Hanafin Patrick O, Sermet-Gaudelus Isabelle, Griese Matthias, Kappler Matthias, Ellemunter Helmut, Schwarz Carsten, Wilson John, Tan Marsha, Velkov Tony, Rao Gauri G, Schneider-Futschik Elena K
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, Paris, France, Institut Necker-Enfants Malades, INSERM U1151, Université Paris Sorbonne, Paris, France.
Front Pharmacol. 2021 Aug 2;12:577263. doi: 10.3389/fphar.2021.577263. eCollection 2021.
The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited. Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV). Peak plasma concentrations (C) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on C values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor ( < 0.001, < 0.001, and < 0.001, respectively). The Spearman's rho test indicated that patient weight and age have an effect on the C of lumacaftor ( = 0.003 and < 0.001, respectively) and ivacaftor metabolite M1 ( = 0.020 and < 0.001, respectively). Age ( < 0.001) was found to effect on C of ivacaftor M6 and on T of ivacaftor M1 ( = 0.026). A large impact of patient characteristics on the IIV of PK parameters C and T, was observed among the CF patients. Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.
像依伐卡托这样的囊性纤维化跨膜传导调节因子（CFTR）调节剂的出现，彻底改变了囊性纤维化（CF）的治疗方式。然而，由于CF疾病表现存在大量差异，CFTR调节剂治疗下患者结局的变异性导致在统一反应方面存在固有挑战。可用于依伐卡托-鲁马卡托囊性纤维化（CF）跨膜传导调节因子（CFTR）调节剂药物组合的药代动力学（PK）数据有限。次要目标是确定：（1）患者特征；（2）依伐卡托-鲁马卡托之间导致个体间变异性（IIV）的相互作用。与标签信息相比，依伐卡托-鲁马卡托的血浆峰浓度（C）比预期低10倍以上。单因素方差分析表明，患者所在地点对依伐卡托代谢物依伐卡托-M1、依伐卡托-M6和鲁马卡托的C值有影响（分别为<0.001、<0.001和<0.001）。Spearman秩相关检验表明，患者体重和年龄对鲁马卡托的C值（分别为=0.003和<0.001）以及依伐卡托代谢物M1的C值（分别为=0.020和<0.001）有影响。发现年龄（<0.001）对依伐卡托M6的C值以及依伐卡托M1的T值有影响（=0.026）。在CF患者中观察到患者特征对PK参数C和T的IIV有很大影响。了解变异性的多种来源有助于减少个体患者的变异性，并确保患者结局的一致性。
