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10.3109/13506129.2015.1063485

http://scihub22266oqcxt.onion/10.3109/13506129.2015.1063485
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C4549186!4549186!26193961
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suck abstract from ncbi


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pmid26193961      Amyloid 2015 ; 22 (3): 175-80
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  • Personalized Medicine Approach for Optimizing the Dose of Tafamidis to Potentially Ameliorate Wild-type Transthyretin Amyloidosis (Cardiomyopathy) #MMPMID26193961
  • Cho Y; Baranczak A; Helmke S; Teruya S; Horn EM; Maurer MS; Kelly JW
  • Amyloid 2015[Sep]; 22 (3): 175-80 PMID26193961show ga
  • Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently Pfizer, Inc. is enrolling a 400-person clinical trial to test the efficacy of 20 or 80 mg of tafamidis to ameliorate transthyretin (TTR)-associated cardiomyopathy using clinical endpoints. Herein, we provide guidance for how to optimize the dose of tafamidis for each WT TTR cardiomyopathy patient using its mechanism of action as the key readout, i.e., we identify the dose of tafamidis that maximally kinetically stabilizes TTR in the blood. Tetramer dissociation is rate limiting for TTR aggregation, which appears to drive the pathology in the TTR amyloidosis. Hence we measure the TTR tetramer dissociation rate (kinetic stability) in the patients? plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tells us that a subset of patients exhibiting higher tafamidis plasma concentrations are maximally kinetically stabilized at the 20 mg tafamidis dose, whereas the patient studied herein required a 60 mg once daily dose to achieve maximum kinetic stabilization. We anticipate that establishing the dose of tafamidis that achieves maximal TTR kinetic stabilization will translate into a maximal clinical effect, but that remains to be demonstrated.
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