Lorna Ewart

Translational pharmacokinetic-pharmacodynamic modeling of QTc effects in dog and human.

INTRODUCTIONnPreclinical assessment of the heart rate corrected QT interval (QTc) is an important component of the cardiovascular safety evaluation in drug discovery. Here we aimed to quantify the translational relationship between QTc prolongation and shortening in the conscious telemetered dog and humans by a retrospective pharmacokinetic-pharmacodynamic (PKPD) analysis.nnnMETHODSnQTc effects of 2 proprietary compounds and 2 reference drugs (moxifloxacin and dofetilide) were quantified in conscious dogs and healthy volunteers via a linear and Emax pharmacokinetic-pharmacodynamic models. The translational relationship was quantified by correlating the QTc response from dog and human at matching free drug concentrations.nnnRESULTSnA consistent translational relationship was found at low delta-QTc intervals indicating that a QTc change of 2.5-8 ms in dog would correspond to a 10 ms change in human.nnnDISCUSSIONnThe translational relationship developed here can be used to predict the QTc liability in human using preclinical dog data. It could therefore help protect the health of human volunteers, for example by appropriate clinical study design and dose selection, as well as improve future decision-making and help reduce compound attrition due to changes in QT interval.

A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions

INTRODUCTIONnParts A and B of the ICH S7 guidelines on safety pharmacology describe the in vivo studies that must be conducted prior to first time in man administration of any new pharmaceutical. ICH S7A requires a consideration of the sensitivity and reproducibility of the test systems used. This could encompass maintaining a dataset of historical pre-dose values, power analyses, as well as a demonstration of acceptable model sensitivity and robust pharmacological validation. During the process of outsourcing safety pharmacology studies to Charles River Laboratories, AstraZeneca set out to ensure that models were performed identically in each facility and saw this as an opportunity to review the inter-laboratory variability of these essential models.nnnMETHODSnThe five in vivo studies outsourced were the conscious dog telemetry model for cardiovascular assessment, the rat whole body plethysmography model for respiratory assessment, the rat modified Irwin screen for central nervous system assessment, the rat charcoal meal study for gastrointestinal assessment and the rat metabolic cage study for assessment of renal function. Each study was validated with known reference compounds and data were compared across facilities. Statistical power was also calculated for each model.nnnRESULTSnThe results obtained indicated that each of the studies could be performed with comparable statistical power and could achieve a similar outcome, independent of facility.nnnDISCUSSIONnThe consistency of results obtained from these models across multiple facilities was high thus providing confidence that the models can be run in different facilities and maintain compliance with ICH S7A and B.

Application of Data Mining and Visualization Techniques for the Prediction of Drug-Induced Nausea in Man

The therapeutic value of many drugs can be limited by gastrointestinal (GI) adverse effects such as nausea and vomiting. Nausea is a subjective human sensation, hence little is known about preclinical biomarkers that may accurately and effectively predict its presence in man. The aim of this analysis was to use informatics and data-mining tools to identify plausible preclinical GI effects that may be associated with nausea and that could be of potential use in its prediction. A total of 86 marketed drugs were used in this analysis, and the main outcome was a confirmation that nausogenic and non-nausogenic drugs can be clearly separated based on their preclinical GI observations. Specifically, combinations of common preclinical GI effects (vomiting, diarrhea, and salivary hypersecretion) proved to be strong predictors. The model was subsequently validated with a subset of 20 blinded proprietary small molecules and successfully predicted clinical outcome in 90% of cases. This investigation demonstrated the feasibility of data-mining approaches to facilitate discovery of novel, plausible associations that can be used to understand drug-induced adverse effects.

