VYNDAQEL (tafamidis meglumine capsules) 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 26 variants tested ex vivo.

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

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 Meglumine Pharmacokinetic Parameters in Patients with ATTR-CM

 

Tafamidis

meglumine

Cmax (µg/mL)

Tmaxa

(h)

t½

(h)

AUCtau (µg*h/mL)

CL

(L/h)

Vss

(L)

Steady-state meanb

20 mg, QD

3.00

1.75
(0.5, 10.5)

57

60.39

0.203

16.6

80 mg, QD

11.99

241.50
 
a Median (5th, 95th quantile) Tmax values across 1000 simulated trials of n = 30 patients with ATTR-CM;
 
b Population PK estimates assuming 80 kg body weight and ≥ 65 years of age across 1000 simulated trials of n = 30 patients with ATTR-CM;
 
CL = apparent oral clearance; Vss = steady-state apparent oral volume of distribution

The pharmacokinetic profile of tafamidis was characterized in healthy volunteers (n = 333) and patients with transthyretin amyloidosis (n = 427).  Steady-state PK parameters were estimated by a population PK analysis.  Tafamidis apparent oral clearance was affected by age and body weight. Over the range of 57.5 to 93 kg (corresponding to the 10th and 90th percentile of the observed weights) the clearance changed from 0.85-fold to 1.14-fold relative to the median weight and it decreased by 14.5% in subjects ≥ 65 years of age compared to younger subjects.

Absorption:

After oral administration of VYNDAQEL 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 a high fat, high calorie meal altered the rate of absorption, but not the extent of absorption. These results support the administration of VYNDAQEL with or without food.

Distribution:

Tafamidis is highly protein bound (>99%) in plasma. The apparent steady‑state volume of distribution is 16 liters.

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 0.228 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 VYNDAQEL relative to the amount of TTR would be sufficient for stabilization of the TTR tetramer in these patients.

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

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

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