Dataset Information

Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

ABSTRACT: Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ??J-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ??QTc and ??J-Tpeak c by ? 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ?QTc prolongation, but shortened ?J-Tpeak c and prolonged ?Tpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.

SUBMITTER: Vicente J

PROVIDER: S-EPMC6654598 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

Vicente Jose J Zusterzeel Robbert R Johannesen Lars L Ochoa-Jimenez Roberto R Mason Jay W JW Sanabria Carlos C Kemp Sarah S Sager Philip T PT Patel Vikram V Matta Murali K MK Liu Jiang J Florian Jeffry J Garnett Christine C Stockbridge Norman N Strauss David G DG

Clinical pharmacology and therapeutics 20190118 4

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-T<sub>peak</sub> (J-T<sub>peak</sub> c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and ...[more]

PMID: 30447156

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Project description:Potassium (K(+)) channels are specialized membrane proteins that are able to facilitate and regulate the conduction of K(+) through cell membranes. Comprising five specific cation binding sites (S(0)-S(4)) formed by the backbone carbonyl groups of conserved residues common to all K(+) channels, the narrow selectivity filter allows fast conduction of K(+) while being highly selective for K(+) over Na(+). To extend our knowledge of the microscopic mechanism underlying selectivity in K(+) channels, we characterize the free energy landscapes governing the entry and translocation of a Na(+) or a K(+) from the extracellular side into the selectivity filter of KcsA. The entry process of an extracellular ion is examined in the presence of two additional K(+) in the pore, and the three-ion potential of mean force is computed using extensive all-atom umbrella sampling molecular dynamics simulations. A comparison of the potentials of mean force yields a number of important results. First, the free energy minima corresponding to configurations with extracellular K(+) or Na(+) in binding site S(0) or S(1) are similar in depth, suggesting that the thermodynamic selectivity governed by the free energy minima for those two binding sites is insignificant. Second, the free energy barriers between stable multi-ion configurations are generally higher for Na(+) than for K(+), implying that the kinetics of ion conduction is slower when a Na(+) enters the pore. Third, the region corresponding to binding site S(2) near the center of the narrow pore emerges as the most selective for K(+) over Na(+). In particular, while there is a stable minimum for K(+) in site S(2), Na(+) faces a steep free energy increase with no local free energy well in this region. Lastly, analysis shows that selectivity is not correlated with the overall coordination number of the ion entering the pore, but is predominantly affected by changes in the type of coordinating ligands (carbonyls versus water molecules). These results further highlight the importance of the central region near binding site S(2) in the selectivity filter of K(+) channels.

Dataset Information

Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

Publications

Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

Similar Datasets

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