Characterization of indoleamine-2,3-dioxygenase 1, tryptophan-2,3-dioxygenase, and Ido1/Tdo2 knockout mice.

Indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO2) degrade tryptophan (Trp) to kynurenine (Kyn), and these enzymes have promise as therapeutic targets. A comprehensive characterization of potential safety liabilities of IDO1 and TDO2 inhibitors using knockout (KO) mice has not been assessed, nor has the dual Ido1/Tdo2 KO been reported. Here we characterized male and female mice with KOs for Ido1, Tdo2, and Ido1/Tdo2 and compared findings to the wild type (WT) mouse strain, evaluated for 14 days, using metabolomics, transcriptional profiling, behavioral analysis, spleen immunophenotyping, comprehensive histopathological analysis, and serum clinical chemistry. Multiple metabolomic changes were seen in KO mice. For catabolism of Trp to Kyn and anthranilic acid, both substrates were decreased in liver of Tdo2 and dual KO mice. Metabolism of Trp to serotonin and its metabolites resulted in an increase in 5-Hydroxyindole-3-acetic acid in the Tdo2 and dual KO mice. Ido1 and dual KO mice displayed a Kyn reduction in plasma but not in liver. Nicotinamide synthesis and conversion of glucose to lactic acid were not impacted. A slight decrease in serum alkaline phosphatase was seen in all KOs, and small changes in liver gene expression of genes unrelated to tryptophan metabolism were observed. Regarding other parameters, no genotype-specific changes were observed. In summary, this work shows metabolomic pathway changes for metabolites downstream of tryptophan in these KO mice, and suggests that inhibition of the IDO1 and TDO2 enzymes would be well tolerated whether inhibited individually or in combination since no safety liabilities were uncovered.

Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors.

A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

Characterizing Pharmacokinetic-Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation.

We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K)δ inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3Kδ inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC50 values for PI3Kδ inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.2, 4.8, 0.8, and 0.5 µM. In the ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kδ inhibitors produced a dose-dependent inhibition of bronchoalveolar lavage eosinophils (maximum effect between 80% and 99%). In a follow-up experiment designed to investigate PK attributes [maximum (or peak) plasma concentration (Cmax), area under the curve (AUC), time on target (ToT)] that govern PI3Kδ efficacy, MSD-496486311 [3 mg/kg every day (QD) and 100 mg/kg QD] produced 16% and 93% inhibition of eosinophils, whereas doses (20 mg/kg QD, 10 mg/kg twice per day, and 3 mg/kg three times per day) produced 54% to 66% inhibition. Our profiling suggests that impact of PI3Kδ inhibitors on eosinophils is supported by a PK target with a ToT over the course of treatment close to the PD IC50 rather than strictly driven by AUC, Cmax, or Cmin (minimum blood plasma concentration) coverage. Additional studies in an Altenaria alternata rat model, a sheep Ascaris-sensitive sheep model, and a TH1-driven rat ozone exposure model did not challenge our hypothesis, suggesting that an IC50 level of TE (target engagement) sustained for 24 hours is required to produce efficacy in these traditional models. We conclude that the PK/PD observations in our animal models appear to align with clinical results associated with a TH2 airway disease.

A Historical View and Vision into the Future of the Field of Safety Pharmacology.

