,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 timecurve (AUC) of tafamidis were observed for VYNDAMAX 61-mg capsule compared to VYNDAQELadministered as four 20-mg capsules.
Tafamidis exposure increases proportionally over single (up to 480 mg) or multiple (up to 80 mg) (1 to 6 timesthe 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 followingadministration of a high fat, high calorie meal.
Distribution
The apparent steady state volume of distribution of tafamidis is approximately 18.5 liters. Plasma proteinbinding 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 is0.263 L/hr. The degree of drug accumulation at steady state after repeated tafamidis daily dosing isapproximately 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 theglucuronide 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 ImpairmentPatients 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 oftafamidis relative to the amount of TTR is sufficient to maintain stabilization of the TTR tetramer in thesepatients. 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 severehepatic impairment on tafamidis is unknown.
Drug Interaction Studies
Clinical Studies
No clinically significant differences in the pharmacokinetics of midazolam (a CYP3A4 substrate) or on theformation of its active metabolite (1-hydroxymidazolam) were observed when a single 7.5-mg dose ofmidazolam 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 inducesnor inhibits other UDP glucuronosyltransferase (UGT) systemically.
Transporter Systems: Tafamidis inhibits breast cancer resistant protein (BCRP). In vit |
