A comparison of the performance of contemporary, historical, and cross-lab controls in QTc assessment in conscious nonhuman primates.

Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies. We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls. Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP. The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies.

Assessment of cardiac parameters after the administration of nicorandil before primary percutaneous coronary intervention.

Objective: To assess cardiac troponin I and creatine kinase-myocardial band levels, electrocardiogram changes and major adverse cardiac events after treatment with nicorandil before primary percutaneous coronary intervention. METHODS: The comparative, analytical study was conducted from October to November 2022 at the Pharmacology Department of Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan, in collaboration with the Rawalpindi Institute of Cardiology, Rawalpindi. The sample comprised ST-elevated myocardial infarction patients of either gender aged at least 30 years with an ejection fraction of at least 35% undergoing primary percutaneous coronary intervention. Participants were selected based on the above-mentioned inclusion and informed consent was taken before their enrolment in this research study. The sample was randomised into control group A receiving conventional acute coronary syndrome treatment, and intervention group B receiving nicorandil in addition to the conventional treatment. Cardiac troponin I and creatine kinase-myocardial band levels, electrocardiogram changes, and major adverse cardiac events noted and compared. Data was analysed using SPSS 26. RESULTS: Of the 140 patients, 70(50%) were in each of the 2 groups. In group B, 60(85.7%) patients achieved a completely settled ST segment on electrocardiogram compared to 25(35.7%) in group A (p=0.001). There was a significant inter-group difference with respect to cardiac troponin I value 6 hours after percutaneous coronary intervention and major adverse cardiac events (p<0.05), but creatine kinase-myocardial band level was no significantly different between the groups (p=0.761). Conclusion: Prophylactic use of nicorandil in ST-elevated myocardial infarction patients decreased the incidence of reperfusion injury.

The Efficacy, Effectiveness, and Efficiency of Integrated QTc Assessment: Rationalizing Approaches to New Drug Modalities.

After nearly 3 decades of regulatory activity concerning new drugs' potential for delayed cardiac repolarization an integrated risk assessment paradigm for small molecule drugs has been established. Regulatory guidance also suggests that for large, targeted proteins and monoclonal antibodies no quantitative clinical QTc assessment is necessary. The expansion of new drug modalities prompts the question: "Should these new modalities be treated like small molecule drugs or like monoclonal antibodies?"

Role of acetylcholine spasm provocation test as a pathophysiological assessment in nonobstructive coronary artery disease.

Coronary angiography (CAG) sometimes shows nonobstructive coronary arteries in patients with suspected angina or acute coronary syndrome (ACS). The high prevalence of nonobstructive coronary artery disease (CAD) in those patients has recently been reported not only in Japan but also in Western countries, and is clinically attracting attention. Coronary spasm is considered to be one of the leading causes of both suspected stable angina and ACS with nonobstructive coronary arteries. Coronary spasm could also be associated with left ventricular dysfunction leading to heart failure, which could be improved following the administration of calcium channel blockers. Because we rarely capture spontaneous attacks of coronary spasm with electrocardiograms or Holter recordings, an invasive diagnostic modality, acetylcholine (ACh) provocation test, can be useful in detecting coronary spasm during CAG. Furthermore, we can use the ACh-provocation test to identify high-risk patients with coronary spasm complicated with organic coronary stenosis, and then treat with intensive care. Nonobstructive CAD includes not only epicardial coronary spasm but also microvascular spasm or dysfunction that can be associated with recurrent anginal attacks and poor quality of life. ACh-provocation test could also be helpful for the assessment of microvascular spasm or dysfunction. We hope that cardiologists will increasingly perform ACh-provocation test to assess the pathophysiology of nonobstructive CAD.

Assessment of cardiac risk in chronic asymptomatic alcoholics using blood pressure and electrocardiogram, and the relation with duration of drinking.

