Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability.

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.

Update on ICH E14/S7B Cardiac Safety Regulations: The Expanded Role of Preclinical Assays and the "Double-Negative" Scenario.

For nearly 2 decades, regulators have adopted a harmonized approach to drug development, which has succeeded in bringing new pharmaceuticals to market without significant cardiac liability. Ushered in by technological advancements and better understanding of cellular electrophysiology, the initial paradigm detailed in the 2005 International Conference for Harmonization E14 and S7B documents has undergone evolutionary changes designed to streamline drug development and improve regulatory decision-making and product labeling. The intent of this review is to summarize the new US Food and Drug Administration (FDA) Question and Answer update from August 2020 and key messaging from a subsequent FDA webinar describing best practices for preclinical and clinical data integration into a QT risk prediction model.

Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults.

Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period.

Dietary manipulation and testosterone replacement therapy may explain changes in body composition after spinal cord injury: A retrospective case report.

Background: Reduced level of physical activity, high-fat diet and skeletal muscle atrophy are key factors that are likely to contribute to deleterious changes in body composition and metabolic following spinal cord injury (SCI). Reduced caloric intake with lowering percentage macronutrients of fat and increasing protein intake may likely to improve body composition parameters and decrease ectopic adiposity after SCI.

Aim: To highlight the effects of dietary manipulation and testosterone replacement therapy (TRT) on body composition after SCI.

QT Assessment in Early Drug Development: The Long and the Short of It.

The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death.

Prediction of thigh skeletal muscle mass using dual energy x-ray absorptiometry compared to magnetic resonance imaging after spinal cord injury.

A rapid decline in lean mass (LM), fat-free mass (FFM) and increased intramuscular fat (IMF) predispose persons with spinal cord injury (SCI) to chronic medical conditions including dyslipidemia, insulin resistance, type 2 diabetes mellitus and cardiovascular disease. (1) To determine the relationship between dual energy x ray absorptiometry (DXA) and gold standard magnetic resonance imaging (MRI) LM values; (2) to develop predictive equations based on this relationship for assessing thigh LM in persons with chronic SCI. Cross-sectional predicational design.

Semi-automated segmentation of magnetic resonance images for thigh skeletal muscle and fat using threshold technique after spinal cord injury.

Magnetic resonance imaging is considered the "gold standard" technique for quantifying thigh muscle and fat cross-sectional area. We have developed a semi-automated technique to segment seven thigh compartments in persons with spinal cord injury. Thigh magnetic resonance images from 18 men (18-50 years old) with traumatic motor-complete spinal cord injury were analyzed in a blinded fashion using the threshold technique.

Feasibility of robotic exoskeleton ambulation in a C4 person with incomplete spinal cord injury: a case report.

Introduction: To determine whether an individual with C4 incomplete spinal cord injury (SCI) with limited hand functions can effectively operate a powered exoskeleton (Ekso) to improve parameters of physical activity as determined by swing-time, up-time, walk-time, and total number of steps.

Case Presentation: A 21-year-old male with incomplete chronic (>1 year postinjury) SCI C4, participated in a clinical exoskeleton program to determine the feasibility of standing up and walking with limited hand functions. The participant was invited to attend 3 sessions including fitting, familiarization and gait training separated by one week intervals.

Evaluating cardiac risk: exposure response analysis in early clinical drug development.

The assessment of a drug's cardiac liability has undergone considerable metamorphosis by regulators since International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14 guideline was introduced in 2005. Drug developers now have a choice in how proarrhythmia risk can be evaluated; the options include a dedicated thorough QT (TQT) study or exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early clinical development. The alternative approach of ER modeling was incorporated into a guidance document in 2015 as a primary analysis tool which could be utilized in early phase dose escalation studies as an option to perform a dedicated TQT trial.

Validation of Anthropometric Muscle Cross-Sectional Area Equation after Spinal Cord Injury.

The purposes of this study were to cross-validate a previously derived anthropometric estimation equation specific to the spinal cord injury population and determine the ratios of absolute skeletal muscle cross-sectional area (CSA) for the quadriceps, hamstrings, and adductor muscle groups based on magnetic resonance imaging. The validation cohort consisted of eleven men with chronic (>1 yr. post injury) spinal cord injury (SCI).

Paradigms of Lower Extremity Electrical Stimulation Training After Spinal Cord Injury.

Skeletal muscle atrophy, increased adiposity and reduced physical activity are key changes observed after spinal cord injury (SCI) and are associated with numerous cardiometabolic health consequences. These changes are likely to increase the risk of developing chronic secondary conditions and impact the quality of life in persons with SCI. Surface neuromuscular electrical stimulation evoked resistance training (NMES-RT) was developed as a strategy to attenuate the process of skeletal muscle atrophy, decrease ectopic adiposity, improve insulin sensitivity and enhance mitochondrial capacity.

A feasibility pilot using telehealth videoconference monitoring of home-based NMES resistance training in persons with spinal cord injury.

Introduction: The objective of the study was to investigate the feasibility and initial efficacy of telehealth communication in conjunction with surface neuromuscular electrical stimulation (NMES) resistance training (RT) to induce muscle hypertrophy.

Materials And Methods: This was a home-based setting of within-subject control design of trained vs controlled limbs. Five men with chronic (>1 year postinjury) motor-complete spinal cord injury (SCI) participated in a twice-weekly telehealth videoconference program using home-based NMES-RT for 8 weeks.

MRI analysis and clinical significance of lower extremity muscle cross-sectional area after spinal cord injury.

Shortly after spinal cord injury (SCI), the musculoskeletal system undergoes detrimental changes in size and composition, predominantly below the level of injury. The loss of muscle size and strength, along with increased immobility, predisposes persons with SCI to rapid and severe loss in bone mineral density and other health related consequences. Previous studies have highlighted the significance of measuring thigh muscle cross-sectional area, however, measuring the size and composition of muscles of the lower leg may provide insights on how to decrease the risk of various comorbidities.

Early drug development: assessment of proarrhythmic risk and cardiovascular safety.

hERG assays and thorough ECG trials have been mandated since 2005 to evaluate the QT interval and potential proarrhythmic risk of new chemical entities. The high cost of these studies and the shortcomings inherent in these binary and limited approaches to drug evaluation have prompted regulators to search for more cost effective and mechanistic paradigms to assess drug liability as exemplified by the CiPA initiative and the exposure response ICH E14(R3) guidance document. Areas covered: This review profiles the changing regulatory landscape as it pertains to early drug development and outlines the analyses that can be performed to characterize preclinical and early clinical cardiovascular risk.