An evaluation of detection sensitivity and pharmacokinetic profile for conscious telemetered cynomolgus monkeys

• Published in: Journal of pharmacological and toxicological methods Vol. 133; p. 107615
• Main Authors: An, Shanshan, He, Miao, Wu, Rui
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2025
• ISSN: 1056-8719
• DOI: 10.1016/j.vascn.2025.107615

E14/S7B Q&As guideline outlined the best practice considerations for non-clinical in vivo QT studies. Assay sensitivity of relevant functional endpoints, the analysis of QTc interval together with adequate pharmacokinetic sampling, and the independence of QTc to RR intervals through QTc versus RR plots were encouraged. These provide high-quality preclinical data for an integrated nonclinical and clinical risk assessment and support a possible waiver for a TQT study. Average sensitivities for the Latin-square design (4 × 4) telemetered cynomolgus monkeys were calculated for ECG (QT, QTcI, PR, and QRS intervals) parameters. The effects of Moxifloxacin were studied in monkeys. Pharmacokinetic data were generated together with the monitoring of cardiovascular changes in order to compare effects relative to human exposure. In the validated study, eight conscious telemetered NHPs received with vechicle, Ondansetron (0.5 mg/kg/dose), Moxifloxacin (30 mg/kg/dose) and Moxifloxacin (90 mg/kg/dose) by oral gavage in a 4 × 4 Latin-Square manner with a 5-days washout period from dose 1 to dose 4. Blood samples were collected from monkeys at 90 mg/kg/dose at approximately 0, 0.5, 1, 2, 4, 6 and 8, 24 h post-dose in dose 5 after the completion of dose 4 for determination of Moxifloxacin plasma concentrations. ECG data were collected for at least 60 min prior to dosing (predose baseline) and continuously for at least 24 h post-dose. The QTc (QTc = QT – β × (RR-500) was calculated for each 1‑minute mean with individual QT correction based on QT-RR relationship on each dosing days. The output of the power analysis is the minimal detectable effect at 80 % power and a 95 % probability level with SAS System. The peak ΔΔQTc were within the range of 23 ms to 24 ms. The mean peak ΔΔQTc were observed between 4 and 6 h post-dose and thereafter declined. The study provided an average sensitivity to detect a 6.2 msec and 5.4 msec QTc change in male and female NHPs, respectively. This indicated that a less than 10 msec sensitivity was achieved in the 4 × 4 Latin square cardiovascular study design. A maximum increase of 24 ms was observed following administration of 90 mg/kg Moxifloxacin. Interrogation of the PK–QTc relationship indicated a direct relationship between the systemic exposure of Moxifloxacin and increased QTc. In conclusion, the inclusion of power analysis (i.e., QTc sensitivity and QTc versus RR plots) data in a regulatory submission provides key information about the quality of the in vivo QTc assessment. The exposure dependent increases in QTc observed following oral administration of Moxifloxacin to the cynomolgus monkey are in close agreement with those previously reported in human subjects.