Background The Global Status Report 2017 reveals that 11% of Indians indulge in binge drinking. Chronic alcohol intake may lead to cardiac problems and hypertension. The aim of this study was to evaluate cardiovascular risk among asymptomatic chronic alcoholics. Methods A total of 80 asymptomatic chronic alcoholics of South Indian origin, from the psychiatry ward of Sri Ramachandra Institute of Higher Education and Research, India were diagnosed with alcohol dependence syndrome(ADS). Group I includes alcoholics for 10 years or less and group II includes alcoholics for more than 10 years. Alcohol consumption was measured using the DSM IV criteria. Blood pressure (BP) and electrocardiographic (ECG) data were measured on admission and 2 weeks later. The paired t-test compared a significant outcome of the two sets of data at p ≤ 0.05 level of significance. Results Forty percent of the patients were found to be hypertensive and only 2.5% were found to be pre-hypertensive on admission. The mean age of the hypertensives was 46.9 and nonhypertensives was 42.1 The difference in the BP evaluated after 2 weeks was staggering - systolic BP had a mean fall of 6.1 mm Hg (p < 0.001) and diastolic BP 2.25 mm Hg (p = 0.001). The electrocardiogram results showed significant changes like left ventricular hypertrophy, abnormal T waves, and QT prolongation. Conclusions Chronic alcoholism is a major criterion for heart abnormalities such as elevated BP and left ventricular enlargement, and our study supports this as we see that alcohol consumption for more than 10 years shows significant deterioration. Further clinical observations and long-term prospective studies are needed to confirm these observations.

Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates.

Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf) allows for analysis of the PK-QTc relationship using early Phase I data to assess QTc liability. In this paper, we compared the cardiac risk assessment based on the early Phase I analysis with that from a thorough QTc study across eleven drug candidate programs, and demonstrate that the conclusions are largely the same. The early Phase I analysis is based upon a linear mixed effect model with known covariance structure (Dosne et al. in Stat Med 36(24):3844-3857, 2017). The treatment effect was evaluated at the supratherapeutic Cmax as observed in the thorough QTc study using a non-parametric bootstrap analysis to generate 90% confidence intervals for the treatment effect, and implementation of the standardized methodology in R and SAS software yielded consistent results. The risk assessment based on the concentration-response analysis on the early Phase I data was concordant with that based on the standard analysis of the thorough QTc study for nine out of the eleven drug candidates. This retrospective analysis is consistent with and supportive of the conclusion of a previous prospective analysis by Darpo et al. (Clin Pharmacol Ther 97(4):326-335, 2015) to evaluate whether C-QTc analysis can detect QTc effects in a small study with healthy subjects.

Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication.

PF614, a novel trypsin activated abuse protection (TAAP) prodrug of oxycodone, is being studied as chronic pain analgesic with extended release and abuse resistant properties. A series of nonclinical safety studies were conducted to support PF614 introduction to clinical trials. Ames assays (PF614 and its metabolites), comet assay (PF614 ≤ 50 mg/kg/day oral gavage in rats) and micronucleus assay (PF614 ≤ 175 mg/kg/day oral gavage in rats) were negative. hERG assay IC50 for PF614 was ≥300 µM. PF614 (0.1 and 10 µM) showed a low permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) and was not a P-gp or BCRP substrate or inhibitor. The mean percent unbound PF614 among all concentrations in plasma ranged from 91.2 to 98.4, 79.4 to 100, and 52.9-79.9% in rat, dog, and human, respectively. Also, PF614 was metabolically stable in rat, dog, and human hepatocytes with no metabolites identified. Safety pharmacology study in dog indicated moderately lower heart rate at ≥ 2 mg/kg oral gavage doses. Toxicity studies of PF614 in rat and dog with daily oral doses of 25 and 18 mg/kg, respectively, for 14 Days were well tolerated with favorable safety profile supporting its further clinical evaluation.

Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors.

The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.

A Phase 1 Assessment of the QT Interval in Healthy Adults Following Exposure to Rolapitant, a Cancer Supportive Care Antiemetic.

This 2-part study evaluated the QT/QTc prolongation potential and safety and pharmacokinetics of the antiemetic rolapitant, a neurokinin-1 receptor antagonist. Part 1 was a randomized, placebo-controlled single-dose-escalation study assessing the safety of a single high dose of rolapitant. Part 2 was a randomized, placebo- and positive-controlled, double-blind parallel-group study including 4 treatment arms: rolapitant at the highest safe dose established in part 1, placebo, moxifloxacin 400 mg (positive control), and rolapitant at the presumed therapeutic dose (180 mg). Among 184 adults, rolapitant was absorbed following oral administration under fasting conditions, with a median Tmax of 4 to 6 hours (range, 2-8 hours) and was safe at all doses up to 720 mg. No differences in mean change in QTcF were observed between placebo and rolapitant from baseline or at any point. At any point, the upper bound of the confidence interval for the mean difference between placebo and rolapitant was no greater than 4.4 milliseconds, and the mean difference between placebo and rolapitant was no greater than 1.7 milliseconds, suggesting an insignificant change in QTc with rolapitant. Rolapitant is safe and does not prolong the QT interval at doses up to 720 mg relative to placebo in healthy adults.

Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.

Can We Improve Physical Health Monitoring for Patients Taking Antipsychotics on a Mental Health Inpatient Unit?

BACKGROUND: Patients with severe mental illness are at risk of medical complications, including cardiovascular disease, metabolic syndrome, and diabetes. Given this vulnerability, combined with metabolic risks of antipsychotics, physical health monitoring is critical. Inpatient admission is an opportunity to screen for medical comorbidities. Our objective was to improve the rates of physical health monitoring on an inpatient psychiatry unit through implementation of an electronic standardized order set. METHODS: Using a clinical audit tool, we completed a baseline retrospective audit (96 eligible charts) of patients aged 18 to 100 years, discharged between January and March 2012, prescribed an antipsychotic for 3 or more days. We then developed and implemented a standard electronic admission order set and provided training to inpatient clinical staff. We completed a second chart audit of patients discharged between January and March 2016 (190 eligible charts) to measure improvement in physical health monitoring and intervention rates for abnormal results. RESULTS: In the 2012 audit, thyroid-stimulating hormone (TSH), blood pressure, blood glucose, fasting lipids, electrocardiogram (ECG), and height/weight were measured in 71%, 92%, 31%, 36%, 51%, and 75% of patients, respectively. In the 2016 audit, TSH, blood pressure, blood glucose, fasting lipids, ECG, and height/weight were measured in 86%, 96%, 96%, 64%, 87%, and 71% of patients, respectively. There were statistically significant improvements (P < 0.05) in monitoring rates for blood glucose, lipids, ECG, and TSH. Intervention rates for abnormal blood glucose and/or lipids (feedback to family doctor and/or patient, consultation to hospitalist, endocrinology, and/or dietician) did not change between 2012 and 2016. CONCLUSIONS: Electronic standardized order set can be used as a tool to improve screening for physical health comorbidity in patients with severe mental illness receiving antipsychotic medications.

Noninvasive assessment of dofetilide plasma concentration using a deep learning (neural network) analysis of the surface electrocardiogram: A proof of concept study.

BACKGROUND: Dofetilide is an effective antiarrhythmic medication for rhythm control in atrial fibrillation, but carries a significant risk of pro-arrhythmia and requires meticulous dosing and monitoring. The cornerstone of this monitoring, measurement of the QT/QTc interval, is an imperfect surrogate for plasma concentration, efficacy, and risk of pro-arrhythmic potential. OBJECTIVE: The aim of our study was to test the application of a deep learning approach (using a convolutional neural network) to assess morphological changes on the surface ECG (beyond the QT interval) in relation to dofetilide plasma concentrations. METHODS: We obtained publically available serial ECGs and plasma drug concentrations from 42 healthy subjects who received dofetilide or placebo in a placebo-controlled cross-over randomized controlled clinical trial. Three replicate 10-s ECGs were extracted at predefined time-points with simultaneous measurement of dofetilide plasma concentration We developed a deep learning algorithm to predict dofetilide plasma concentration in 30 subjects and then tested the model in the remaining 12 subjects. We compared the deep leaning approach to a linear model based only on QTc. RESULTS: Fourty two healthy subjects (21 females, 21 males) were studied with a mean age of 26.9 ± 5.5 years. A linear model of the QTc correlated reasonably well with dofetilide drug levels (r = 0.64). The best correlation to dofetilide level was achieved with the deep learning model (r = 0.85). CONCLUSION: This proof of concept study suggests that artificial intelligence (deep learning/neural network) applied to the surface ECG is superior to analysis of the QT interval alone in predicting plasma dofetilide concentration.

Challenges in implementing and obtaining acceptance for J-Tpeak assessment as the clinical component of CiPA.

