VYNDAMAX (tafamidis) 10 Clinical Pharmacology

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10.1 Mechanism of Action

Tafamidis is a selective stabilizer of transthyretin (TTR). Tafamidis binds to TTR at the thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate‑limiting step in the amyloidogenic process.

10.2 Pharmacodynamics

A TTR stabilization assay was utilized as a pharmacodynamic marker and assessed the stability of the TTR tetramer under denaturation conditions. Tafamidis stabilized both the wild‑type TTR tetramer and the tetramers of 14 TTR variants tested clinically after once‑daily dosing. Tafamidis also stabilized the TTR tetramer for an additional 25 variants tested ex vivo.

The 80 mg dose for VYNDAQEL (tafamidis meglumine) was selected based on maximal TTR % stabilization data from PK studies.  The clinical relevance of a higher TTR stabilization is not known.

The recommended dose of VYNDAMAX (tafamidis) is 61 mg orally once daily.

Cardiac Electrophysiology

At single dose of 400 mg, approximately 2.2 times the steady state peak plasma concentration (Cmax) at the recommended dose, tafamidis does not prolong the QTc interval to any clinically relevant extent.

10.3 Pharmacokinetics

Table 4 - Summary of Tafamidis Pharmacokinetic Parameters1 in Healthy Volunteers after a Single Dose of 1 x 61 mg Tafamidis Capsule.

Condition

N, n 2

AUC0-168hr (mcg.hr/mL)

AUCI (mcg.hr/mL)

Cmax (mcg/mL)

Tmax (hr)

t½ (hr)

Fasting

16, 15

210.1 (14)

225.9 (12)

3.886 (19)

4.00 (2.00 – 12.00)

48.60 (24)

Fed

17, 14

236.7 (20)

247.9 (18)

5.125 (16)

3.00 (0.50 – 6.03)

49.81 (26)
1.
Arithmetic mean (%CV) for all except: median (range) for Tmax
2.
N = Number of subjects in the treatment group; n = Number of Subjects where t1/2 and AUCI were determined.

 

Absorption:

After oral administration of VYNDAMAX (tafamidis) once daily, the maximum peak concentration (Cmax) is achieved at a median time (tmax) within 4 hours after dosing in the fasted state.

Concomitant administration of VYNDAQEL (tafamidis meglumine) with a high fat, high calorie meal decreased the Cmax by 15%, but did not affect the AUC. Concomitant administration of VYNDAMAX (tafamidis) with a high fat, high calorie meal increased the Cmax by 32%, but did not affect the AUC. VYNDAQEL and VYNDAMAX are to be administered with or without food.

VYNDAMAX and VYNDAQEL are not interchangeable on a per mg basis. (See 4.1 Dosing Considerations and 4.2 Recommended Dose and Dosage Adjustment)

Distribution:

Tafamidis is highly protein bound (>99%) in plasma. The apparent steady‑state volume of distribution is 18.5 liters in a 75 kg adult.

Metabolism:

While there is no explicit evidence of biliary excretion of tafamidis in humans, based on preclinical data, it is suggested that tafamidis is metabolized by glucuronidation and excreted via the bile. This route of metabolism and excretion is likely in humans, as approximately 59% of the total administered dose is recovered in feces mostly as unchanged drug, and approximately 22% recovered in urine mostly as the glucuronide metabolite.

Elimination:

The mean half‑life of tafamidis is approximately 49 hours. The apparent oral clearance of tafamidis is 0.263 L/hr. The degree of drug accumulation at steady state after repeated tafamidis daily dosing is approximately 2.5‑fold greater than that observed after a single dose.

Special Populations and Conditions

Ethnic origin: No clinically significant differences in the pharmacokinetics of tafamidis were observed based on race/ethnicity (Caucasian and Japanese).

Pediatrics: Tafamidis has not been studied and is not indicated in this population.

Hepatic Insufficiency: Pharmacokinetic data indicated decreased systemic exposure (approximately 40%) and approximately 68% increase of total clearance (0.52 L/h versus 0.31 L/h) of tafamidis meglumine in subjects with moderate hepatic impairment (Child‑Pugh Class B) compared to healthy subjects. As TTR levels are lower in patients with moderate hepatic impairment than in healthy subjects, the exposure of tafamidis relative to the amount of TTR would be sufficient for stabilization of the TTR tetramer in these patients.

Exposure to VYNDAMAX was similar between subjects with mild hepatic impairment (Child-Pugh Class A) and healthy subjects.

The pharmacokinetics of VYNDAMAX in patients with severe hepatic impairment (Child-Pugh Class C) is unknown.

Renal Insufficiency: VYNDAMAX has not specifically been evaluated in patients with renal impairment.  Limited data are available in patients with severe renal impairment (CrCl ≤30 mL/min).