The Bioequivalence of Tafamidis 61‐mg Free Acid Capsules and Tafamidis Meglumine 4 × 20‐mg Capsules in Healthy Volunteers

Abstract

Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61-mg free acid capsules (test) and tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.

Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma

“…This concentration of tafamidis, assuming it is the same in ATTRwt-CM patients at the 20 mg QD dose, would be expected to slow the rate of TTRwt tetramer dissociation to $14% of normal based on the subunit exchange data presented herein. Increasing the dose of tafamidis to 80 mg once daily (which yields a mean peak plasma concentration of % 28 mM), lowers the rate of TTRwt tetramer dissociation to $3% of normal in our experiments (61 mg Vyndamax formulation affords the same plasma concentration) [43]. Slowing of progression of ATTRv-PN has been observed with diflunisal treatment (250 mg BID), but we lack good information on plasma concentrations.…”

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study

“…In ATTR‐ACT and the LTE, a dose reduction could be requested if patients experienced adverse events that may be associated with poor tolerability. The only actual reduction possible was for patients randomized to 80 mg. As of 20 July 2018, the LTE protocol was amended to transition all patients to tafamidis free acid 61 mg; a new, single capsule formulation bioequivalent to the tafamidis meglumine 80 mg used in ATTR‐ACT 17 ( graphical abstract ). The transition to tafamidis free acid 61 mg followed the protocol amendment date, not a specified duration of treatment.…”

Tafamidis is entering the clinical arena for the treatment of transthyretin‐related cardiomyopathy: certainties and unmet needs

“…2 Indeed, tafamidis 61 mg free acid capsules received authority approval (by the Food and Drug Administration in 2019 and the European Medicines Agency in 2020) for the treatment of amyloid transthyretin cardiomyopathy (ATTR-CM) in its variant or wild-type forms (ATTRv or ATTRwt, respectively). This formulation is bioequivalent to tafamidis meglumine 4 × 20 mg capsules, 3 which was evaluated in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT). 1 In this issue of the Journal, Damy et al 4 address the important issue of the best tafamidis dose, analysing data from the ATTR-ACT study and its long-term extension study.…”

“…Almost all circulating drug (>99.5%) is bound to plasma proteins. 3 The small molecule of tafamidis has the potential to cross the blood-brain barrier, but no more than 1.5% of the circulating drug reaches the cerebrospinal fluid. 15 Tafamidis has a slow elimination, with a mean half-life of approximately 59 h. Glucuronidation is the major metabolic pathway.…”

“…Tafamidis is rapidly absorbed after oral administration, with a median time to peak concentration of about 2 h. Administration with food reduces the rate, but not the extent of absorption of tafamidis. Almost all circulating drug (>99.5%) is bound to plasma proteins 3 . The small molecule of tafamidis has the potential to cross the blood–brain barrier, but no more than 1.5% of the circulating drug reaches the cerebrospinal fluid 15 .…”