9.2 Drug Interactions Overview
In vitro studies:
Cytochrome P450 Enzymes: Tafamidis induces CYP2B6 and CYP3A4 and does not induce CYP1A2. Tafamidis does not inhibit cytochrome P450 enzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and moderately inhibits CYP2C8.
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 potential to inhibit the 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.
Clinical studies:
Transporter Systems: Tafamidis inhibits breast cancer resistant protein (BCRP). In a clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increased approximately 2-fold following multiple doses of 61 mg tafamidis daily dosing.
In a clinical study (n=12) using healthy participants, the renal clearance of the OAT3 substrate rosuvastatin did not change following multiple doses of 61 mg tafamidis daily dosing. This suggests that any inhibition of OAT3 by tafamidis may not result in clinically significant interactions with OAT3 substrates.
9.4 Drug-Drug Interactions
The drugs listed in Table 3 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction.
|
Drug Name |
Source of Evidence |
Effect |
Clinical comment |
|---|---|---|---|
|
CYP3A4 substrates (e.g., midazolam, triazolam) |
In vivo |
Tafamidis (20 mg) did not affect the PK of CYP3A4 substrate midazolam; the effect of 80 mg has not been studied. |
In vitro, tafamidis induces CYP3A4 and may decrease exposure of substrates of this CYP enzyme at the higher dose of 80 mg. Caution should be exercised when VYNDAQEL is co-administered with CYP3A4 substrates. Dose adjustment may be needed for these substrates. |
|
Substrates of breast cancer resistant protein BCRP (e.g., methotrexate, rosuvastatin, imatinib) |
In vitro, in vivo |
Tafamidis inhibits BCRP systemically and in the GI tract and may increase exposure of substrates of this transporter. |
Caution should be exercised when VYNDAQEL is co-administered with BCRP substrates. Dose adjustment may be needed for these substrates. |
|
Substrates of organic anion transporters 1 (OAT1) and OAT3 (e.g., antiretroviral agents, diuretics, methotrexate, NSAIDs, olmesartan, pravastatin) |
In vitro, in vivo |
In vitro data indicates that tafamidis has a potential to inhibit OAT1 and may therefore decrease exposure of substrates of this transporter. |
Caution should be exercised when VYNDAQEL is co-administered with OAT1 and OAT3 substrates. Dose adjustment may be needed for these substrates. There is limited clinical evidence to suggest that any inhibition of OAT3 (specifically) by tafamidis may not result in clinically significant interactions with OAT3 substrates. |
9.5 Drug-Food Interactions
No clinically significant differences in the pharmacokinetics of tafamidis were observed following administration of a high fat, high calorie meal.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been established.
9.7 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.