肺动脉高压患者联合治疗的血浆药物浓度。
Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment.
机构信息
Center for Pulmonary Hypertension, Thorax Clinic at the University Hospital Heidelberg, Heidelberg, Germany.
出版信息
Respiration. 2017;94(1):26-37. doi: 10.1159/000470916. Epub 2017 May 12.
BACKGROUND
Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH).
OBJECTIVE
The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments.
METHODS
PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations. Concentrations were normalized considering dose and time from last medication intake and presented as multiples of the expected mean (MoM) of the respective monotherapies.
RESULTS
A total of 125 PAH patients (84 female, 41 male, 57% idiopathic/heritable) were included. Sildenafil and tadalafil concentrations were lowest in combination with bosentan (MoM 0.44 ± 0.42, 95% confidence interval [CI] 0.30-0.57, and MoM 0.89 ± 0.53, 95% CI 0.50-1.28, respectively) compared to the combination with ambrisentan (MoM 1.3 ± 0.97, 95% CI 0.86-1.73, and MoM 1.67 ± 0.63, 95% CI 1.40-1.94, respectively) and macitentan (MoM 1.16 ± 0.87, 95% CI 0.86-1.46, and MoM 1.59 ± 0.99, 95% CI 0.80-2.38, respectively). The combination of sildenafil and bosentan led to more than twice the expected bosentan concentrations in 53.8%. Patients switching from sildenafil-bosentan to macitentan showed a significant increase in sildenafil concentrations (p < 0.001).
CONCLUSIONS
Only the combination with macitentan or ambrisentan led to targeted mean PDE-5i plasma concentrations and should therefore be preferred to combination with bosentan. Sildenafil-bosentan showed the strongest interaction, with low sildenafil and high bosentan concentrations. The study was not powered to analyze whether lower PDE-5i concentrations cause unsatisfying clinical response. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.
背景
肺动脉高压（PAH）患者接受磷酸二酯酶 5 抑制剂（PDE-5i）西地那非或他达拉非与内皮素受体拮抗剂（ERA）波生坦、安立生坦或马西替坦联合治疗可能会发生相互的药代动力学相互作用。
目的
本研究旨在分析接受不同联合治疗的 PAH 患者的血浆药物浓度。
方法
接受 ERA 和 PDE-5i 联合治疗且至少接受 1 个月靶向剂量治疗的 PAH 患者进行常规评估，包括临床参数和血浆药物浓度。考虑到剂量和最后一次服药时间，将浓度标准化并表示为各自单药治疗的预期平均值（MoM）的倍数。
结果
共纳入 125 例 PAH 患者（84 例女性，41 例男性，57%为特发性/遗传性）。与安立生坦（MoM 1.3±0.97，95%CI 0.86-1.73，MoM 1.67±0.63，95%CI 1.40-1.94）和马西替坦（MoM 1.16±0.87，95%CI 0.86-1.46，MoM 1.59±0.99，95%CI 0.80-2.38）相比，西地那非和他达拉非与波生坦联合治疗时的浓度最低（MoM 0.44±0.42，95%CI 0.30-0.57，MoM 0.89±0.53，95%CI 0.50-1.28）。与安立生坦和马西替坦联合治疗时，西地那非和他达拉非的组合导致超过预期波生坦浓度的两倍，占 53.8%。从西地那非-波生坦转换为马西替坦的患者，西地那非浓度显著升高（p<0.001）。
结论
只有与马西替坦或安立生坦联合治疗才能达到靶向平均 PDE-5i 血浆浓度，因此应优先选择与波生坦联合治疗。西地那非-波生坦显示出最强的相互作用，西地那非浓度低，波生坦浓度高。本研究没有足够的效力来分析较低的 PDE-5i 浓度是否会导致临床疗效不满意。然而，在目标范围内的血浆浓度是理想的，可能会变得越来越重要。
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