Drug-drug Interactions and QT Prolongation as a Commonly Assessed Cardiac Effect – Comprehensive Overview of Clinical Trials

Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological […]

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Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9.

RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple […]

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Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis

Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as […]

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Model-based development of gemcabene, a new lipid-altering agent

The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of gemcabene, a novel lipid-altering agent. The decisions were driven by a model of the likely clinical profile of gemcabene in comparison with its competitors, such as 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), the cholesterol absorption inhibitor […]

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Predicted Heart Rate Effect of Inhaled LABA PF-00610355 in volunteers and COPD patients

The aim of this study was to assess the cardiovascular effects of a new inhaled long-acting β-adrenoceptor agonist PF-00610355 in COPD patients. Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, […]

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Using Model-based Meta-analysis to Improve Decision-making in Drug Development

Making the right choices in drug development often means the difference between getting a new medication to patients and it ending up in the scrap heap of failed programs. There is a surfeit of publicly available information on approved drugs as well as those currently in development. How can sponsors turn clinical trial data into understanding that helps chart the course for investigational drugs?

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Therapeutic index of anticoagulants for prevention of venous thromboembolism following orthopedic surgery: a dose-response meta-analysis

Information on the comparative effectiveness of drugs is crucial for drug development decisions, in addition to being needed by regulators, prescribers, and payers. We have carried out a dose-response meta-analysis of three end points each for efficacy and bleeding for various anticoagulants evaluated for the prevention of venous thromboembolism (VTE) following orthopedic surgery to assess […]

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Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients

Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. The objective of this study was to develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on […]

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Meta-analysis of the diagnostic accuracy of transesophageal echocardiography for assessment of atherosclerosis in the ascending aorta in patients undergoing cardiac surgery

Stroke after cardiac surgery may be caused by emboli emerging from an atherosclerotic ascending aorta (AA). Epiaortic ultrasound scanning (EUS), the current ‘gold’ standard for detecting AA atherosclerosis, has not gained widespread use because there is a lack of optimized ultrasound devices, it lengthens the procedure, it endangers sterility, and there is a false belief […]

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Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery

A combination of general anesthesia (GA) with thoracic epidural anesthesia (TEA) may have a beneficial effect on clinical outcomes after cardiac surgery. We have performed a meta-analysis to compare mortality and cardiac, respiratory, and neurologic complications in patients undergoing cardiac surgery with GA alone or a combination of GA with TEA. Randomized studies comparing outcomes […]

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Systematic review: diagnostic accuracy of clinical decision rules for venous thromboembolism in elderly

Physicians committed to the care of elderly patients are challenged with the diagnosis of venous thromboembolism (VTE: deep venous thrombosis and pulmonary embolism) due to a higher incidence, co-morbidities masking signs and symptoms and burdening referrals. Clinical decision rules (CDRs) have been developed and implemented for VTE. Yet, until now, no study has evaluated the […]

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Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis

This article is a review the evidence on the diagnostic accuracy of the currently available point of care D-dimer tests for excluding venous thromboembolism. We conducted a systematic review of research on the accuracy of point of care D-dimer tests, using bivariate regression to examine sources of variation and to estimate sensitivity and specificity. Studies […]

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Under-reporting of venous and arterial thrombotic events in randomized clinical trials: a meta-analysis

For the detection of unwanted outcomes of new interventions, physicians rely on adverse event reporting. We attempt to quantify the reported incidence of venous thromboembolism (VTE) and arterial thrombosis (AT) in randomized clinical trials (RCTs), and evaluate the extent of under-reporting. We selected all therapeutic RCTs published in the four highest-impact general medicine journals between […]

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