Evaluation of QT interval correction formulas (QTc) and ECG reference intervals in conscious and anesthetized ferrets

A modern program of safety pharmacology evaluation of original drugs necessarily includes cardiovascular system (CVS) studies. In case of in vivo studies of cardiovascular function, it is necessary to evaluate the effect of the drug on blood pressure (BP), heart rate (HR) and electrocardiogram (ECG) parameters in conscious or anesthetized animals. Anesthetic agents can cause significant alterations in hemodynamics, which must be taken into account when interpreting the results. The ICH 7B guideline describes in detail the strategy of the QT interval assessment as an important marker predicting fatal arrhythmias. Physiologically the QT interval shortens as the HR increases and lengthens as the heart rate slows. In that regard it is necessary to correct the QT interval for HR to eliminate the impact of HR on the QT interval (QTc). In clinical practice there are several commonly used formulas: Bazett, Fridericia, Sagie and Van de Water. Data from 114 male and 116 female anesthetized ferrets related to toxicology studies were retrospectively analyzed in this study. Xyla (1–2 mg/kg) and Zoletil (12 mg/kg) were used for the anesthesia in mono mode. Additionally ECG and BP in conscious animals were measured (81 males and 33 females).The results showed that Bazett’s correction formula was the most suitable for QT correction in conscious animals and animals anesthetized with Zoletil. Van de Water’s correction formula showed the best rate correction in animals anesthetized with Xylazine. It is important to note that these formulas were equally well suited for both males and females. An assessment of the effect of anesthesia on ECG parameters showed that the use of xylazine is not preferable when recording an ECG. The use of Xylazine caused a sinus arrhythmia and increase average difference between the maximum and minimum RR intervals, indicating its proarrhythmogenic effect. Xylazine also had an effect on duration and amplitude all intervals and waves. The ECG of ferrets anesthetized with Zoletil was characterized by sinus rhythm without severe sinus arrhythmia as conscious in animals. The anesthesia with Zoletil and Xylazine did not appeared to have an significant effect on blood pressure in ferrets. The reference intervals for the main ECG parameters [RR, P, PQ, QRS, QT duration (in ms) and R, P, Q, S, T amplitude (in mV)] and BP were established. In the future reference interval database will allow for more correct assessment of changes in the functional parameters of the cardiovascular system in ferrets in the pharmacological safety testing.