(M1230-10-66) Assessment of the Effect of Resmetirom, a Liver-Directed, Orally Active, Selective Thyroid Hormone Receptor-β Agonist, on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects

Purpose: To assess the effect of resmetirom repeated oral dosing on the pharmacokinetics (PK) of R‑ and S-warfarin) and pharmacodynamics (PD), international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPPT)), of warfarin in healthy subjects. Resmetirom is designed specifically to target the underlying causes of non-alcoholic steatohepatitis (NASH) by reducing liver fat (steatosis), liver inflammation, hepatocyte cell death, and liver fibrosis. Resmetirom significantly reduced hepatic fat in NASH patients after 36 weeks of dosing (Harrison et, al., 2019).

Methods: The study was a phase 1, single-center, open-label, sequential drug interaction study. Warfarin was administered orally at 5 mg on Days 1, 2 and 3, then titrated for each subject (N= 25) to achieve an INR value of 1.2 to 2.2 on Days 4 through 9. Each subject’s maintenance dose was then administered on Days 10 through 21. Resmetirom 100 mg was administered orally once daily for 8 days on Days 14 through 21. Blood samples for PK and PD were collected at predetermined times. R- and S-warfarin PK parameters were calculated following warfarin alone (Day 12) or co-administered with resmetirom (Day 21). Resmetirom and MGL-3623 (main metabolite) PK parameters were calculated following single (Day 14) and repeated (Day 21) resmetirom doses. Samples for INR, PT, and aPPT were collected at screening, prior to warfarin dosing on Day -2, predose on Days 1 through 21, 24 hours after the last dose on Day 22 and at 48 hours on Day 23, and at End-of-Study visit (Day 28). The PK and PD of warfarin in the absence and presence of resmetirom were assessed using the bioequivalence crossover model using WinNonlin Professional v 8.3. The primary PK outcome measure was the point estimate of the geometric mean ratio (%GMR) for test/reference (with 90% confidence interval [CI]) for AUC of R‑warfarin and S-warfarin (the more active moiety) with (test, Day 21) and without (reference, Day 12) co‑administration of resmetirom. Warfarin PD was evaluated during chronic warfarin dosing in the absence (Day 14 predose) and the presence (Day 21 predose) of resmetirom using the same model. The primary PD outcome measure was the change in INR after the addition of resmetirom.

Results: PK: The geometric mean AUC_(0-24) and C_max values for R-warfarin and S-warfarin in the absence (Day 12) or presence (Day 21) of resmetirom are shown in Table 1. The %GMR AUC_(0‑24) test/reference ratios were 93% (90% CI, 88% to 99%) for R-warfarin and 99% (90% CI, 88% to 99%) for S-warfarin (Table 1). The corresponding %GMR values C_max were 95% (90% CI, 90% to 100%) for R-warfarin and 98% (90% CI, 91% to 105%) for S-warfarin. PD: The geometric mean INR value following individually dose‑adjusted warfarin dosing prior to addition of resmetirom (ie, Day 14 predose) was 1.70, and was 1.87 during chronic dosing with resmetirom (Day 21 predose -- Table 2). The %GMR test/reference ratio was 110% (90% CI, 102% to 117%). Regarding secondary PD measures, the corresponding geometric mean values in the absence and presence of resmetirom were 17 and 18 seconds for PT and 34 and 34 seconds for aPTT. The resulting %GMR test/reference ratios were 109% (90% CI, 102% to 116%) for PT and 100% (90% CI, 97% to 104%) for aPTT (Table 2). The 90% CI values, along with INR, PT, and aPPT levels displayed in Figure 1 indicate that 8 consecutive days of co-administration of 100 mg/day resmetirom and warfarin did not change the PD (INR, PT, and aPPT) or PK exposure (C_max and AUC_(0-24)) of R-warfarin and S-warfarin. Warfarine PD had reached a steady state (Figure 1). Resmetirom was absorbed into systemic circulation and MGL-3623 was detected with median T_max values of 4.00 h. Both analytes displayed short T_1/2 (Tables 3 and 4). Following repeated dosing, resmetirom displayed slight accumulation, while MGL-3623 did not. Other PK parameters are listed in Tables 3 and 4.

Conclusion: The 90% CI for PK and PD are within the 80.00-125.00 limit indicating that oral dosing of resmetirom 100 mg/day for 8 consecutive days did not change the PK or PD of warfarin. Both study treatments were well tolerated with no serious adverse effects.

References: Harrison, S., Bashir, M., Guy, C., Zhou, R., Moylan, C., Frias, J., Alkhouri, N., Bansal, M., Baum, S., Neuschwander-Tetri, B., Taub, R., and Moussa, S. (2019).
Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Volume 394, Number 10213, p1965-2038.

Tables 1 and 2

Tables 3 and 4

Figure 1