Publications (57) View all
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Article: A Public-Private Consortium Advances Cardiac Safety Evaluation: Achievements of the HESI Cardiac Safety Technical Committee.
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ABSTRACT: The evaluation of cardiovascular side-effects is a critical element in the development of all new drugs and chemicals. Cardiac safety issues have been and continue to be a major cause of attrition andwithdrawal due to Adverse Drug Reactions (ADRs) in pharmaceutical drug development. The HESI Technical Committee on Cardiac Safety, an international consortium of academic, government, and industry scientists, provides a unique opportunity to share resources and expertise to improve cardiovascular safety evaluation for new drugs and chemicals.This article describes theevolution of the HESI Cardiac Safety Technical Committee from 2000-2013 and the positive impacts resulting from this collaboration.Journal of pharmacological and toxicological methods 04/2013; · 2.32 Impact Factor -
Article: Translational pharmacokinetic-pharmacodynamic modeling of QTc effects in dog and human.
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ABSTRACT: Preclinical 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. QTc 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. A consistent translational relationship was found at low delta-QTc intervals indicating that a QTc change of 2.5 - 8ms in dog would correspond to a 10ms change in human. This translational relationship between dog and human can be used to predict the QTc liability in human.Journal of pharmacological and toxicological methods 04/2013; · 2.32 Impact Factor -
Article: An evaluation of the non-invasive faecal pellet assessment method as an early drug discovery screen for gastrointestinal liability.
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ABSTRACT: INTRODUCTION: Gastrointestinal adverse effects contribute significantly to drug attrition as well as reduced patient compliance. Determination of gastrointestinal liability early in a compound's preclinical development would be a valuable tool. We evaluated the non-invasive faecal pellet method in the rat, assessed the feasibility of adding the endpoint to other study types and investigated correlation with the charcoal meal method. METHODS: Han Wistar rats, pair housed in metabolism cages, received a single dose of vehicle, atropine, bethanechol, loperamide or metoclopramide. The number, weight and appearance of pellets produced were assessed over 10hours and at 24hours post-dose. The endpoint was also added to a modified Irwin screen (testing atropine, theophylline, clonidine, amphetamine, baclofen or quinine) and a whole body plethysmography study (testing theophylline or bethanechol). Pellets were collected from home cages out to 4hours post-dose (Irwin) or following a 45minutes plethysmography session. To assess correlation with stomach emptying and intestinal transit charcoal meal data was generated where published data was not available. RESULTS: Atropine decreased, while bethanechol and metoclopramide increased the number and weight of faecal pellets produced. Atropine produced darker, harder pellets and bethanechol lighter, softer pellets. Loperamide reduced pellet production at later time points only. Theophylline increased (Irwin and plethysmography) and atropine (Irwin) decreased pellet number and weight. Effects were maximal at the Tmax and detected in all study environments. Primary data generation was not affected by pellet collection. Pellet findings were generally comparable to charcoal meal transit data, with compounds showing an inhibition (atropine, loperamide, amphetamine, baclofen, clonidine, quinine) or stimulation (bethanechol) in both models. DISCUSSION: We have demonstrated that the faecal pellet method can detect expected reference compound induced changes in pellet transit. The technique is a useful non-invasive 'add-on' to other study types allowing gastrointestinal effects to be flagged earlier in preclinical development.Journal of pharmacological and toxicological methods 03/2013; · 2.32 Impact Factor -
Article: The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds.
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ABSTRACT: Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt(max) and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration-effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal.Toxicology and Applied Pharmacology 06/2012; 263(2):171-83. · 4.45 Impact Factor -
Article: Refinement of the charcoal meal study by reduction of the fasting period.
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ABSTRACT: The aim of this investigation was to determine whether a shorter fasting period than the one historically employed for the charcoal meal test, could be used when measuring gastric emptying and intestinal transit within the same animal, and to ascertain whether the scientific outcome would be affected by this benefit to animal welfare. Rats and mice were fasted for 0, 3, 6 or 18 hours before the oral administration of vehicle or atropine. One hour later, the animals were orally administered a charcoal meal, then 20 minutes later, they were killed and the stomach and small intestine were removed. Intestinal transit time (the position of the charcoal front as a percentage of the total length of the small intestine) and relative gastric emptying (weight of stomach contents) were measured. Rats and mice fasted for six hours showed results for gastric emptying and intestinal transit which were similar to those obtained in animals fasted for 18 hours. Reducing the fasting period reduced the body weight loss in both species, and mice on shorter fasts could be group-housed, as hunger-induced fighting was lessened. Therefore, a fasting period of six hours was subsequently adopted for charcoal meal studies at our institution.Alternatives to laboratory animals: ATLA 05/2012; 40(2):99-107. · 1.58 Impact Factor
