Effect of Pharmacologic Interaction Between Endothelin-Receptor-Antagonists and Phosphodiesterase-5 Inhibitors on Medication Serum Levels and Clinical Disease Status in Patients Wih Pulmonary Arterial Hypertension
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 125
- 试验地点
- 1
- 主要终点
- Characterisation of Medication Levels
研究概览
简要总结
The development of disease-targeted medication for the treatment of pulmonary arterial hypertension (PAH) has significantly improved within the last years, leading to the development of 10 approved agents. Combination treatment with Endothelin-Receptor-Antagonists (ERA) and Phosphodiesterase-Type-5-Inibitors (PDE-5-Inhibitor) has become increasingly important for the treatment of PAH. In a recent press release, the results of the AMBITION study reported that an upfront combination treatment immediately after diagnosis leads to a delayed disease progression [4]. Thus, the question if there is a clinically relevant pharmaco-dynamic drug-drug interaction is of rising interest.
详细描述
Mechanisms of action Three ERAs have been approved for the treatment of PAH including the dual inhibitors Bosentan and Macitentan and the selective Endothelin Receptor type A inhibitor (ETA-Inhibitor) Ambrisentan. The dual antagonists inhibit both ETA- and the type B (ETB)-receptor, while the selective antagonist only affects the ETA-receptor [2]. The physiologic ligand of the receptors is Endothelin-1, which binds to the ETA-receptor and causes vasoconstriction and proliferation of the vascular smooth muscle cells. The binding to the ETB-receptor leads to an endogenous production of NO and prostacyclin in the endothelial cells.
PDE-5-Inhibitors include the two substances Sildenafil and Tadalafil. They inhibit the degradation of cyclic guanosine monophosphate (cGMPs), which triggers the vasodilative effect of endothelial NO.
Interaction There is evidence for the pharmacokinetic interaction (inhibition / induction of critical targets of drug metabolism and drug distribution) of both substance classes: the PDE-5-Inhibitors Sildenafil and Tadalafil are mainly eliminated in the liver by the hepatic enzyme Cytochrom-P450-Oxygenase type 3A4 (CYP3A4). The dual inhibitor Bosentan is both a substrate and an inductor of the Cytochrom-P450-Oxydase type 3A4 and type 2C9 [5,6].
It has already been shown in an in vivo-study, that simultaneous application of PDE-5-Inhibitors and Bosentan leads to a systemic reduction of the PDE-5-Inhibitor concentration of 40%, due to the CYP3A4-inducing effect of Bosentan [5]. Sildenafil, in contrast, leads to a decreased degradation of Bosentan in the liver with an approximately 50% increase in plasma leves. An anticipated result, especially when higher dosages of Sildenafil are applied, is the accumulation of Bosentan and reduction of Sildenafil levels.
A recent in vitro-study has shown that Tadalafil may also serve as CYP3A4-inductor, while this effect has not been detected for Sildenafil [7].
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women ≥ 18 years old
- •Diagnosis of PAH according to ESC/ERS-guidelines: patients with manifest pulmonary arterial hypertension, mean pulmonary arterial pressure ≥25mmHg, measured by right heart catheterization.
- •Combination treatment with ERA (Bosentan, Ambrisentan or Macitentan) and PDE-5-Inhibitor (Sildenafil or Tadalafil) for more than 3 months.
排除标准
- •Underage patients
- •Pregnancy or lactation
结局指标
主要结局
Characterisation of Medication Levels
时间窗: baseline vs. measurement after 3-6 months
comparison of different combination treatment arms (mean ± standard deviation), measurement of endothelin receptor antagonist plasma concentrations and PDE-5I plasma concentrations, results given es multiple of the expected mean plasma concentration (MOM). Due to technical setup measurement of plasma concentrations of macitentan was not possible. The expected mean concentration ranges (MOM) refer to data extracted from published plasma concentration-time profiles measured during monotherapy with sildenafil, tadalafil, bosentan, and ambrisentan and served as comparative values. Each individually measured drug concentration was set in proportion to the expected mean concentration and expressed as a multiple of the expected mean (MoM), with values \<1 denoting lower and values \>1 higher values than the expected mean.
次要结局
- Clinical Relevance 6 Minute Walking Distance(baseline vs. measurement 3-6 months after switch)
- Impact of Medication Adjustment(baseline vs. measurement 3-6 months after switch)
- Clinical Relevance NTproBNP(baseline vs. measurement after 3-6 months)
- Clinical Relevance Echocardiography Tricuspid Annular Plane Systolic Excursion (TAPSE)(baseline vs. measurement after 3-6 months)
- Clinical Relevance Blood Gas Analysis Oxygen Saturation(baseline vs. measurement after 3-6 months)
- Clinical Relevance Echocardiography Systolic Pulmonary Arterial Pressure (sPAP)(baseline vs. measurement after 3-6 months)
研究者
Prof. Dr. med. Ekkehard Gruenig
Prof. Dr. med.
Heidelberg University