INTRODUCTION: This paper is based on a presentation held at the Annual Safety Pharmacology Society meeting in September 2017, at which challenges for the clinical component of CiPA were presented. FDA has published an automated algorithm for measurement of the J-Tpeak interval on a median beat from a vector magnitude lead derived from a 12-lead ECG. CiPA proposes that J-Tpeak prolongation < 10 ms can be used for drugs with a QTc effect < 20 ms to differentiate between safe and unsafe delayed repolarization and to reduce the level of ECG monitoring in late stage clinical trials. METHODS: We applied FDA's algorithm, complemented with iCOMPAS, to moxifloxacin and dolasetron data from the IQ-CSRC study with 9 subjects on active and 6 on placebo. The effect on QTcF and corrected J-Tpeak (J-Tpeak_c) was analyzed using concentration-effect modeling. RESULTS: There was a good correlation between QTcF and J-Tpeak_c prolongation after oral dosing of 400 mg moxifloxacin with placebo-adjusted, change-from-baseline (ΔΔ) J-Tpeak_c of ~12 ms at concentrations that caused ΔΔQTcF of ~20 ms. On dolasetron, J-Tpeak_c was highly variable, no prolongation was seen and an effect on ΔΔJ-Tpeak_c > 10 ms could be excluded across the observed plasma concentration range. DISCUSSION: In this limited analysis performed on the IQ-CSRC study waveforms using FDA's automated algorithm, J-Tpeak prolongation was observed on moxifloxacin, but not on dolasetron, despite clinical observations of proarrhythmias with both drugs. Challenges for the implementation of the J-Tpeak interval as a replacement or complement to the QTc interval, include to demonstrate that the proposed clinical algorithm using a J-Tpeak threshold of 10 ms, can be used to categorize drugs with a QT effect up to ~20 ms as having low pro-arrhythmic risk.

Assessment of tobacco smoke effects on neonatal cardiorespiratory control using a semi-automated processing approach.

A semi-automated processing approach was developed to assess the effects of early postnatal environmental tobacco smoke (ETS) on the cardiorespiratory control of newborn lambs. The system consists of several steps beginning with artifact rejection, followed by the selection of stationary segments, and ending with feature extraction. This approach was used in six lambs exposed to 20 cigarettes/day for the first 15 days of life, while another six control lambs were exposed to room air. On postnatal day 16, electrocardiograph and respiratory signals were obtained from a 6-h polysomnographic recording. The effects of postnatal ETS exposure on heart rate variability, respiratory rate variability, and cardiorespiratory interrelations were explored. The unique results suggest that early postnatal ETS exposure increases respiratory rate variability and decreases the coupling between cardiac and respiratory systems. Potentially harmful consequences in early life include unstable breathing and decreased adaptability of cardiorespiratory function, particularly during early life challenges, such as prematurity or viral infection. Graphical abstract ᅟ.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review.

BACKGROUND: The cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio-oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life-threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario. METHODS AND RESULTS: In this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare. CONCLUSIONS: Our systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram.

A quantitative systems toxicology (QST) model for citalopram was established to simulate, in silico, a 'virtual twin' of a real patient to predict the occurrence of cardiotoxic events previously reported in patients under various clinical conditions. The QST model considers the effects of citalopram and its most notable electrophysiologically active primary (desmethylcitalopram) and secondary (didesmethylcitalopram) metabolites, on cardiac electrophysiology. The in vitro cardiac ion channel current inhibition data was coupled with the biophysically detailed model of human cardiac electrophysiology to investigate the impact of (i) the inhibition of multiple ion currents (IKr, IKs, ICaL); (ii) the inclusion of metabolites in the QST model; and (iii) unbound or total plasma as the operating drug concentration, in predicting clinically observed QT prolongation. The inclusion of multiple ion channel current inhibition and metabolites in the simulation with unbound plasma citalopram concentration provided the lowest prediction error. The predictive performance of the model was verified with three additional therapeutic and supra-therapeutic drug exposure clinical cases. The results indicate that considering only the hERG ion channel inhibition of only the parent drug is potentially misleading, and the inclusion of active metabolite data and the influence of other ion channel currents should be considered to improve the prediction of potential cardiac toxicity. Mechanistic modelling can help bridge the gaps existing in the quantitative translation from preclinical cardiac safety assessment to clinical toxicology. Moreover, this study shows that the QST models, in combination with appropriate drug and systems parameters, can pave the way towards personalised safety assessment.

Model averaging for robust assessment of QT prolongation by concentration-response analysis.

Assessing the QT prolongation potential of a drug is typically done based on pivotal safety studies called thorough QT studies. Model-based estimation of the drug-induced QT prolongation at the estimated mean maximum drug concentration could increase efficiency over the currently used intersection-union test. However, robustness against model misspecification needs to be guaranteed in pivotal settings. The objective of this work was to develop an efficient, fully prespecified model-based inference method for thorough QT studies, which controls the type I error and provides satisfactory test power. This is achieved by model averaging: The proposed estimator of the concentration-response relationship is a weighted average of a parametric (linear) and a nonparametric (monotonic I-splines) estimator, with weights based on mean integrated square error. The desired properties of the method were confirmed in an extensive simulation study, which demonstrated that the proposed method controlled the type I error adequately, and that its power was higher than the power of the nonparametric method alone. The method can be extended from thorough QT studies to the analysis of QT data from pooled phase I studies.

