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Clin Transl Sci ; 13(5): 923-931, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32144955

RESUMO

This thorough QT (TQT) study evaluated the effect of zanubrutinib on electrocardiogram (ECG) parameters by using concentration-QTc (C-QTc) analysis as the primary analysis for this study. Part A of the study determined the safety and tolerability of a single supratherapeutic dose of zanubrutinib (480 mg) in healthy volunteers. Part B was a randomized, blinded, placebo-controlled and positive-controlled, four-way crossover, TQT study of single therapeutic (160 mg) and supratherapeutic (480 mg) doses of zanubrutinib, placebo, and open-label moxifloxacin 400 mg. Thirty-two participants received at least 1 dose of zanubrutinib, and 26 participants completed all 4 periods. Zanubrutinib did not have any effect on heart rate or cardiac conduction (pulse rate, QRS interval, or T-wave morphology) and was generally well-tolerated. Using C-QTc analysis, the predicted placebo-corrected change-from-baseline QT interval using Fridericia's formula (ΔΔQTcF) was -3.4 msec (90% confidence interval: -4.9 to -1.9 msec) at peak concentrations of the 480 mg dose. A QT effect (ΔΔQTcF) exceeding 10 msec could be excluded within the observed concentration range at 160 and 480 mg doses. Assay sensitivity was established by moxifloxacin with 90% lower bound exceeding 5 msec. Implementing a C-QTc analysis prospectively in this TQT study resulted in a substantially smaller sample size to maintain a similar study power as shown in the traditional time-point analysis. A single 160-mg or 480-mg zanubrutinib dose did not prolong the QTc interval or have any other clinically relevant effects on ECG parameters.


Assuntos
Síndrome do QT Longo/diagnóstico , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Adulto Jovem
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