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Abstract：
Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF.
A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor.
We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times.
Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.
A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor.
We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times.
Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.
摘要：
Ivacaftor是目前唯一被批准的CFTR增效剂，自CFTR校正器开发以来，其应用日益广泛。Ivacaftor被CYP3A4代谢，因此在用CYP3A4抑制药物治疗Ivacaftor的患者时需要减少剂量。由于此建议是基于健康志愿者的研究，而不是囊性纤维化（CF）患者的研究，我们需要在两组中对此进行调查,以便能够将这些数据外推到CF.
一组CF患者和健康受试者暴露于单剂量伊伐卡夫与强（利托那韦）联合使用，中度（克拉霉素）和轻度（阿奇霉素）CYP3A4抑制剂。测量所有血液样品中的Ivacaftor浓度，以计算ivacaftor的药代动力学参数。
我们发现，健康志愿者的ivacaftor暴露量高于CF受试者。然而,这种差异在统计学上并不显著。在两个研究组之间没有观察到CYP3A4抑制剂的相互作用潜力的差异。强效CYP3A4抑制剂利托那韦，对ivacaftor的暴露增加了7倍。
我们的数据支持目前在CF患者中与CYP3A4抑制剂共同治疗的情况下对ivacaftor剂量调整的建议。然而,健康受试者的ivacaftor暴露量高于CF患者。需要进一步的研究来调查这种差异的原因和含义。
一组CF患者和健康受试者暴露于单剂量伊伐卡夫与强（利托那韦）联合使用，中度（克拉霉素）和轻度（阿奇霉素）CYP3A4抑制剂。测量所有血液样品中的Ivacaftor浓度，以计算ivacaftor的药代动力学参数。
我们发现，健康志愿者的ivacaftor暴露量高于CF受试者。然而,这种差异在统计学上并不显著。在两个研究组之间没有观察到CYP3A4抑制剂的相互作用潜力的差异。强效CYP3A4抑制剂利托那韦，对ivacaftor的暴露增加了7倍。
我们的数据支持目前在CF患者中与CYP3A4抑制剂共同治疗的情况下对ivacaftor剂量调整的建议。然而,健康受试者的ivacaftor暴露量高于CF患者。需要进一步的研究来调查这种差异的原因和含义。
