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. Consequently, there has been a paradigm shift to assess a compound's cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.

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). Ten individuals were classified as AIS A or B and one participant was classified as an AIS C. Significant correlations were found between the anthropometrically predicted CSAs and MRI-derived CSAs for the whole muscle including bone and intramuscular fat (r2=0.72, SEE=10.6 cm2, P<0.001), absolute muscle excluding bone and intramuscular fat (r2=0.60, SEE=10.1 cm2, P=0.005), and absolute quadriceps muscle (r2=0.67, SEE=5.5 cm2, P=0.002). The quadriceps, hamstrings and the adductor muscle groups represented 52±5%, 23±6%, and 20±4%, respectively, of the absolute muscle CSA. Our results suggest that the utilization of a previously developed anthropometric equation is applicable to a different validation cohort with SCI. The equation has the ability to predict whole muscle CSA, absolute muscle CSA excluding bone and intramuscular fat, and absolute muscle CSA of the quadriceps in individuals with chronic SCI.

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 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.

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. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.

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

Objectives: 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. Study Design: Cross-sectional predicational design. Settings: Clinical research medical center. Participants: Thirty-two men with chronic (>1 y post-injury) motor complete SCI. Methods: Participants completed total body DXA scans to determine thigh LM and were compared to measurements acquired from trans-axial MRI. Outcome measures: MRI was used to measure whole muscle mass (MMMRI-WM), absolute muscle mass (MMMRI-ABS) after excluding IMF, and knee extensor muscle mass (MMMRI-KE). DXA was used to measure thigh LM (LMDXA) and (FFMDXA). To predict MMMRI-KE, LMDXA was multiplied by 0.52 and yielded LMDXA-KE. Results: LMDXA predicted MMMRI-WM [r2 = 0.90, standard error of the estimate (SEE) = 0.23 kg, P < 0.0001] and MMMRI-ABS (r2 = 0.82, SEE = 0.28 kg, P < 0.0001). LMDXA-KE predicted MMMRI-KE (r2 = 0.78, SEE = 0.16 kg, P < 0.0001). Conclusion: DXA measurements revealed an acceptable agreement with the gold standard MRI and may be a viable alternative for assessing thigh skeletal muscle mass after SCI.

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. METHODS: A 31-year-old male with T5 SCI was administered transdermal TRT daily for 16 wk. Caloric intake and percentage macronutrients were analyzed using dietary recalls. Magnetic resonance imaging and dual-energy x-ray absorptiometry were used to measure changes in body composition. RESULTS: Caloric intake and fat percentage were reduced by 445 kcal/d and 6.5%, respectively. Total body weight decreased by 8%, body fat decreased by 29%, and lean mass increased by 7%. Thigh subcutaneous adipose tissue cross-sectional area was reduced by 31%. CONCLUSION: Manipulation of caloric intake, fat percentage, and protein percentage may have influenced body composition after SCI.

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. Walk-time, up-time and total number of steps were measured during each training session. A complete body composition assessment using dual-energy X-ray absorptiometry (DXA) of the spine, knees and hips was conducted before training.Using a platform walker and cuffing both hands, the participant managed to stand up and ambulate successfully using exoskeleton. Over the course of 2 weeks, maximum walk-time increased from 7 to 17 min and number of steps increased from 83 to 589 steps. The total up-time increased from 19 to 31 min. DISCUSSION: Exoskeleton training may be a safe and feasible approach for persons with higher levels of SCI after effectively providing a supportive assistive device for weight shifting. The current case study demonstrates the use of a powered exoskeleton for an individual with high level tetraplegia (C4 and above) and limited hand functions.

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. The cross-sectional area values acquired by thresholding were compared to the manual tracing technique. The percentage errors for thigh circumference were (threshold: 170.71 ± 38.67; manual: 169.45 ± 38.27 cm2) 0.74%, subcutaneous adipose tissue (threshold: 65.99±30.79; manual: 62.68 ± 30.22) 5.2%, whole muscle (threshold: 98.18 ± 20.19; manual: 98.20 ± 20.08 cm2) 0.13%, femoral bone (threshold: 6.53 ± 1.09; manual: 6.53 ± 1.09 cm2) 0.64%, bone marrow fat (threshold: 3.12 ± 1.12; manual: 3.1 ± 1.11 cm2) 0.36%, knee extensor (threshold: 43.98 ± 7.66; manual: 44.61 ± 7.81 cm2) 1.78% and % intramuscular fat (threshold: 10.45 ± 4.29; manual: 10.92 ± 8.35%) 0.47%. Collectively, these results suggest that the threshold technique provided a robust accuracy in measuring the seven main thigh compartments, while greatly reducing the analysis time.

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. This review will describe the current state of ER modeling of intensive ECG data collected during early clinical drug development; the requirements with regard to the use of a positive control; and address the challenges and opportunities of this alternative approach to assessing QT liability.

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. However, NMES-RT is limited to only a single muscle group. Involving multiple muscle groups of the lower extremities may maximize the health benefits of training. Functional electrical stimulation-lower extremity cycling (FES-LEC) allows for the activation of 6 muscle groups, which is likely to evoke greater metabolic and cardiovascular adaptation. Appropriate knowledge of the stimulation parameters is key to maximizing the outcomes of electrical stimulation training in persons with SCI. Adopting strategies for long-term use of NMES-RT and FES-LEC during rehabilitation may maintain the integrity of the musculoskeletal system, a pre-requisite for clinical trials aiming to restore walking after injury. The current manuscript presents a combined protocol using NMES-RT prior to FES-LEC. We hypothesize that muscles conditioned for 12 weeks prior to cycling will be capable of generating greater power, cycle against higher resistance and result in greater adaptation in persons with SCI.

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. The purpose of the current review was to summarize the methodological approach to manually trace and measure the muscles of the lower leg in individuals with SCI, using magnetic resonance imaging. We also intend to highlight the significance of analyzing lower leg muscle cross-sectional area and its relationship to musculoskeletal and vascular systems in persons with SCI.

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. Stimulation was applied to the knee extensor muscle group of the trained leg, while the untrained leg served as a control. Participants received real-time feedback to ensure a proper setup of electrodes and stimulator to monitor subject safety throughout the entire training session. Magnetic resonance imaging was used to measure cross-sectional areas (CSAs) and intramuscular fat (IMF) of the whole thigh and individual muscle groups. Average two-way travel time, distance traveled in miles and total cost of gas per mile were calculated. RESULTS: Participants had 100% compliance. Trained whole and absolute knee extensor muscle CSA increased by 13% (P=0.002) and 18% (P=0.0002), with no changes in the controlled limb. Absolute knee flexor and adductor CSAs increased by 3% (P=0.02) and 13% (P=0.0001), respectively. Absolute whole thigh and knee extensor IMF CSAs decreased significantly in the trained limb by 14% (P=0.01) and 36% (P=0.0005), respectively, with no changes in controlled limb. DISCUSSION: The pilot work documented that using telehealth communication is a safe, feasible and potentially cost-reducing approach for monitoring home-based NMES-RT in persons with chronic SCI. All trained muscles showed detectable muscle hypertrophy with concomitant decrease in ectopic adipose tissue.

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

INTRODUCTION: 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. Expert commentary: It is further acknowledged that the narrow focus on the QT interval needs to be expanded to include a more comprehensive evaluation of cardiovascular risk since unanticipated off target effects have led to the withdrawal of multiple drugs after they had been approved and marketed.