The metabolism of elexacaftor is extensive and primarily catalyzed via CYP3A4/5. Its main active metabolite, M23-ELX, carries a similar potency as the parent drug. The precise metabolic pathway of elexacaftor has not yet been elucidated in published research.
As elexacaftor is currently only available in the combination product TrikaftaTM (ivacaftor/tezacaftor/elexacaftor), data regarding overdose of elexacaftor on its own is unavailable. Treatment of TrikaftaTM overdose should consist of general supportive and symptomatic treatment, including monitoring of vital signs and close observation of the affected patient.
In large randomized controlled trials of ivacaftor with or without lumacaftor or tezacaftor, up to 25% of subjects had some degree of serum aminotransferase elevations during therapy. The elevations, however, were generally transient and mild and were above 3 times the upper limit of normal (ULN) in only 2% to 5% of patients. The abnormalities were usually asymptomatic and often resolved spontaneously without dose adjustment. Furthermore, in several studies, similar rates of serum enzyme elevations were noted in the placebo treated groups. Nevertheless, serum aminotransferase elevations resulted in dose modification or interruption in 1% to 2% of patients on ivacaftor alone or with lumacaftor or tezacaftor.
In prelicensure clinical trials of the triple therapy of elexacaftor, tezacaftor and ivacaftor, higher rates of serum enzyme elevations were reported which in some cases were accompanied by elevations in serum bilirubin. Most abnormalities resolved spontaneously and enzymes rapidly improved upon discontinuation. Since approval of triple therapy, several case reports of clinically apparent liver injury including jaundice have been reported, generally arising after weeks or months of treatment and resolving with discontinuation. In addition, case series of acute cholecystitis developing within days or weeks of starting triple therapy have been reported, and are probably due to the increased biliary fluid secretion and clearance of biliary sludge and stones with the sudden increased bile flow. Gallstones are frequent in patients with cystic fibrosis and often result in cholecystectomy. There have been no reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome linked to elexacaftor, tezacaftor and ivacaftor therapy. Patients with cystic fibrosis can, not infrequently, have underlying liver disease with chronic, intermittent serum aminotransferase and alkaline phosphatase elevations, occasionally associated with progressive fibrosis or nodular regenerative hyperplasia and non-cirrhotic portal hypertension.
Combination of elexacaftor, tezacaftor, and ivacaftor likelihood score: D (possible cause of clinically apparent liver injury).
来源:LiverTox
毒理性
蛋白质结合
伊莱克萨夫托尔在血浆中>99%与蛋白结合，主要与白蛋白结合。
Elexacaftor is >99% protein bound in plasma, primarily to albumin.
The absolute oral bioavailability of elexacaftor is approximately 80%. The steady-state AUC<sub>0-24h</sub> and C<sub>max</sub> following once daily dosing with elexacaftor 200mg are 162 mcg∙h/mL and 8.7 mcg/mL, respectively, and the median T<sub>max</sub> is 6 hours. The AUC of elexacaftor is increased 1.9-2.5-fold following a moderate-fat meal - for this reason, it is recommended to give Trikafta<sup>TM</sup> with fat-containing food.
Approximately 87.3% of an administered radio-labeled dose of elexacaftor was found in the feces, mostly as metabolites, while only 0.23% of that same dose was found excreted in the urine.
来源:DrugBank
吸收、分配和排泄
分布容积
艾列克莎夫托尔的表观分布容积为53.7升。
The apparent volume of distribution of elexacaftor is 53.7 L.
来源:DrugBank
吸收、分配和排泄
清除
伊雷克萨夫托尔的平均表观清除率为1.18升/小时。
The mean apparent clearance of elexacaftor is 1.18 L/h.
[EN] MODULATOR OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR, PHARMACEUTICAL COMPOSITIONS, METHODS OF TREATMENT, AND PROCESS FOR MAKING THE MODULATOR [FR] MODULATEUR DE RÉGULATEUR DE CONDUCTANCE TRANSMEMBRANAIRE DE FIBROSE KYSTIQUE, COMPOSITIONS PHARMACEUTIQUES, PROCÉDÉS DE TRAITEMENT ET PROCÉDÉ DE FABRICATION DU MODULATEUR
[EN] MODULATOR OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR, PHARMACEUTICAL COMPOSITIONS, METHODS OF TREATMENT, AND PROCESS FOR MAKING THE MODULATOR [FR] MODULATEUR DE RÉGULATEUR DE CONDUCTANCE TRANSMEMBRANAIRE DE FIBROSE KYSTIQUE, COMPOSITIONS PHARMACEUTIQUES, PROCÉDÉS DE TRAITEMENT ET PROCÉDÉ DE FABRICATION DU MODULATEUR
PHARMACEUTICAL COMPOSITIONS FOR TREATING CYSTIC FIBROSIS
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20190240197A1
公开（公告）日：2019-08-08
A pharmaceutical composition comprising Compound I:
Methods of treating cystic fibrosis comprising administering one or more of such pharmaceutical compositions to a patient.
一种包含化合物I的药物组合物：治疗囊性纤维化的方法，包括向患者施用其中一种或多种此类药物组合物。
[EN] METHODS OF TREATMENT FOR CYSTIC FIBROSIS<br/>[FR] MÉTHODES DE TRAITEMENT DE LA MUCOVISCIDOSE
申请人：VERTEX PHARMA
公开号：WO2020242935A1
公开（公告）日：2020-12-03
This application describes methods of treating cystic fibrosis comprising administering Compound I:, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing.
PROCESSES FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20210246117A1
公开（公告）日：2021-08-12
The disclosure provides processes for preparing a compound of Formula (I).
该披露提供了制备化合物式（I）的过程。
[EN] PROCESSES FOR PREPARING PYRROLIDINE COMPOUNDS<br/>[FR] PROCÉDÉS DE PRÉPARATION DE COMPOSÉS DE PYRROLIDINE
申请人：VERTEX PHARMA
公开号：WO2019028228A1
公开（公告）日：2019-02-07
Processes for preparing 5,5-dimethyl-3-methylenepyrrolidin-2-one, (S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, (S)-2,4,4-trimethylpyrrolidine, and (R)-2,4,4-trimethylpyrrolidine, and their salt forms are disclosed.
[EN] MACROCYCLES CONTAINING A 1,3,4-OXADIAZOLE RING FOR USE AS MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR<br/>[FR] MACROCYCLES CONTENANT UN CYCLE 1,3,4-OXADIAZOLE DESTINÉS À ÊTRE UTILISÉS EN TANT QUE MODULATEURS DU RÉGULATEUR DE LA CONDUCTANCE TRANSMEMBRANAIRE DE LA FIBROSE KYSTIQUE
申请人：VERTEX PHARMA
公开号：WO2022109573A1
公开（公告）日：2022-05-27
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.
