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VYNDAQEL® OR VYNDAMAX™ (tafamidis meglumine or tafamidis) Clinical Pharmacology

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tafamidis is a selective stabilizer of 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.

12.2 Pharmacodynamics

A proprietary TTR stabilization assay was utilized as a pharmacodynamic marker and assessed the stability of the TTR tetramer ex vivo. The TTR stabilization assay quantifies immunoturbidimetric measurement of the stable TTR tetramer in plasma pre- and post-treatment with 2-day in vitro denaturation with urea. Using this proprietary assay, a dose-dependent trend for greater TTR tetramer stabilization is observed for VYNDAQEL 80-mg compared to VYNDAQEL 20-mg. However, the clinical relevance of a higher TTR tetramer stabilization towards cardiovascular outcomes is not known.

VYNDAQEL 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 25 variants tested ex vivo.

VYNDAQEL and VYNDAMAX may decrease serum concentrations of total thyroxine, without an accompanying change in thyroid stimulating hormone (TSH). This reduction in total thyroxine values is probably the result of reduced thyroxine binding to or displacement from transthyretin (TTR) due to the high binding affinity of tafamidis to the TTR thyroxine receptor. No corresponding clinical findings consistent with hypothyroidism have been observed.

Biomarkers associated with heart failure (NT-proBNP and Troponin I) favored VYNDAQEL over placebo.

Cardiac Electrophysiology

At 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.

12.3 Pharmacokinetics

No clinically significant differences in steady state Cmax and area under the plasma concentration over time curve (AUC) of tafamidis were observed for VYNDAMAX 61-mg capsule compared to VYNDAQEL administered as four 20-mg capsules.

Tafamidis exposure increases proportionally over single (up to 480 mg) or multiple (up to 80 mg) (1 to 6 times the approved recommended dosage) once daily dosing.

The apparent clearance were similar after single and repeated administration of VYNDAQEL 80 mg.

Absorption

Median tafamidis peak concentrations occurred within 4 hours following dosing.

Effect of Food

No clinically significant differences in the pharmacokinetics of tafamidis were observed following administration of a high fat, high calorie meal.

Distribution

The apparent steady state volume of distribution of tafamidis meglumine is 16 liters and 18.5 liters for tafamidis. Plasma protein binding of tafamidis is >99% in vitro. Tafamidis primarily binds to TTR.

Elimination

The mean half life of tafamidis is approximately 49 hours. The apparent oral clearance of tafamidis meglumine is 0.228 L/h (0.263 L/h for tafamidis). 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.

Metabolism

The metabolism of tafamidis has not been fully characterized. However, glucuronidation has been observed.

Excretion

After a single oral dose of tafamidis meglumine 20 mg, approximately 59% of the dose was recovered in feces (mostly as the unchanged drug) and approximately 22% of the dose was recovered in urine (mostly as the glucuronide metabolite).

Specific Populations

No clinically significant differences in the pharmacokinetics of tafamidis were observed based on age, race/ethnicity (Caucasian and Japanese) or renal impairment.

Patients with Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh Score of 7 to 9) had decreased systemic exposure (approximately 40%) and increased clearance (approximately 68%) of tafamidis compared to healthy subjects. As TTR levels are lower in subjects with moderate hepatic impairment than in healthy subjects, the exposure of tafamidis relative to the amount of TTR is sufficient to maintain stabilization of the TTR tetramer in these patients. No clinically significant differences in the pharmacokinetics of tafamidis were observed in patients with mild hepatic impairment (Child Pugh Score of 5 to 6) compared to healthy subjects. The effect of severe hepatic impairment on tafamidis is unknown.

Drug Interaction Studies

Clinical Studies

No clinically significant differences in the pharmacokinetics of midazolam (a CYP3A4 substrate) or on the formation of its active metabolite (1-hydroxymidazolam) were observed when a single 7.5-mg dose of midazolam was administered prior to and after a 14-day regimen of VYNDAQEL 20-mg once daily.

In Vitro Studies

Cytochrome P450 Enzymes: Tafamidis induces CYP2B6 and CYP3A4 and does not induce CYP1A2. Tafamidis does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4/5 or CYP2D6.

UDP glucuronosyltransferase (UGT): Tafamidis inhibits intestinal activities of UGT1A1 but neither induces nor inhibits other UDP glucuronosyltransferase (UGT) systemically.

Transporter Systems: Tafamidis inhibits breast cancer resistant protein (BCRP). In vitro studies and model predictions show that tafamidis has a low potential to inhibit organic anion transporters OAT1 and OAT3 at clinically relevant concentrations. Tafamidis did not show a potential to inhibit Multi-Drug Resistant Protein (MDR1) (also known as P-glycoprotein; P-gp), organic cation transporter OCT2, multidrug and toxin extrusion transporters MATE1 and MATE2K and, organic anion transporting polypeptide OATP1B1 and OATP1B3.

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