Dataset Information

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.

SUBMITTER: Lockwood PA

PROVIDER: S-EPMC7754314 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Lockwood Peter A PA Le Vu H VH O'Gorman Melissa T MT Patterson Terrell A TA Sultan Marla B MB Tankisheva Ekaterina E Wang Qiang Q Riley Steve S

Clinical pharmacology in drug development 20200320 7

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 heredit ...[more]

PMID: 32196976

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Project description:UnlabelledThe present study aimed to investigate the pharmacokinetic properties of febuxostat in healthy Chinese male volunteers and evaluate whether the two formulations of febuxostat 40-mg and 80-mg tablets are bioequivalent. A randomized, open-label, 4-way crossover study was conducted in healthy Chinese male volunteers under fasting conditions. 24 eligible subjects were randomized in a 1:1:1:1 ratio to receive a single dose of test or reference formulation of febuxostat 40-mg or 80-mg tablet. The washout period between each administration was 1 week. Plasma febuxostat was quantified by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Tolerability was evaluated by monitoring adverse events, physical examinations, 12-lead ECG and laboratory tests. After single-dosing of 1 tablet of 40-mg febuxostat, the pharmacokinetic parameters of test and reference formulations were: Tmax 1.22±0.87 and 1.85±1.03 h, Cmax 1689.16±461.31 and 1613.80±608.43 ng·mL-1, AUC0-t 5139.87±1349.28 and 5517.91±2024.26 ng·mL-1·h, AUC0-∞ 5263.06±1339.16 and 5640.48±2040.22 ng·mL-1·h, t1/2 4.82±2.61 and 4.85±1.78 h, respectively. After single-dosing of 1 tablet of 80-mg febuxostat, the pharmacokinetic parameters of test and reference formulations were: Tmax 1.71±1.21 and 2.23±1.55 h, Cmax 2744.47±1157.44 and 2998.17±1200.13 ng·mL-1, AUC0-t 9634.03±2768.25 and 10467.95±3501.65 ng·mL-1·h, AUC0-∞ 9834.32±2730.51 and 10626.63±3504.08 ng·mL-1·h, t1/2 6.25±2.44 and 5.46±1.65 h, respectively. For single-dosing of 1 tablet of 40-mg febuxostat, 90% CIs for the test/reference ratio of AUC0-t, AUC0-∞ and Cmax were 89.79 to 102.55, 90.14 to 102.56 and 93.99 to 129.63, respectively. For single-dosing of 1 tablet of 80-mg febuxostat, 90% CIs for the test/reference ratio of AUC0-t, AUC0-∞ and Cmax were 86.67 to 100.00, 87.50 to 100.51 and 79.48 to 105.99, respectively. This single dose study revealed similar pharmacokinetic properties in healthy Chinese male volunteers as those found in Caucasic population. The test and reference febuxostat tablets formulations met the regulatory criteria for bioequivalence at 40-mg and 80-mg strengths in fasting healthy Chinese male volunteers.Trial registrationChictr.org ChiCTR-TTRCC-14004288.

Project description:Background and objectiveA novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 µg/capsule) while maintaining the same delivered dose (10 µg/actuation). This study describes the pharmacokinetic bioequivalence to the reference product.MethodsThis randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 μg delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 μg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler(®) (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid-liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (C max), area under the concentration-time curve (AUC) from time zero hours to the last observed concentration at time t (AUC t ), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80-125 %. Safety assessment was a secondary endpoint.ResultsA total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: C max (CI 87.26-106.60 %), AUC t (CI 101.33-111.64 %), and AUC0.5 (CI 97.95-113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration).ConclusionsBoth products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.

Dataset Information

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

Publications

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

Similar Datasets

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