Chris Pollard

A framework to assess the translation of safety pharmacology data to humans

This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models. Such assessments require a systematic quantitative analysis of safety pharmacology parameters as well as clinical Phase I adverse events. Once the sensitivity, specificity and predictive capacity of models have been determined, they can be aligned within specific phases of the drug discovery and development pipeline for maximal impact, or removed from the screening cascade altogether. Furthermore, data will contribute to evidence-based decision-making based on the knowledge of the model sensitivity and specificity. This strategy should therefore contribute to the reduction of candidate drug attrition and a more appropriate use of animals. More data are needed to increase the power of analysis and enable more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic (PK/PD) relationships as well as non-clinical and clinical outcomes for determining concordance. This task requires the collaboration and agreement of pharmaceutical companies to share data anonymously on proprietary and candidate drugs.

Value of non‐clinical cardiac repolarization assays in supporting the discovery and development of safer medicines

Non‐clinical QT‐related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure–activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure–activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows. For compounds progressing into pre‐clinical development, the ‘core battery’ QT‐related data enable an integrated risk assessment to: (i) fulfil regulatory requirements; (ii) assess the safety and risk–benefit for compound progression to man; (iii) contribute to defining the starting dose during the phase I clinical trials; (iv) influence the design of the phase I clinical trials; (v) identify clinically relevant safety biomarkers; and (vi) contribute to the patient risk management plan. Once a compound progresses into clinical development, QT‐related data can be applied in the context of risk management and risk mitigation. The data from ‘follow‐up’ studies can be used to: (i) support regulatory approval; (ii) investigate discrepancies that may have emerged within and/or between non‐clinical and clinical data; (iii) understand the mechanism of an undesirable pharmacodynamic effect; (iv) provide reassurance for progression into multiple dosing in humans and/or large‐scale clinical trials; and (v) assess drug–drug interactions. Based on emerging data, the integrated risk assessment is then reviewed in this article, and the benefit–risk for compound progression was re‐assessed. Project examples are provided to illustrate the impact of non‐clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval.

Pharmacological and electrophysiological characterization of nine, single nucleotide polymorphisms of the hERG-encoded potassium channel

Background and purpose:  Potencies of compounds blocking KV11.1 [human ether‐ago‐go‐related gene (hERG)] are commonly assessed using cell lines expressing the Caucasian wild‐type (WT) variant. Here we tested whether such potencies would be different for hERG single nucleotide polymorphisms (SNPs).

Early clinical development: Evaluation of drug-induced torsades de pointes risk☆

Drug-induced arrhythmias or QT interval prolongation is one of the two most common reasons for drugs to be denied regulatory approval or to have warnings imposed on their clinical labelling. The assessment of torsades de pointes (TdP) risk during clinical development of a new pharmaceutical compound has been an issue of debate since the original description of drug-induced proarrhythmia. TdP risk assessment is complicated by the very low incidence (e.g., <1/100,000 patient years of exposure) of clinical events for non-antiarrhythmic agents and thus the improbable likelihood of observing even one event during clinical development. Thus surrogate methods of determining risk are necessary. A clinical approach to the issue of TdP risk assessment during drug development has been developed and implemented internationally. These efforts have markedly reduced the likelihood that drugs with unknown TdP risks will be commercialized, have resulted in fostering extensive productive pre-clinical and clinical research, and subsequent improved understanding of drug-induced proarrhythmia. Current research efforts are directed to increasing the efficiency of clinical QT assessment and the impact of pre-clinical assessment on clinical development. This article describes the clinical evaluation of TdP risk during drug development and how pre-clinical assessment can impact the early clinical development TdP risk assessment.

Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.

Drug-induced blood pressure increase – recommendations for assessment in clinical and non-clinical studies

ABSTRACT Introduction: Changes in blood pressure (BP) are now proactively examined throughout the drug development process as an integral aspect of safety monitoring. This is because hypertension is a very strong risk factor for cardiovascular events and drug-induced increases in BP have attracted increased regulatory attention. However, there is currently no guidance from regulatory agencies on the minimum BP data required for submissions, and there are no specific criteria for what constitutes a safety signal for increased BP in non clinical studies. Areas covered: Evaluation of BP increases through the drug discovery and development process. Expert opinion: Research into the effects of drugs should begin before clinical development is initiated and continue throughout the clinical trial program. Non clinical studies should inform a benefit–risk analysis that will aid decision-making of whether to enter the drug into Phase I development. The degree of acceptable risk will vary according to the therapy area, treatment indication and intended population for the new drug, and the approach to BP assessment and risk mitigation should be tailored accordingly. However, BP monitoring should always be included in clinical trials, and data collected from multiple studies, to convincingly prove or refute a suspicion of BP effects.