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Darpo B.,Karolinska Institutet | Garnett C.,Certara
British Journal of Clinical Pharmacology

Exposure-response (ER) analysis has emerged as an important tool to interpret QT data from thorough QT (TQT) studies and allows the prediction of effects in the targeted patient population. Recently, ER analysis has also been applied to data from early clinical pharmacology studies, such as single and multiple ascending dose studies, in which high plasma concentrations are often achieved. In line with this, there is an on-going discussion between sponsors, academicians and regulators on whether 'early QT assessment' can provide sufficiently high confidence in assessment of QT prolongation to replace the TQT study. In this article, we discuss how QT assessment can be applied to early clinical studies ('early QT assessment') and what we believe is needed to achieve the same high confidence in the data as we currently obtain from data from the TQT study. The power to exclude a QTc effect exceeding 10ms in small sample sizes using ER analysis will be discussed and compared with time-matched analysis, as described in the ICH E14 guidance. Two examples of early QT assessment are shared; one negative and one positive, and the challenge in terms of demonstrating assay sensitivity in the absence of a pharmacological positive control will be discussed. Finally, we describe a recent research proposal, which may generate data to support the replacement of the TQT study with data from QT assessment in early phase 1 studies. © 2012 The British Pharmacological Society. Source

Dubey R.,Birla Institute of Technology | Ghosh M.,Birla Institute of Technology | Sinha B.N.,Birla Institute of Technology | Muthukrishnan V.,Certara
Journal of Chromatographic Science

For the first time, we developed and validated a highly sensitive, selective and rapid HPLC-ESI-MS-MS method for simultaneous quantification of metolazone (MET), losartan (LOS) and its metabolite losartan carboxylic acid (LCA) in rat plasma. After solid-phase extraction, the analytes and internal standard (irbesartan) were extracted from 100 μL plasma sample on an Agilent Poroshell 120, EC-C18 (50 × 4.6 mm, i.d., 2.7 μm) column using 5 μL injection volume with a total run time of 3 min. Acidified methanol/water mixture was used as a mobile phase. The parent → product ion transitions for MET (m/z 366.0 → 258.9), LOS (m/z 423.2 → 207.0), LCA (m/z 437.0 → 235.1) and IS (m/z 429.2 → 207.0) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring and positive ion mode. The method was found to be linear in the range of 0.05-250 for MET, 2-3,000 for LOS and 4-3,500 ng/mL for LCA. The method was validated with respect to selectivity, linearity, accuracy, precision, recovery and stability according to accepted regulatory guidelines. The described method was successfully applied to preclinical pharmacokinetic studies of analytes after an oral administration of mixture of MET (1 mg/kg) and LOS (10 mg/kg) in rats. © The Author 2015. Published by Oxford University Press. Source

Darpo B.,Karolinska Institutet | Karnad D.R.,Quintiles | Badilini F.,AMPS LLC | Florian J.,U.S. Food and Drug Administration | And 4 more authors.
British Journal of Clinical Pharmacology

Aim To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. Methods Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. Results Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTcI) most effectively removed the heart rate dependency of the QTc interval. Mean QT cI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTcI in both genders. The largest mean change in QTcI (ΔQTcI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml-1 (range 1.1-2.8) vs. 1.4 μg ml-1 (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTcI relationship was steeper in women (30 ms per μg ml-1 vs. 23 ms per μg ml-1 in men; P = 0.0135). Conclusions The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization. © 2013 The British Pharmacological Society. Source

Tandon R.,Ludwig Maximilians University of Munich | Unzner T.,Ludwig Maximilians University of Munich | Nigst T.A.,Ludwig Maximilians University of Munich | De Rycke N.,University of Versailles | And 4 more authors.
Chemistry - A European Journal

New heterocyclic derivatives of 9-azajulolidine have been synthesized and characterized with respect to their nucleophilicity and Lewis basicity. The Lewis basicity of these bases as quantified through their theoretically calculated methyl-cation affinities correlate well with the experimentally measured reaction rates for addition to benzhydryl cations. All newly synthesized pyridines show exceptional catalytic activities in benchmark acylation reactions, which correlate only poorly with Lewis basicity or nucleophilicity parameters. A combination of Lewis basicity with charge and geometric parameters in the framework of a three-component quantitative structure-activity relationship (QSAR) model is, however, highly predictive. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Xie F.,Glaxosmithkline | Ke A.B.,Certara | Bowers G.D.,Glaxosmithkline | Zamek-Gliszczynski M.J.,Glaxosmithkline
Journal of Pharmacology and Experimental Therapeutics

Blood cells are considered an important distributional compartment for metformin based on the high blood-to-plasma partition ratio (B/P) in humans (> 10 at Cmin). However, literature reports of metformin's intrinsic in vitro B/P values are lacking. At present, the extent and rate of metformin cellular partitioning was determined in incubations of fresh human and rat blood with [14C]metformin for up to 1 week at concentrations spanning steady-state plasma Cmin, Cmax, and a concentration associated with lactic acidosis. The results showed that metformin's intrinsic equilibrium B/P was ∼0.8-1.4 in blood, which is < 10% of the reported clinical value. Kinetics of metformin partitioning into human blood cells and repartitioning back into plasma were slow (repartitioning half-life ∼32-39 hours). These data, along with in vivo rapid and efficient renal clearance of plasma metformin (plasma renal extraction ratio ∼90%-100%), explain why the clinical terminal half-life of metformin in plasma (6 hours) is 3- to 4-fold shorter than the half-life in whole blood (18 hours) and erythrocytes (23 hours). The rate constant for metformin repartitioning from blood cells to plasma (∼0.02 h-1) is far slower than the clinical renal elimination rate constant (0.3 h-1). Blood distributional rate constants were incorporated into a metformin physiologically-based pharmacokinetic model, which predicted the differential elimination half-life in plasma and blood. The present study demonstrates that the extent of cellular drug partitioning in blood observed in a dynamic in vivo system may be very different from the static in vitro values when repartitioning from blood cells is far slower than clearance of drug in plasma. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Source

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