Drug Interaction Report

MONITOR: Coadministration with resmetirom may increase the plasma concentrations and effects of drugs that are substrates of hepatic uptake transporters organic anion transporting polypeptides (OATP) 1B1, OATP 1B3, and/or the intestinal and hepatobiliary efflux transporter breast cancer resistance protein (BCRP). Resmetirom is both a substrate and an inhibitor of these transporters. Clinical studies exist for resmetirom with OATP1B1 and OATP1B3 substrates, simvastatin, and pravastatin; as well as with rosuvastatin and atorvastatin which are BCRP, OATP1B1 and OATP1B3 substrates. Resmetirom was shown to increase the systemic exposure (AUC) of simvastatin, pravastatin, rosuvastatin, and atorvastatin by 1.7-fold, 1.4-fold, 1.8-fold, and 1.4-fold, respectively. Clinical data are not available for other OATP 1B1, OATP 1B3 and/or BCRP substrates.

MANAGEMENT: Caution and closer monitoring may be advised if resmetirom is coadministered with drugs that are substrates of the OATP 1B1, OATP 1B3, and/or BCRP transporters. Dosage adjustments as well as clinical and laboratory monitoring for the development of adverse effects may be appropriate for some drugs whenever resmetirom is added to or withdrawn from therapy. Individual product labeling should be consulted for further guidance.

ADJUST DOSE: Smoking may decrease the plasma concentrations of riociguat. The proposed mechanism is induction of the CYP450 1A1-mediated metabolism of riociguat by polycyclic aromatic hydrocarbons present in cigarette smoke. CYP450 1A1 is responsible for the formation of the major active metabolite, M1, which has just 1/3 to 1/10 the pharmacologic activity of riociguat. According to the product labeling, plasma concentrations of riociguat are reduced by 50% to 60% in smokers compared to nonsmokers.

MANAGEMENT: Patients should be advised to stop smoking. Riociguat dosages higher than 2.5 mg three times a day may be considered in cigarette smokers, if tolerated, to match the exposure seen in nonsmoking patients. However, safety and effectiveness of higher dosages have not been established. A dosage reduction should be considered in patients who stop smoking during treatment with riociguat. The tablet form of riociguat can generally be taken with or without food. Some authorities recommend not to switch between fed and fasted riociguat intake because of increased peak plasma levels of riociguat in the fasting compared to the fed state.