Vyndamax Drug Interactions

In a clinical study in healthy volunteers, tafamidis did not induce or inhibit the cytochrome P450 enzyme CYP3A4.
In vitro data also indicated that tafamidis does not significantly inhibit cytochrome P450 enzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. In addition, tafamidis did not induce CYP1A2, but did induce CYP2B6 in vitro, however based on the negative clinical CYP3A4 induction results, it can be concluded that the likelihood of CYP2B6 clinical induction is low.
In vitro studies suggest that it is unlikely tafamidis will cause drug interactions at clinically relevant concentrations with substrates of UDP-glucuronosyltransferase (UGT) systemically. Tafamidis may inhibit intestinal activities of UGT1A1.
Tafamidis showed a low potential to inhibit Multi-Drug Resistant Protein (MDR1) (also known as P-glycoprotein; P-gp) systemically and in the gastrointestinal (GI) tract, organic cation transporter 2 (OCT2), multidrug and toxin extrusion transporter 1 (MATE1) and MATE2K, organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 at clinically relevant concentrations.
Tafamidis has the potential to inhibit the efflux transporter BCRP (breast cancer resistant protein) and may increase systemic exposure of substrates of this transporter (e.g., methotrexate, rosuvastatin, imatinib). In a clinical study in healthy participants, the exposure of BCRP substrate rosuvastatin increased approximately 2-fold following multiple doses of 61 mg tafamidis daily dosing. Dose adjustment may be needed for these substrates.
Tafamidis may have the potential to inhibit organic anion transporter 1 (OAT1) and may cause drug-drug interactions with substrates of this transporter (e.g., non-steroidal anti-inflammatory drugs, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir, cidofovir, zidovudine, zalcitabine). However, additional risk assessments based on the R-value model (AUCi/AUC =1+(C_max,u/Ki)) were performed and the maximal predicted change in AUC of OAT1 substrates was determined to be less than 1.25 for the 20 mg tafamidis meglumine daily dose, 80 mg tafamidis meglumine daily dose, and 61 mg tafamidis daily dose, therefore, inhibition of OAT1 transporter by tafamidis is not expected to result in clinically significant interactions.
Tafamidis does not inhibit the organic anion transporter 3 (OAT3). In a clinical study in healthy participants, the renal clearance of the OAT3 substrate rosuvastatin did not change following multiple doses of 61 mg tafamidis daily dosing.
Patients receiving substrates of both BCRP and OAT with tafamidis should be assessed as exposure of these drugs may be increased e.g., methotrexate AUC might be increased by ~50%.
No interaction studies have been performed evaluating the effect of other medicinal products on tafamidis.
Laboratory test abnormality: Tafamidis may decrease serum concentrations of total thyroxine, without an accompanying change in free thyroxine (T4) or thyroid stimulating hormone (TSH). This observation in total thyroxine values may likely be the result of reduced thyroxine binding to or displacement from transthyretin (TTR) due to the high binding affinity tafamidis has to the TTR thyroxine receptor. No corresponding clinical findings consistent with thyroid dysfunction have been observed.