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首页> 外文期刊>Pulmonary therapy. >Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor
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Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor

机译：囊性纤维化转换从单组合Elexacafer / Tezacaftor / Ivacafacter / Ivacafacter / Ivacafacter / Ivacafacter / Ivacafacter患者CFTR调制的生理基础药代动力学建模

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IntroductionThe triple-combination (TC) cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor, tezacaftor, and ivacaftor was shown to be safe and efficacious in phase 3 trials of people with cystic fibrosis (pwCF)?≥?12?years of age with?≥?1 F508del-CFTR allele. Here, a simulation study predicted ivacaftor, tezacaftor, and elexacaftor exposures and impacts on CFTR modulation following transition from ivacaftor [a cytochrome P450 3A (CYP3A) substrate], lumacaftor (a CYP3A inducer)/ivacaftor, or tezacaftor/ivacaftor to TC.MethodsPhysiologically based pharmacokinetic (PBPK) modeling was used to evaluate plasma exposures during transition from mono- or dual-combination CFTR modulator regimens to TC. PBPK models were parameterized using data from human hepatocytes to account for CYP3A induction by lumacaftor and validated to match clinical data from healthy volunteers and pwCF. Using dosing regimens for pwCF?≥?12?years of age, simulations were performed for ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor dosing for 14?days followed by immediate transition to elexacaftor/tezacaftor/ivacaftor dosing for 14?days. Drug exposures during transitions were compared with respective half-maximal effective concentrations (ECsub50/sub) estimated from efficacy endpoint data from clinical studies.ResultsIn simulations of immediate transition from ivacaftor or tezacaftor/ivacaftor to TC, the preceding treatment had no impact on ivacaftor, tezacaftor, or elexacaftor exposures. In simulations of immediate transition from lumacaftor/ivacaftor to TC, ivacaftor exposure decreased to 64% of maximum effective concentration (EC), due to reduction in ivacaftor dose and residual CYP3A4 induction, then returned to 90–95% of maximum EC. Lumacaftor-mediated CYP3A induction resolved within approximately 2?weeks. In all simulations, ivacaftor, tezacaftor, and elexacaftor exposures approached steady state within 2?weeks following transition and, at all times, ivacaftor and?≥?1 CFTR corrector remained above ECsub50/sub.ConclusionPBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor regimen results in sustained CFTR modulation in pwCF?≥?12?years of age.
机译：简介三重组合（TC）囊性纤维化跨膜电导调节器（CFTR）调制器方案Elexacaferor，Tezacaftor和Ivacafacter被证明是在囊性纤维化（PWCF）的3阶段的3阶段安全性和有效的效果？≥？12？岁月≥？1 f508del-cftr等位基因。在此，仿真研究预测Ivacafetor，Tezacaftor和elexacaferor曝光以及对从Ivacaftor [细胞色素P450 3a（Cyp3a）底物]，Lumacaferor（Cyp3a诱导剂）/ Ivacaftoder或Tezacafactor / Ivacafaceor至Tc.methosphysoological的影响后的CFTR调制对CFTR调制的影响。基于基础的药代动力学（PBPK）建模用于评估从单或双组合CFTR调节方案到TC的转变过程中的血浆曝光。 PBPK模型使用来自人肝细胞的数据进行参数化，以解释Lumacaferor的CYP3A诱导，并验证以使来自健康志愿者和PWCF的临床数据匹配。使用给药方案的PWCF？≥？12年龄，对Ivacafactor，Lumacafor / Ivacafaceor和Tezacafactor / Ivacafactor / Ivacafacter的模拟进行了14天，然后立即过渡到Elexacaftor / Tezacafactor / Ivacafactor给药14.天。将在从临床研究中的疗效终点数据估计的各自的半最大有效浓度（EC 50 ）进行转变期间的药物暴露。从Ivacafactor或Tezacafactor / Ivacafacter的直接转变为TC，鉴定了从Ivacafactor或Tezacaferor / IvacaferoR的仿真进行了比模拟对Ivacafeafer，Tezacaftor或Elexacaferor曝光没有影响。在从Lumacafactor / Ivacafacter到Tc的直接过渡的模拟中，由于Ivacafacter剂量和残余CYP3A4诱导的降低，IVAcafeoder暴露率降低至最大有效浓度（EC）的64％，然后恢复到最大EC的90-95％的90-95％。 Lumacafacter介导的CYP3A诱导在约2个周内进行解决。在所有模拟中，Ivacafactor，Tezacaftor和Elexacaferor曝光在过渡后2？周内接近稳态，并且始终是Ivacaftor和？≥？1 CFTR校正器保持在EC 50 .conclusionpbpk建模上，表示直接过渡到来自IVAcafeafer，Lumacaftor / IVAcaftor / Ivacafector / IVAcaftor / Ivacafector / Ivacafector / IvacaferoR植物中的Elexacaftor / Tezacafacter / Ivacafacter方案的转型导致PWCF中持续的CFTR调制？≥1岁以下。

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