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Future perspectives in pulmonary arterial hypertension.

ABSTRACT: While there have been advances in the field of pulmonary arterial hypertension (PAH), disease management remains suboptimal for many patients. The development of novel treatments and strategies can provide opportunities to target other mechanisms that play a role in the complex pathobiology of PAH outside of the three main pathophysiological pathways. In this review, we highlight some of the potential PAH therapies or techniques that are being, or have been, investigated in phase II clinical trials. This review also discusses potential points for consideration in the development of novel therapies that target putative disease mediators or modifiers.

SUBMITTER: Simonneau G

PROVIDER: S-EPMC9487553 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Future perspectives in pulmonary arterial hypertension.

Simonneau Gérald G Hoeper Marius M MM McLaughlin Vallerie V Rubin Lewis L Galiè Nazzareno N

European respiratory review : an official journal of the European Respiratory Society 20161201 142

While there have been advances in the field of pulmonary arterial hypertension (PAH), disease management remains suboptimal for many patients. The development of novel treatments and strategies can provide opportunities to target other mechanisms that play a role in the complex pathobiology of PAH outside of the three main pathophysiological pathways. In this review, we highlight some of the potential PAH therapies or techniques that are being, or have been, investigated in phase II clinical tri ...[more]

PMID: 27903660

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Project description:Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

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Future perspectives in pulmonary arterial hypertension.

Publications

Future perspectives in pulmonary arterial hypertension.

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