067: Absolute Oral Bioavailability of Milvexian Spray-dried Dispersion Formulation Under Fasted & Fed Conditions in Healthy Adult Participants Using an Intravenous Microtracer Approach

Statement of Purpose: Milvexian is an oral, small-molecule factor XIa inhibitor being developed to prevent and treat thromboembolic events. This study aimed to explain prior observations in milvexian disposition, including: greater than dose-proportional steady-state exposure with twice-daily (BID) dosing and differences in the urinary fraction excreted depending on the formulation dosed (oral solution vs spray-dried dispersion [SDD]); observations which were suspected to be due to differences in absolute bioavailability (F) due to food effect and formulation. Thus, an absolute bioavailability study of the oral milvexian SDD formulation dosed under fed and fasted conditions and the oral milvexian solution was conducted in healthy adults using an intravenous (IV) microtracer.

Description of Methods & Materials: A Phase 1, open-label, partially randomized, 4-sequence, 5-period crossover study, with a 3-day washout between milvexian treatment groups, was conducted in healthy adults. In Period 1, all participants received single-dose 200 mg oral milvexian solution with a 100 μg 14C milvexian IV microtracer (given at the time of maximum observed plasma concentration [T_max] of the oral dose [1-hour post-dose]) in the fasted state. Following washout, participants were randomly assigned to 1 of 4 treatment sequences where they received a single dose of milvexian (25 or 200 mg SDD capsule) under fed (high-fat meal) or fasted conditions. Milvexian pharmacokinetic (PK; plasma and urine) data were collected for up to 72 hours post-dose. PK parameters were derived using noncompartmental analysis.

Data & Results: Seventeen participants were dosed, and 14 completed all treatment periods. Under fasted conditions, the F of milvexian was 100% following administration of the 200 mg oral solution, and 58% and 54% following administration of the 25 and 200 mg SDD capsules, respectively (Table 1). Under fed conditions, the F of milvexian SDD 25 and 200 mg capsules were 44% and 76%, respectively. A dose-dependent food effect was observed: at 25 mg, there was a 25% decrease in milvexian F under fed vs fasted conditions (44% vs 58%, respectively) and at 200 mg, there was an 40% increase in milvexian F under fed vs fasted conditions (76% vs 54%, respectively). The 200 mg oral solution had the highest observed C_max, and no change in T_max (4-5 hours) was observed between fed and fasted conditions with the SDD capsule formulation (Figure 1). Mean urinary excretion of milvexian was 25.6% for the 200 mg oral solution and ranged from 13.2% to 19.1% for the 25 and 200 mg SDD capsules.

Interpretation, Conclusion or Significance: The study found that SDD capsule administration of milvexian at 25 and 200 mg doses increased milvexian F in a dose-dependent manner under fed but not fasted conditions. The oral solution achieved 100% F, while the SDD capsule had an F range of 44%-76%, depending on dosage and food intake. The dose-dependent increase in milvexian F with SDD capsules under fed conditions explains previously observed exposure following BID administration when food intake was not controlled. Differences in milvexian F between oral solution and SDD capsules explain variations in urinary fraction excreted between the two formulations. These findings provide insights into milvexian PK for further development.

Disclosures: PJ, SS, HB, LJC, DH, AB, AA-H, VP, BM and SM are employees of Bristol Myers Squibb and may own stock in Bristol Myers Squibb. AM is an employee of Syneos Health acting as a consultant for Bristol Myers Squibb.