Professor Gerhard Zbinden recognized in the 1970s that the standards of the day for testing new candidate drugs in preclinical toxicity studies failed to identify acute pharmacodynamic adverse events that had the potential to harm participants in clinical trials. From his vision emerged the field of safety pharmacology, formally defined in the International Conference on Harmonization (ICH) S7A guidelines as "those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above." Initially, evaluations of small-molecule pharmacodynamic safety utilized efficacy models and were an ancillary responsibility of discovery scientists. However, over time, the relationship of these studies to overall safety was reflected by the regulatory agencies who, in directing the practice of safety pharmacology through guidance documents, prompted transition of responsibility to drug safety departments (e.g., toxicology). Events that have further shaped the field over the past 15 years include the ICH S7B guidance, evolution of molecular technologies leading to identification of new therapeutic targets with uncertain toxicities, introduction of data collection using more sophisticated and refined technologies, and utilization of transgenic animal models probing critical scientific questions regarding novel targets of toxicity. The collapse of the worldwide economy in the latter half of the first decade of the twenty-first century, continuing high rates of compound attrition during clinical development and post-approval and sharply increasing costs of drug development have led to significant strategy changes, contraction of the size of pharmaceutical organizations, and refocusing of therapeutic areas of investigation. With these changes has come movement away from dedicated internal safety pharmacology capability to utilization of capabilities within external contract research organizations. This movement has created the opportunity for the safety pharmacology discipline to come "full circle" and return to the drug discovery arena (target identification through clinical candidate selection) to contribute to the mitigation of the high rate of candidate drug failure through better compound selection decision making. Finally, the changing focus of science and losses in didactic training of scientists in whole animal physiology and pharmacology have revealed a serious gap in the future availability of qualified individuals to apply the principles of safety pharmacology in support of drug discovery and development. This is a significant deficiency that at present is only partially met with academic and professional society programs advancing a minimal level of training. In summary, with the exception that the future availability of suitably trained scientists is a critical need for the field that remains to be effectively addressed, the prospects for the future of safety pharmacology are hopeful and promising, and challenging for those individuals who want to assume this responsibility. What began in the early part of the new millennium as a relatively simple model of testing to assure the safety of Phase I clinical subjects and patients from acute deleterious effects on life-supporting organ systems has grown with experience and time to a science that mobilizes the principles of cellular and molecular biology and attempts to predict acute adverse events and those associated with long-term treatment. These challenges call for scientists with a broad range of in-depth scientific knowledge and an ability to adapt to a dynamic and forever changing industry. Identifying individuals who will serve today and training those who will serve in the future will fall to all of us who are committed to this important field of science.

Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1).

Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.

Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.

Murderous Racism as Normal Psychosis: The Case of Dylann Roof.

Dylann Roof killed nine people in a Black church in 2015 in order to start a "war" between the white and Black races. This case is used here to develop a psychoanalytic theory of murderous racism, and even genocide. Major concepts from Freud (self-preservation, hatred, narcissism, life and death drives, delusion), Klein (projective identification), and Bion (psychotic and nonpsychotic parts of the personality) are employed. Particular attention is given to the hearing to determine Roof's capacity to represent himself after he dismissed his lawyers, who wanted to use an insanity defense to avoid the death penalty. This hearing was confronted with an undecidable dilemma, which led to legal cooperation with Roof's suicidal impulses. The deconstructive approach to undecidability, and its use in questions of law, especially as concerns the relation between psychoanalysis and the death penalty, leads to tentative recommendations for the prevention of racist murder.

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.

Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.

Is there a role for the no observed adverse effect level in safety pharmacology?

In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining 'adversity' and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary 'toxic/non-toxic' rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure level.

Response of safety pharmacologists to challenges arising from the rapidly evolving changes in the pharmaceutical industry.

This commentary highlights and expands upon the thoughts conveyed in the lecture by Dr. Alan S. Bass, recipient of the 2017 Distinguished Service Award from the Safety Pharmacology Society, given on 27 September 2017 in Berlin, Germany. The lecture discussed the societal, scientific, technological, regulatory and economic events that dramatically impacted the pharmaceutical industry and ultimately led to significant changes in the strategic operations and practices of safety pharmacology. It focused on the emerging challenges and opportunities, and considered the lessons learned from drug failures and the influences of world events, including the financial crisis that ultimately led to a collapse of the world economies from which we are now recovering. Events such as these, which continue to today, challenge the assumptions that form the foundation of our discipline and dramatically affect the way that safety pharmacology is practiced. These include the latest scientific and technological developments contributing to the design and advancement of safe medicines. More broadly, they reflect the philosophical mission of safety pharmacology and the roles and responsibilities served by safety pharmacologists. As the discipline of Safety Pharmacology continues to evolve, develop and mature, the reader is invited to reflect on past experiences as a framework towards a vision of the future of the field.

Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability.

PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.

Points to consider emerging from a mini-workshop on cardiac safety: assessing torsades de pointes liability.

A mini-workshop on cardiac safety focusing on assessing drug-induced Torsades de Pointes (TdP) liability was convened as part of the 6th Annual Meeting of the Safety Pharmacology Society. The purpose of this brief publication is to disseminate the salient points emanating from this workshop as a means of engaging the scientific community in the appropriate discussions needed to advance this important field of human safety. The recommendations in this publication extend those of the workshop on "Moving Towards Better Predictors of Drug-Induced Torsades de Pointes" held in November 2005 under the auspice of the International Life Sciences Institute, Health and Environmental Sciences Institute; they fall into four key areas: molecular and cellular biology underlying TdP, dynamics of periodicity, models of TdP proarrhythmia and key considerations for demonstrating utility of non-clinical models. The reader is encouraged to consider the recommendations emanating from the two workshops and align these with ongoing studies in their laboratories. The authors intend to convene a workshop in 2009/2010 to judge advancements in the field of study of drug-induced TdP and make recommendations for a focused validation of those methods holding the greatest promise of improving the predictivity of this unwanted human cardiac risk.

