Riociguate

Pontos-chaves

  • Riociguate é um estimulador da guanilato ciclase solúvel (GCs), o primeiro de uma classe distinta de tratamentos específicos para a hipertensão pulmonar (HP).1,2
  • Riociguate tem um mecanismo duplo de ação para aumentar os níveis intracelulares de monofosfato cíclico de guanosina (cGMP). Estimula diretamente a guanilato ciclase solúvel (GCs), independentemente do óxido nítrico (NO), e sensibiliza a GCs para o NO endógeno, estabilizando a ligação NO-GCs.3
  • Evidências pré-clínicas mostram que Riociguate melhora a hemodinâmica pulmonar, atenua a hipertrofia ventricular direita, atua contra a proliferação e a fibrose, melhora a disfunção endotelial em modelos com HP e reduz danos cardíacos e renais em vários modelos animais.3,4–12
  • A farmacocinética de Riociguate oral é caracterizada por absorção rápida e completa, alta biodisponibilidade, exposição proporcional à dose e ausência de efeitos alimentares clinicamente relevantes .13,14
  • Há uma relação direta entre as concentrações plasmáticas de Riociguate e parâmetros hemodinâmicos em voluntários saudáveis e em pacientes com HP .15–17
  • Não há evidências de interação entre Riociguate, varfarina ou aspirina,18,19 mas, a administração concomitante de Riociguate com inibidores da fosfodiesterase tipo 5 é contraindicada .20,21

  • Ghofrani HA, Galiè N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330–40.
  • Ghofrani HA, D’Armini A, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319–29.
  • Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in pulmonary hypertension. In Handbook of Experimental Pharmacology: Pharmacotherapy of Pulmonary Hypertension. Humbert M, Evgenov OV, Stasch JP (Eds). Springer-Verlag, 2013.
  • Schermuly RT, Stasch JP, Pullamsetti SS et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008;32:881–91.
  • Pichl A, Parajuli N, Seimetz M et al. Stimulation of soluble guanylate cyclase by riociguat prevents tobacco smoke-induced pulmonary hypertension in mice. Pneumologie 2012;66:A310.
  • Lang M, Kojonazarov B, Tian X et al. The soluble guanylate cyclase stimulator riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats. PLoS One 2012;7:e43433.
  • Sharkovska Y, Kalk P, Lawrenz B et al. Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models. J Hypertens 2010;28:1666–75.
  • Geschka S, Kretschmer A, Sharkovska Y et al. Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats. PLoS One 2011;6:e21853.
  • Evgenov OV, Zou L, Zhang M et al. Stimulation of soluble guanylate cyclase attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2011;183:A2715.
  • Schymura Y, Janssen W, Eule U et al. Antifibrotic effects of riociguat in a murine model of chronic right ventricular pressure overload. Am J Resp Crit Care Med 2012;185:A6850.
  • Ott IM, Alter ML, von Websky K et al. Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade. PLoS One 2012;7:e42623.
  • Seimetz M, Parajuli N, Pichl A et al. Effects of the soluble guanylate cyclase stimulator riociguat on emphysema development in tobaccosmoke exposed mice. Am J Respir Crit Care Med 2011;183:Abstract 1307.
  • Frey R, Becker C, Saleh Set al. Clinical pharmacokinetic and pharmacodynamic profile of riociguat. Clin Pharmacokinet 2018;57:647–61.
  • Becker C, Frey R, Hesse C et al. Absorption of riociguat (BAY 63-2521): bioavailability, food effects, and dose proportionality. Pulm Circ 2016;6(Suppl 1):S27–S34.
  • Frey R, Mück W, Unger S et al. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol 2008;48:926–34.
  • Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33:785–92.
  • Saleh S, Becker C, Frey R et al. Population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of riociguat in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulm Circ 2016;6(Suppl 1):S86–S96.
  • Frey R, Mück W, Kirschbaum N et al. Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol 2011;51:1051–60.
  • Frey R, Reber M, Krätzschmar J et al. Riociguat (BAY 63-2521) and aspirin: a randomized, pharmacodynamic, and pharmacokinetic interaction study. Pulm Circ 2016;6(Suppl 1):S35–S42.
  • Galiè N, Muller K, Scalise et al. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in PAH. Eur Respir J 2015;45:1314–22
  • ADEMPAS® (riociguate). São Paulo: Bayer S.A. Bula do profissional. VE0118-CCDS5. Disponível em: http://www.anvisa.gov.br/datavisa/fila_bula/frmVisualizarBula.asp?pNuTransacao=4940502019&pIdAnexo=11205267

Próxima:Uma Classe Distinta de Tratamento para a Hipertensão Pulmonar