of myocardial necrosis in humans and in preclinical species. The use of ultrasensitive assays for serum cardiac troponin I (cTnI) as a biomarker in safety studies is hampered by interindividual differences. In this study, we investigated the effect of handling procedures on serum cTnI and explored modeling and simulation approaches to mitigate the impact of these interindividual differences. Femoral-catheterized male Crl:WI(Han) rats (n = 16/group) were left undisturbed in their cages with no handling; subjected to 5 min of isoflurane/O2 anesthesia (A); or placed into a rodent restrainer followed by simulated tail vein injection (RR). Serum cTnI concentrations were assessed over a 24-h period using an ultrasensitive assay, and the study was repeated for confirmation. The mean serum cTnI concentration pre-procedure was 4.2 pg/mL, and remained stable throughout the duration of the study in the rats submitted to the A procedure. Serum cTnI concentrations increased transiently after the RR procedure with a median time to maximum concentration (T max), of 1 and 2 h and a mean maximum value concentration (C max), of 53.0 and 7.2 pg/mL in the initial and repeat studies, respectively. A population pharmacodynamic model identified interindividual, procedure- and study-specific effects on serum cTnI concentrations in rats. It is concluded that a modeling and simulation approach more appropriately describes and statistically analyzes the data obtained with this ultrasensitive assays.
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Mikaelian et al. (2013) studied this question. Handling procedures (rodent restrainer with simulated tail vein injection) vs. Undisturbed in cages or isoflurane/O2 anesthesia was evaluated on Serum cTnI concentrations. Handling procedures involving a rodent restrainer transiently increased serum cTnI concentrations in rats, with mean maximum values of 53.0 and 7.2 pg/mL in initial and repeat studies.
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