Personalized medicine approach for optimizing the dose of tafamidis to potentially ameliorate wild-type transthyretin amyloidosis (cardiomyopathy)
| Autor: | Stephen Helmke, Mathew S. Maurer, Aleksandra Baranczak, Evelyn M. Horn, Jeffery W. Kelly, Sergio Teruya, Younhee Cho |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Tafamidis medicine.medical_specialty endocrine system Cardiomyopathy Gene Expression Pharmacology Article chemistry.chemical_compound Internal medicine Escherichia coli Internal Medicine medicine Clinical endpoint Humans Prealbumin Drug Dosage Calculations Precision Medicine Aged 80 and over Amyloid Neuropathies Familial Benzoxazoles biology Protein Stability business.industry Amyloidosis Wild type nutritional and metabolic diseases medicine.disease Recombinant Proteins Clinical trial Kinetics Transthyretin Neuroprotective Agents Endocrinology chemistry biology.protein Personalized medicine Drug Monitoring Cardiomyopathies business |
| DOI: | 10.6084/m9.figshare.1568455 |
| Popis: | 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 of the TTR amyloidoses. Hence, we measure the TTR tetramer dissociation rate (kinetic stability) in the patient's plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tell 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. Trial registration:ClinicalTrials.gov identifier: NCT01994889. |
| Databáze: | OpenAIRE |
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