Natalie R. Rose, Ashritha R. Chalamalla, Bryan A. Garcia, Stefanie Krick, Jonathan Bergeron, Hossein Sadeghi, Dennis E. Schellhase, Kevin J. Ryan, Alexander E. Dowell, Edward P. Acosta, Jennifer S. Guimbellot
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引用次数: 0
摘要
Elexacaftor、tezacaftor、ivacaftor(ETI)是一种 CFTR 调节剂复方制剂,已被批准用于 90% 的 2 岁以上囊性纤维化患者(pwCF)。虽然大多数囊性纤维化患者都能很好地耐受这种疗法,但有些患者对标准剂量不耐受,还有些患者则反应甚微。临床医疗人员可能会调整 ETI 的剂量以解决这些问题,但这些调整并没有很好的药代动力学证据作为指导。我们的批准后研究旨在描述 15 名服用标准剂量或减量剂量的参与者体内 ETI 血浆浓度的药代动力学变异性。通过 LC-MS/MS 对早晨用药前采集的血浆样本中的 ETI 进行定量。结果显示,无论采用哪种给药方案,在剂量等效归一化后,每种化合物的差异均不显著。两个给药组的大多数参与者的血药浓度都能引起对 ETI 治疗的临床反应。这些研究结果表明,减少剂量可能是在控制不耐受的同时保持临床疗效的一种可行策略。
Pharmacokinetic variability of CFTR modulators from standard and alternative regimens
Elexacaftor, tezacaftor, ivacaftor (ETI) is a CFTR modulator combination approved for use in ∼90 % of people with cystic fibrosis (pwCF) over 2 years old. While most pwCF tolerate this therapy well, some are intolerant to standard dosing, and others show little response. Clinical providers may adjust ETI dosing to combat these issues, but these adjustments are not well guided by pharmacokinetic evidence. Our post-approval study aimed to describe pharmacokinetic variability of ETI plasma concentrations in 15 participants who were administered a standard or reduced dose. ETI were quantified by LC-MS/MS in plasma samples taken prior to the morning dose. Results showed non-significant differences for each compound regardless of dosing regimen and after dose equivalence normalization. The majority of participants in both dosing groups had concentrations expected to elicit clinical response to ETI therapy. These findings indicate that dose reduction may be a viable strategy to maintain clinical benefit while managing intolerance.
期刊介绍:
Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews.
Research Areas Include:
• All major diseases of the lung
• Physiology
• Pathology
• Drug delivery
• Metabolism
• Pulmonary Toxicology.