How do the top 12 pharmaceutical companies operate safety pharmacology

INTRODUCTIONnHow does safety pharmacology operate in large pharmaceutical companies today? By understanding our current position, can we prepare safety pharmacology to successfully navigate the complex process of drug discovery and development?nnnMETHODSnA short anonymous survey was conducted, by invitation, to safety pharmacology representatives of the top 12 pharmaceutical companies, as defined by 2009 revenue figures. A series of multiple choice questions was designed to explore group size, accountabilities, roles and responsibilities of group members, outsourcing policy and publication record.nnnRESULTSnA 92% response rate was obtained. Six out of 11 companies have 10 to 30 full time equivalents in safety pharmacology, who hold similar roles and responsibilities; although the majority of members are not qualified at PhD level or equivalent. Accountabilities were similar across companies and all groups have accountability for core battery in vivo studies and problem solving activities but differences do exist for example with in vitro safety screening and pharmacodynamic/pharmokinetic modeling (PK/PD). The majority of companies outsource less than 25% of studies, with in vitro profiling being the most commonly outsourced activity. Finally, safety pharmacology groups are publishing 1 to 4 articles each year.nnnCONCLUSIONnThis short survey has highlighted areas of similarity and differences in the way large pharmaceutical companies operate safety pharmacology.

Pharmacological validation of a telemetric model for the measurement of bronchoconstriction in conscious rats.

INTRODUCTIONnTelemetric measurement of intra-pleural pressure in conscious animals that are restrained in head-out plethysmography chambers enables determination of airway resistance. Originally proposed over 10 years ago, pharmacological validation of this technique is limited. Here airway resistance in conscious, instrumented rats was compared to measurement in anaesthetised rats via a fluid filled oesophageal catheter following administration of two different pharmacological agents.nnnMETHODSnMale rats were implanted with telemetry devices and were trained to accept the restraint of head-out plethysmography chambers. A separate group of male rats were anaesthetised, placed in a body-enclosed plethysmography chamber and were prepared with a tracheal, oesphageal and jugular vein cannulae. Methacholine or NECA were given intravenously and changes in ventilation and airway resistance were measured.nnnRESULTSnThe pressure signal obtained in the telemetered rats was found to be extremely variable. Variability was confounded by excessive struggling, particularly during the infusion periods. Misplacement of the pressure sensitive catheter tip and prior habituation to the chamber were not factors in signal variability. Consequently, no dose-response relationship to either pharmacological agent was established in this model. Dose-dependent increases in resistance to both methacholine and NECA were measured in anaesthetised rats using body-enclosed plethysmography.nnnDISCUSSIONnGiven the variability of the pressure signal within and between rats, the feasibility of a model in conscious rats for the measurement of airway resistance is questioned. Improved restraint methods or alternative models in conscious animals should therefore be explored. In the meantime, assessment of airway resistance is best confined to the anaesthetised rat.

The validation of an in vitro colonic motility assay as a biomarker for gastrointestinal adverse drug reactions

Motility-related gastrointestinal adverse drug reactions (GADRs), such as constipation and diarrhea, are some of the most frequently reported adverse events associated with the clinical development of new chemical entities, and for marketed drugs. However, biomarkers capable of detecting such GADRs are lacking. Here, we describe an in vitro assay developed to detect and quantify changes in intestinal motility as a surrogate biomarker for constipation/diarrhea-type GADRs. In vitro recordings of intraluminal pressure were used to monitor the presence of colonic peristaltic motor complexes (CPMCs) in mouse colonic segments. CPMC frequency, contractile and total mechanical activity were assessed. To validate the assay, two experimental protocols were conducted. Initially, five drugs with known gastrointestinal effects were tested to determine optimal parameters describing excitation and inhibition as markers for disturbances in colonic motility. This was followed by a blinded evaluation of nine drugs associated with or without clinically identified constipation/diarrhea-type GADRs. Concentration-response relationships were determined for these drugs and the effects were compared with their maximal free therapeutic plasma concentration in humans. The assay detected stimulatory and inhibitory responses, likely correlating to the occurrence of diarrhea or constipation. Concentration-related effects were identified and potential mechanisms of action were inferred for several drugs. Based on the results from the fourteen drugs asssessed, the sensitivity of the assay was calculated at 90%, with a specificity of 75% and predictive capacity of 86%. These results support the potential use of this assay in screening for motility-related GADRs during early discovery phase, safety pharmacology assessment.

Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials

Motility‐related gastrointestinal (GI) adverse drug reactions (GADRs) such as diarrhea and constipation are a common and deleterious feature associated with drug development. Novel biomarkers of GI function are therefore required to aid decision making on the GI liability of compounds in development.