RESUMO
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 ΔΔJ-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 ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -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.
Assuntos
Biomarcadores/metabolismo , Eletrocardiografia/efeitos dos fármacos , Canais Iônicos/antagonistas & inibidores , Moduladores de Transporte de Membrana/uso terapêutico , Preparações Farmacêuticas/administração & dosagem , Adulto , Estudos Cross-Over , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Torsades de Pointes/tratamento farmacológico , Torsades de Pointes/metabolismoRESUMO
In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1â s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.