Administration of deuterated cftr potentiators

A technology for preparation and tablet, applied in 0010] The present invention relates to the new field of ivacaftor derivatives, which can solve problems such as unpredictable effects and inconsiderations

Pending Publication Date: 2018-08-03
VERTEX PHARMA EURO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The variability in deuterium effects has also led experts to question or not consider deuterium modification as a viable drug design strategy to suppress undesirable metabolism (see Foster p. 35 and Fisher p. 101)
[0009] Even when deuterium atoms are incorporated into known metabolic sites, the effects of deuterium modification on drug metabolic properties are unpredictable

Method used

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  • Administration of deuterated cftr potentiators
  • Administration of deuterated cftr potentiators
  • Administration of deuterated cftr potentiators

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0064] Such methods of preparation include the step of bringing into association the molecule to be administered with ingredients such as the carrier which constitute one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, liposomes or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0065] In certain embodiments, the compounds are administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; powder or granules; in an aqueous or non-aqueous liquid as a solution or suspension; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packaged in liposomes; or as a bolus, etc. Soft gelatin capsules may be used to contain this suspension, which may be adv...

Embodiment 1

[0094] Example 1. Phase 1 single ascending dose (SAD) clinical trial

[0095] Ten healthy male and female volunteers participated in a single ascending dose study of 3 doses of CTP-656 (75, 150 and 300 mg), cross-comparing 150 mg of CTP-656 and 150 mg of Kalydeco® (trade name Ivaca support) ( Figure 5 ). Each dose of CTP-656 was given as an aqueous suspension, and Kalydeco as a tablet. All doses of CTP-656 and Kalydeco were administered within 30 minutes of the start of a high-fat breakfast. There was a 7 day washout between doses. The objectives of the study were to compare the pharmacokinetics of single ascending doses (75, 150, and 300 mg) of CTP-656, to compare the pharmacokinetics of single doses of 150 mg CTP-656 and 150 mg Kalydeco, and to evaluate the pharmacokinetics of CTP-656. Safety and Tolerability.

[0096] Overall, CTP-656 administered as a single dose at doses of 75 mg, 150 mg, and 300 mg (following a high-fat meal) was generally well tolerated in healthy...

Embodiment 2

[0107] Example 2. Relationship of Parent and Metabolite Pharmacokinetic Profiles

[0108] Such as image 3 As shown in , after a single dose, deuteration significantly affects the metabolism of the deuterated ivacaftor analog CTP-656 compared with ivacaftor. Ivacaftor, CTP-656 and their metabolites are shown in Image 6 middle. The production of metabolites D8-M1 and D6-M6 from CTP-656 was significantly reduced relative to the production of metabolites M1 and M6 from ivacaftor. Therefore, compared to the ivacaftor to M1 ratio of 0.58, the AUC of CTP-656 / D8-M1 0-24hr The parent to M1 ratio of 2.0. CTP-656 / D8-M1 C max and C 24hr The maternal to M1 ratios were 2.1 and 2.2, respectively. Further, compared with the ratio of ivacaftor to M6 of 1.5, the AUC of CTP-656 / D6-M6 0-24hr The parent to M6 ratio was 4.0. CTP-656 / D6-M6 compared with 1.4 and 0.97 for ivacaftor / M6 max and C 24hr The parent to M6 ratios were 4.3 and 2.5, respectively. Such as image 3 As seen in (a),...

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Abstract

Disclosed is a method of treating in a subject of treating diseases and conditions that are beneficially treated by administering a CFTR potentiator The method comprises administering to the subject an amount in the range of about 50 mg to about 200 mg once a day of Compound (I) or (II) or pharmaceutically acceptable salts thereof, This invention also provides compositions comprising Compound (I)or (II) and the use of such compositions in methods.

Description

[0001] related application [0002] This application claims U.S. Provisional Patent Application No. 62 / 221531, filed September 21, 2015, U.S. Provisional Patent Application No. 62 / 238511, filed October 7, 2015, and U.S. Provisional Patent Application No. 62 / 238,511, filed June 10, 2016 Benefit and Priority of Application No. 62 / 348855. The content of the foregoing applications is hereby incorporated by reference in its entirety. Background of the invention [0003] Many current drugs have poor absorption, distribution, metabolism and / or excretion (ADME) properties, which prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. Although formulation techniques and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One suc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47C07D215/56
CPCC07D215/56A61K31/47A61P11/00A61K9/2054A61K9/2018A61K9/2013A61K9/2009A61K9/146A61K9/145A61K9/20A61K9/16A61K9/0053A61P11/12
Inventor V.布拉曼
Owner VERTEX PHARMA EURO
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