Estimation of QT interval prolongation through model-averaging.

The current method to analyze concentration-QT interval data, which is based on predictions conditional on a best model, fails to take into account the uncertainty of the model. Previous studies have suggested that failure to take into account model uncertainty using a best model approach can result in confidence intervals that are overly optimistic and may be too narrow. Theoretically, more realistic estimates are obtained using model-averaging where the overall point estimate and confidence interval are a weighted-average from a set of candidate models, the weights of which are equal to each model's Akaike weight. Monte Carlo simulation was used to determine the degree of narrowness in the confidence interval for the degree of QT prolongation under a single ascending dose and thorough QT trial design. Results showed that model averaging performed as well as the best model approach under most conditions with no numeric advantage to using a model averaging approach. No difference was observed in the coverage of the confidence intervals when the best model and model averaging was done by AIC, AICc, or BIC, although in certain circumstances the coverage of the confidence interval themselves tended to be too narrow when using BIC. Modelers can continue to use the best model approach for concentration-QT modeling with confidence, although model averaging may offer more face validity, may be of value in cases where there is uncertainty or misspecification in the best model, and be more palatable to a non-technical reviewer than the best model approach.

Translational science approach for assessment of cardiovascular effects and proarrhythmogenic potential of the beta-3 adrenergic agonist mirabegron.

INTRODUCTION: Translational assessment of cardiac safety parameters is a challenge in clinical development of beta-3 adrenoceptor agonists. The preclinical tools are presented that were used for assessing human safety for mirabegron. METHODS: Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (IKr, IKs, Ito, INa, and ICa,L), on QT-interval, subendocardial APD90, Tpeak-end interval, and arrhythmia's in ventricular dog wedge tissue in vitro and on cardiovascular function (BP, HR, and QTc) in conscious dogs. RESULTS: In conscious dogs, mirabegron (0.01-10mg/kg, p.o.) dose-dependently increased HR, reduced SBP but DBP was unchanged. Propranolol blocked the decrease in SBP and attenuated HR increase at 100mg/kg mirabegron. Mirabegron, at 30, 60, or 100mg/kg, p.o., had no significant effect on the QTc interval. In paced dog ventricular wedge, neither mirabegron nor metabolites M5, M11, M12, M14, and M16 prolonged QT, altered transmural dispersion of repolarization, induced premature ventricular contractions, or induced ventricular tachycardia. Mirabegron nor its metabolites inhibited IKr, IKs, Ito INa, or ICa,L at clinically relevant concentrations. DISCUSSION: Up to exposure levels well exceeding human clinical exposure no discernible effects on ion channel conductance or on arrhythmogenic parameters in ventricular wedge resulted for mirabegron, or its main metabolites, confirming human cardiac safety findings. In vivo, dose-related increases in HR with effects markedly higher than seen clinically, was mediated in part by cross-activation of beta-1 adrenoceptors. This non-clinical cardiac safety test program therefore proved predictive for human cardiac safety for mirabegron.

Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice.

INTRODUCTION: The Safety Pharmacology Society (SPS) has conducted a survey of its membership to identify industry practices related to testing considered in the Comprehensive In vitro Proarrhythmia Assay (CiPA). METHODS: Survey topics included nonclinical approaches to address proarrhythmia issues, conduct of in silico studies, in vitro ion channel testing methods used, drugs used as positive controls during the conduct of cardiac ion channel studies, types of arrhythmias observed in non-clinical studies and use of the anticipated CiPA ion channel assay. RESULTS: In silico studies were used to evaluate effects on ventricular action potentials by only 15% of responders. In vitro assays were used mostly to assess QT prolongation (95%), cardiac Ca2+ and Na+ channel blockade (82%) and QT shortening or QRS prolongation (53%). For de-risking of candidate drugs for proarrhythmia, those assays most relevant to CiPA including cell lines stably expressing ion channels used to determine potency of drug block were most frequently used (89%) and human stem cell-derived or induced pluripotent stem cell cardiomyocytes (46%). Those in vivo assays related to general proarrhythmia derisking include ECG recording using implanted telemetry technology (88%), jacketed external telemetry (62%) and anesthetized animal models (53%). While the CiPA initiative was supported by 92% of responders, there may be some disconnect between current practice and future expectations, as explained. DISCUSSION: Proarrhythmia liability assessment in drug development presently includes study types consistent with CiPA. It is anticipated that CiPA will develop into a workable solution to the concern that proarrhythmia liability testing remains suboptimal.