Structure-activity relationship
The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib. A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO2NHCH3 substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 – 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).Celecoxib is compound 22; the 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximize potency, while the 3-trifluoromethyl group provides superior selectivity and potency. To explain the selectivity of celecoxib, it is necessary to analyze the free energy of binding difference between the drug molecule and COX-1 compared to COX-2 enzymes. The structural modifications highlight the importance of binding to residue 523 in the side binding pocket of the cyclooxygenase enzyme, which is an isoleucine in COX-1 and a valine in COX-2.
UK agencies estimated the cost per quality adjusted life year (QALY) at between £335,000 and £1,274,000 —well above the National Institute for Health and Care Excellence thresholds.The medication was not covered under the Ontario Drug Benefit plan until June 2014, when the Government of Ontario and the manufacturer negotiated for what "Ontario Health Minister Deb Matthews had called a "fair price" for taxpayers". The negotiations took 16 months and it was estimated that around 20 Ontarians required the medication at the time.The province of Alberta began covering the medication in July 2014, and in September the province of Saskatchewan became the third province to include it in its provincial medication plan.Delay in agreement on a price for Vertex to charge national health plans led to patient group protests in Wales, England, and Australia.As of March 2016, the combination medication cost $259,000 a year in the United States. Research
The clinical trials used in the regulatory approval of ivacaftor are described here. G551D mutation
Of the approximately 70,000 cases of cystic fibrosis worldwide, 4% (~3,000) are due to a mutation called G551D. The safety and efficacy of ivacaftor for the treatment of cystic fibrosis in patients with this mutation was examined in two clinical trials.The first trial was performed in adults having baseline respiratory function (FEV1) between 32% and 98% of normal for persons of similar age, height, and weight. The baseline average was 64%. Improvement in FEV1 was rapid and sustained.