Clin Transl Sci. 2022 Nov 11. doi: 10.1111/cts.13454. Online ahead of print.
ABSTRACT
In prior clinical studies, levocetirizine (LEVO) has demonstrated no effect on ventricular repolarization (QTc intervals), therefore it is a relevant negative control to assess in nonclinical assays to define low proarrhythmic risk. LEVO was tested in beagle dog and cynomolgus monkey (NHP) telemetry models to understand the nonclinical-clinical translation of this negative control. One oral dose of vehicle, LEVO (10 mg/kg/species) or moxifloxacin (MOXI: 30 mg/kg/dog; 80 mg/kg/NHP) was administered to instrumented animals (N=8/species) using a cross-over dosing design; MOXI was the in-study positive control. Corrected QT values (QTcI) were calculated using an individual animal correction factor. Blood samples were taken for drug exposure during telemetry and for pharmacokinetic (PK) analysis (same animals; different day) for exposure-response (C-QTc) modeling. Statistical analysis of QTc-by-timepoint data showed that LEVO treatment was consistent with vehicle, thus no effect on ventricular repolarization was observed over 24 hr in both species. PK analysis indicated that LEVO-Cmax levels in dog (range: 12300-20100 ng/ml) and NHP (range: 4090-12700 ng/ml) were ≥ 4-fold higher than supra-therapeutic drug levels in clinical QTc studies. Slope analysis values in dog (0.00019 ms/ng/mL) and NHP (0.00016 ms/ng/mL) were similar to the human C-QTc relationship and indicated no relationship between QTc intervals and plasma levels of LEVO. MOXI treatment caused QTc interval prolongation (dog: 18 ms; NHP: 29 ms). The characterization of LEVO in these non-rodent telemetry studies further demonstrates the value and impact of the in vivo QTc assay to define a “no QTc effect” profile and support clinical safety assessment.
PMID:36369797 | DOI:10.1111/cts.13454
