YM150, An Oral Direct Inhibitor of Factor Xa, Demonstrated a Predictable and Dose-Proportional Pharmacokinetic/Pharmacodynamic Profile After Single and Multiple Dosing: Results From Three Studies

YM150 is a potent oral direct factor Xa (FXa) inhibitor that is rapidly and extensively metabolized into YM-222714 after oral administration. YM-222714 predominantly determines the antithrombotic effect of YM150. Three studies were undertaken to assess the pharmacokinetic/pharmacodynamic (PK/PD) profiles of YM150 and YM-222714 in healthy male subjects (aged 18–55 yrs) after single and multiple doses over a wide dose range.

Study 1a was a sequential-group, double-blind (DB), randomized, placebo-controlled, single-dose escalation study (3, 10, 20 and 30 mg; n=6 per dose group, except for 30 mg, where n=5). Study 1b was an open-label, randomized, 2-period crossover study to explore the effect of food on PK (n=10). Study 2 was a sequential-group, DB, randomized, placebo-controlled, multiple-dose escalation study (3, 10, 20 and 30 mg twice daily; n=6 per dose group); subjects received a single dose of YM150 (Day 1) followed by a washout period (48 h) and, thereafter, repeated dosing (Days 3–10). Study 3 was a sequential-group, DB, randomized, placebo-controlled, multiple-dose escalation study (60, 120, 180, 240, 360, 480 and 720 mg once daily; n=12 per dose group, except for 720 mg, where n=6); subjects received a single dose of YM150 (Day 1) followed by a washout period (48 h) and, thereafter, repeated dosing (Days 3–9). In all studies, blood samples were collected for PK/PD analysis up to 48, 72 or 96 hrs post-dose for 3–120, 180–480 and 720 mg dosages, respectively. All doses were tested separately in each study. Data are presented as arithmetic means.

YM-222714 maximum concentration (C_max) and area under the curve (AUC)_inf generally increased proportionally with dose in all studies. After single dosing across the studies (3–720 mg), YM-222714 C_max and AUC_inf ranged from 103–13,550 ng/mL and 404–14,0793 ng·h/mL, respectively; at steady state (SS), similar ranges were observed (C_max: 116–18,680 ng/mL; AUC_tau: 630–16,6009 ng·h/mL). The time to maximum concentration (t_max) of YM-222714 was 0.75–1.08 h after single dosing and at SS in Studies 1 and 2; in Study 3, t_max slightly increased with dose (range for 60–720 mg; single dose, 0.92–2.10 h; SS, 1.00–2.20 h). YM-222714 elimination half-life (t_1/2) was 14.3–20.0 h after single dosing and 14.3–20.5 h at SS. YM150 plasma concentrations were generally below the lower limit of quantification in Studies 1 and 2. In Study 3, YM150 C_max and AUC_inf increased proportionally with dose after single dosing (4.5–65.4 ng/mL and 197–590 ng·h/mL), with a t_1/2 range of 12.5–17.9 h; consistent with this, YM150 C_max and AUC_tau also increased proportionally with dose at SS (6.8–90.0 ng/mL and 43.7–723 ng·h/mL), with a t_1/2 of 16.2–22.3 h. Administration of YM150 10 mg in fed vs fasted state led to an increase in YM-222714 t_max (1.7 vs 0.8 h) and decrease in C_max (253 vs 310 ng/mL); other parameters were similar in both states. Small amounts of YM150 (<0.65%) were excreted unchanged in urine after single dosing and at SS; 20–40% and 25–39% of dose was excreted as YM-222714 after single dosing and at SS, respectively. Across the studies, renal clearance (CL_R) ranged from 1.60–2.91 L/h after single dosing; a similar range was observed at SS (1.37–2.57 L/h). Across studies (YM150 3–720 mg) maximum prothrombin time (PT_max; INR) increased with dose and was similar under single dosing (1.42–14.1) and at SS (1.48–14.3), as was maximum activated partial thromboplastin time (aPTT_max; single dose, 37.0–81.6 s; SS, 38.0–92.4 s). A dose-dependent decrease in FXa activity was observed that was similar after single dosing and at SS (60–720 mg; 58.0–28.1% and 50.7–22.3%, respectively). Treatment with YM150 was generally safe and well tolerated across all studies.

YM150 is rapidly and extensively converted to YM-222714 after oral administration. YM-222714 demonstrated a predictable, dose-proportional PK profile that was similar under single dosing and SS conditions, including a linear increase in C_max and AUC, consistent t_1/2 and no dose effect on CL_R; no relevant food effect was observed, with administration of YM150 in fasted or fed state, having minimal effects on YM-222714 PK. Additionally, YM150 exhibited dose-dependent antithrombotic activity, as shown by increasing PT and aPTT and decreasing FXa activity with dose.

Groenendaal – van de Meent:Astellas Pharma Global Development Europe: Employment. Heeringa:Astellas Pharma Global Development Europe: Employment. Kadokura:Astellas Pharma Inc.: Employment. Verheggen:Astellas Pharma Global Development Europe: Employment. Heinzerling:Astellas Pharma Global Development Europe: Employment.