<p dir="ltr">Torsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia associated with QT interval prolongation. Female sex and age > 65 years are risk factors for QT prolongation and TdP, possibly due to the effect of sex hormones. Progesterone shortens QT interval, while estrogen lengthens QT interval in females. Preclinical and clinical evidence indicates that progesterone has protective effects against drug-induced QT interval prolongation. J-Tpeak (JTp) and Tpeak-Tend (Tpe) intervals are biomarkers of early and late repolarization. Population pharmacokinetic/pharmacodynamic (PK/PD) models can be used to describe exposure-response relationships and identify sources of variability. In this study, data were pooled from four clinical trials with similar study design investigating the effect of progesterone on ibutilide-induced ventricular repolarization lengthening in healthy premenopausal women during menses or ovulation phase and healthy postmenopausal women. A nonlinear mixed effect model of ibutilide - QTc interval was first developed with preliminary data from 33 subjects. The model was then updated with new data from a total of 52 subjects, assessing the effect of progesterone on drug-induced QTc interval lengthening and identifying sources of variability through covariate analysis. Finally, two PK/PD models of ibutilide - baseline corrected JTpc (ΔJTpc) interval and Tpe (ΔTpe) interval were developed to assess the effect of progestogen on ibutilide-induced early and late repolarization lengthening. Progesterone showed protective effect against ibutilide-induced QTc interval lengthening, mainly through the shortening of pre-ibutilide baseline QTc interval. Body weight, age, race, hypertension, electrocardiogram (ECG) type and estradiol concentration were not significant covariates. Progesterone attenuates ibutilide-induced lengthening of late ventricular repolarization but did not show significant effect on ibutilide-induced early repolarization lengthening. Higher estradiol concentration was related to higher ibutilide-induced early repolarization lengthening. Black race was related to lower ibutilide-induced late repolarization lengthening.</p>

Background: The sensitivity to drug-induced QT prolongation is highly variable in heart failure (HF) patients. QT interval prolongation can lead to a life-threatening ventricular arrhythmia known as torsade de Pointes (TdP), which can result in sudden cardiac death. Although QT prolongation is a surrogate marker for sudden cardiac death, the extent of drug-induced QT prolongation, and thus TdP, is largely unpredictable. Therefore, developing a biomarker to predict patients’ sensitivity to drug-induced QTc prolongation could have a profound clinical impact. MicroRNA (miR) are recognized as important regulators of cardiovascular function as they shape the transcriptome by targeting mRNAs for repression of translation. Our multidisciplinary research group has demonstrated that miR-362-3p regulates a potassium channel (i.e., hERG) that is the most widely implicated in drug-induced QTc prolongation. The primary objects of this analysis focus on characterizing serum miR-362-3p expression in the circulation as a potential biomarker to predict subject’s susceptibility to ibutilide exposure induced QT-interval prolongation.<div><br></div><div>Methods: The dataset utilized to develop the PK-PD models were collected from a previous clinical study carried out by Tisdale et al. (Tisdale,et al. 2020).A total of 22 adult subjects who met the inclusion and exclusion criteria were enrolled and divided into three groups: a group of patients with heart failure with preserved ejection fraction (HFpEF, n=10), a group of patients with heart failure with reduced ejection fraction (HFrEF, n=2), and ten healthy subjects in the control group who were matched to subjects in the HFpEF group for age and sex. Following a baseline day of triplicate 12-lead ECGs, all subjects received ibutilide 0.003mg/kg intravenously infused over 10 minutes. Serial collection of blood samples to determine serum Ibutilide concentrations (HPLC/MS), serum miR-362-3 expression (qPCR), with triplicate ECG readings were obtained pre-and-post ibutilide administration. To describe ibutilide serum concentration exposure and the9relationship with Fridericia-corrected QT (QTF) intervals, a non-linear mixed effect modeling approach was used along with clinical and demographic data, and serum miR-362-3p expression was evaluated as potential covariates on the PK/PD model.<div><br></div><div>Results: A three-compartment model best described the time course of ibutilide concentrations profile with a proportional residual error. The individual ibutilide concentrations time profile was then used in an indirect response model where ibutilide concentrations are indirectly driving the QT interval prolongation through inhibition of the output (Kout) parameters linked to an indirect response model with zero‐order input parameter best described the ibutilide concentrations QT interval lengthening relationship. The Individual PK/PD parameters using the base model for the Imax and IC50 were 11.4% (9.9%RES) and 0.36(8.4% RES)ng/mL, respectively. Following stepwise forwarding inclusion steps, the final covariate analyses identified circulating miR-362-3p expression associated with a history of myocardial infarction covariate influencing both the Imax and IC50( p<0.05). <div><br></div><div>Conclusions: An indirect response model has been developed to describe the effects of ibutilide concentrations on QT-intervals. Although the semi-mechanistic model could not be developed; serummiR-362-3p expression was identified as a significant predictor for ibutilide-induced QT-interval prolongation. Moreover, the upregulation of serum miR-362-3p expression enhanced IC50 seen after ibutilide administration. The potential use of miR-362-3p as a biomarker warrants further investigation to identify patients at the greatest risk of TdP </div></div></div>