ILSI-HESI cardiovascular safety subcommittee dataset: an analysis of the statistical properties of QT interval and rate-corrected QT interval (QTc).

INTRODUCTION: The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) Cardiovascular Safety Subcommittee outlined a set of in vivo telemetry studies to determine how well this preclinical model identified compounds known to cause torsades de pointes (TdP) and prolong QT interval in humans. In the original analysis of these data, QT, QTcB (Bazett model), QTcF (Fridericia model), and QTcQ (animal-specific model) were evaluated. We further evaluate the statistical properties of these measurements, using a method that can properly account for the sources of variability in the dataset. METHODS: The ILSI/HESI telemetry studies were conducted as a double Latin square design where eight dogs each received a vehicle control and three dose levels of a compound on four separate dosing days. We statistically analyzed the QT/QTc intervals using a repeated measures analysis of covariance and evaluate the powers for QT, QTcF and QTcQ based on simulations. RESULTS: The analyses for QTcF and QTcB intervals show that all six compounds which were known to cause TdP in humans were identified as positive and all six compounds known to be free of TdP events in their clinical use had no statistically significant treatment-related effects, while the analyses for QTcQ identified all positive compounds except pimozide. The power analysis shows that the method can detect a 7% increment of QT, a 5% increment of QTcF, and a 4% increment of QTcQ, with greater than 80% of power when n=8. DISCUSSION: We describe a repeated measures procedure to perform statistical analysis of covariance on Latin square designs and show that it can be used to detect meaningful changes in the analysis of QT/QTc intervals.

ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation.

INTRODUCTION: Drugs that delay cardiac repolarization pose potential safety risks to patients and cause serious regulatory concern because of the link between QT interval prolongation and the potentially fatal arrhythmia torsades de pointes (TdP). Predicting which drugs will cause TdP is an inexact and difficult science. The utility of non-clinical assays was not well understood due in part to variability in methods, species, and consistency in the assays reported in the literature. The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) outlined a set of studies to determine how well selected commonly used non-clinical assays identified compounds known to cause TdP and prolong QT interval in humans. METHODS: Compounds known to prolong ventricular repolarization and compounds considered safe by years of clinical use were tested in three assays: HERG ionic current, Purkinje fiber repolarization, and in vivo QT studies in conscious telemeterized dogs. RESULTS: The data from each of these assays demonstrate that compounds that may pose a proarrhythmia risk for patients can be distinguished from those that are considered safe. DISCUSSION: Taken collectively, the in-vitro and in-vivo preclinical results can be integrated to develop an accurate preclinical risk assessment to support clinical safety.

Non-clinical evaluation of ventricular repolarization (ICH S7B): results of an interim survey of international pharmaceutical companies.

INTRODUCTION: The propensity of drugs to cause a potentially fatal arrhythmia, torsades des pointes (TdP), is a significant public health issue. The draft International Conference on Harmonization (ICH) S7B guidelines describe a battery of non-clinical studies to evaluate a drug's potential to prolong ventricular repolarization (VR); an accepted surrogate/risk factor for TdP. A worldwide survey of pharmaceutical industry practices, related to ICH S7B was conducted. The findings were presented at the 4th Annual Meeting of the Safety Pharmacology Society (SPS) meeting (Cincinnati, OH, Sept., 2004). METHODS: The survey was distributed by the SPS to 119 pharmaceutical companies; 29 surveys were returned. Survey topics included: (a) General Strategy and Testing for Risk of QT prolongation, (b) Study Timing and Relationship to Development, and (c) Application of GLPs. RESULTS: Respondents indicate that the basis for assessing prolongation of VR was to: remove compounds with an arrhythmic risk to humans (86%), to satisfy regulatory expectations (79%), or to avoid obstacles in the clinical development of a compound (86%). Development of a compound based on prolongation of VR was halted for 52% of respondents (compared to 45% in a 2003 survey). Models used to evaluate changes in VR included: human ether a go-go related gene (hERG) (93%), action potential duration (APD) (68%; compared to 80% in the 2003 survey), and in vivo QT (100%). The distribution of assays being requested by regulatory agencies includes the hERG (83%), APD (28%), and in vivo QT (79%). In spite of uncertainty regarding the final requirements of ICH S7B, organizations continue to implement (36%) and validate (60%) their electrophysiology laboratories. SUMMARY: The survey results indicate that pharmaceutical companies are testing for VR prolongation of drug candidates and that institutions have established in-house or outsourced capabilities to evaluate this potential risk, even in the absence of final guidelines.

Validation of a motor activity system by a robotically controlled vehicle and using standard reference compounds.

INTRODUCTION: A series of experiments were undertaken to evaluate the accuracy, precision, specificity, and sensitivity of an automated, infrared photo beam-based open field motor activity system, the MotorMonitor v. 4.01, Hamilton-Kinder, LLC, for use in a good laboratory practices (GLP) Safety Pharmacology laboratory. METHODS: This evaluation consisted of two phases: (1) system validation, employing known inputs using the EM-100 Controller Photo Beam Validation System, a robotically controlled vehicle representing a rodent and (2) biologic validation, employing groups of rats treated with the standard pharmacologic agents diazepam or D-amphetamine. The MotorMonitor's parameters that described the open-field activity of a subject were: basic movements, total distance, fine movements, x/y horizontal ambulations, rearing, and total rest time. These measurements were evaluated over a number of zones within each enclosure. RESULTS: System validation with the EM-100 Controller Photo Beam Validation System showed that all the parameters accurately and precisely measured what they were intended to measure, with the exception of fine movements and x/y ambulations. Biologic validation using the central nervous system depressant diazepam at 1, 2, or 5 mg/kg, i.p. produced the expected dose-dependent reduction in rat motor activity. In contrast, the central nervous system stimulant D-amphetamine produced the expected increases in rat motor activity at 0.1 and 1 mg/kg, i.p, demonstrating the specificity and sensitivity of the system. DISCUSSION: Taken together, these studies of the accuracy, precision, specificity, and sensitivity show the importance of both system and biologic validation in the evaluation of an automated open field motor activity system for use in a GLP compliant laboratory.

Drugs effects on ventricular repolarization: a critical evaluation of the strengths and weaknesses of current methodologies and regulatory practices.

A growing number of drugs and drug combinations inhibit cardiac potassium ion conductance and ventricular repolarization, and increase cardiac APD, QT interval, and risk of potentially fatal TdP. The past decade has seen an explosion of research advances into the mechanism of action underpinning these observations, and an unprecedented level of collaboration between academia, industry, and regulatory authorities to define effective strategies for accurate prediction of increased TdP risk (if any) in humans, based upon nonclinical and/or clinical endpoints. Because the incidence of TdP is so very low, even for drugs for which the association is known, the risk can only be assessed based upon surrogate markers (signals) in in vitro and in vivo non-clinical studies as well as in clinical trials. In this article, we review both the strengths and weaknesses of current methodologies and regulatory practices for assessment of TdP risk for pharmaceuticals.

Challenges and lessons learned since implementation of the safety pharmacology guidance ICH S7A.

The International Conference on Harmonization, Topic S7A guidance (ICH S7A) on safety pharmacology for human pharmaceuticals has been in effect for 3 years in Europe, the United States and Japan. Surveys of the pharmaceutical industry, regulatory agencies and the audience attending the 4th Annual Meeting of the Safety Pharmacology Society have helped identify and address areas of controversy, as well as those challenges that have emerged since implementation of the guidance worldwide. Overall, ICH S7A has been successfully implemented. The guidance provides for "Good Laboratory Practice" compliant "safety pharmacology core battery" of studies that are generally performed prior to first administration to humans. The approach is science-driven and specifies the use of robust and sophisticated in vitro and/or in vivo assays. There are, however, some areas that require further refinement/clarification such as the specifics of study design including the selection of dose/concentration, choice of species, modeling of the temporal pharmacodynamic changes in relation to pharmacokinetic profile of parent drug and major metabolites, use of an appropriate sample size, statistical power analysis as a means of demonstrating the sensitivity of the model system, testing of human-specific metabolites and demonstrating not only the model's sensitivity, but also its specificity for predicting adverse events in humans. There was also discussion of when these studies are needed in relation to the clinical development plan. Representatives from the pharmaceutical industry and regulatory agencies see the implementation of ICH S7A as a major step forward towards identifying the risk to Phase 1 and 2 volunteers and patients. It remains to be seen, however, whether and in what ways the ICH S7A-based strategy will contribute to the modification of the integrated risk assessment during the latter stages of clinical development or once drugs have been introduced to the marketplace.

Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance.

Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960-2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes.