Healthy Volunteers
Conditions
Keywords
Bioavailability, BMS-986177, 14C-Microtracer, Milvexian
Brief summary
The purpose of this study is to evaluate the absolute oral bioavailability (amount of drug entering the bloodstream) of spray-dried dispersion (SDD) milvexian capsules in the fed and fasted states, and to bridge the exposures seen using only the oral solution.
Interventions
DRUGBMS-986177 Oral Solution
Specified dose on specified days
DRUG[14C]BMS-986177 Solution for Infusion
Specified dose on specified days
DRUGBMS-986177 Spray-dried Dispersion Capsules
Specified dose on specified days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations * Body mass index (BMI) of 18.0 to 32.0 kg/m², inclusive. BMI = weight (kg)/ (height \[m\])²
Exclusion criteria
* History of gastrointestinal (GI) disease, upper or lower GI bleeding within 6 months, intracranial bleeding, tumor, aneurysms * History or evidence of abnormal bleeding or coagulation disorder and/or evidence of coagulopathy, prolonged or unexplained clinically significant bleeding, or frequent unexplained bruising or thrombus formation, or a history of spontaneous bleeding, such as epistaxis, or family history of coagulopathies * Any acute or chronic medical illness considered clinically significant by the investigator * History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory, neurological or psychiatric disorder, as judged by the investigator Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Bioavailability (F) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Absolute bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose. Treatment A (milvexian oral solution with IV microdose) was assessed versus each treatment phase of milvexian administered as: a oral solution (fasted), high dose SDD (Spray-Dried Dispersion) capsule (fed and fasted) and low dose SDD capsule (fed and fasted). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Serious Adverse Events (SAE) | Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks) | The number of participants experiencing SAEs following single oral and IV administration. SAEs are defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or causes prolongation of existing hospitalization. |
| Number of Participants Experiencing Abnormal Vital Sign Measurements | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Occurrence of abnormalities in vital sign measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include: Heart Rate(bpm) Value \> 100 and change from baseline \> 30, or Value \< 55 and change from baseline \< -15 Systolic Blood Pressure(mmHg) Value \> 140 and change from baseline \> 20, or Value \< 90 and change from baseline \< -20 Diastolic Blood Pressure(mmHg) Value \> 90 and change from baseline \> 10, or Value \< 55 and change from baseline \< -10 Respiratory Rate(breaths/min) Value \> 16 or change from baseline \> 10 Temperature (°C) Value \> 38.3°C or change from baseline \> 1.6°C |
| Number of Participants With Abnormal Electrocardiograms (ECGs) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | The number of participants with abnormal findings on ECGs following single oral and IV administration. Participants with ECG intervals outside of a pre-specified range and investigator identified ECG abnormalities will be listed. The following criteria will be used to determine ECG results that are outside of a pre-specified range: PR (msec)-Value \> 200; QRS (msec)-Value \> 120; QT (msec)-Value \> 500 or change from baseline \> 30; QTcF (msec)-Value \> 450 or change from baseline \> 30 |
| Number of Participants With Abnormal Physical Examinations | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | The number of participants with abnormal findings on physical examinations following single oral and IV administration. |
| Number of Participants With Clinical Laboratory Test Abnormalities | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Number of participants with abnormalities in clinical lab test measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include: Alanine transaminase \> 3 × upper limit of normal (ULN) Aspartate transaminase \> 3 × ULN Alkaline phosphatase \> 1.5 × ULN Total bilirubin \> 2 × ULN |
| Maximum Observed Plasma Concentration (Cmax) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Cmax is defined as the maximum observed plasma concentration following single administration in the fed and fasted states to healthy participants. |
| Time of Maximum Observed Plasma Concentration (Tmax) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Tmax is defined as the time of maximum observed plasma concentration in the fed and fasted states to healthy participants. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration following single administration in the fed and fasted states to healthy participants. |
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)] | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity following single administration in the fed and fasted states to healthy participants |
| Apparent Clearance of Drug After Extravascular Administration (CLT/F) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | CLT/F is defined as the apparent clearance of drug after extravascular administration. |
| Number of Participants Experiencing Adverse Events (AEs) | Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks) | The number of participants experiencing AEs following single oral and IV administration. AEs are defined as any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
| Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Vz/F is defined as the apparent volume of distribution at terminal phase after extravascular administration. |
| Total Amount of Unchanged Drug Excreted Into the Urine (Ae) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Ae is defined as the total amount of unchanged drug excreted into the urine following single administration in the fed and fasted states to healthy participants |
| Total Percent Urinary Recovery (%UR) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | %UR is defined as a percent or absolute amount of dose that is recovered in the urine as the unchanged drug. |
| Half-life (T-HALF) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | T-HALF is defined as the time required for half the quantity of a drug to be metabolized or eliminated by normal biological processes. |
| Mean Residence Time (MRT) Following an IV Dose in Treatment A | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Mean residence time (MRT) represents the average time the drug stays in the body and is evaluated for the IV dose of Treatment A only. |
| Volume of Distribution at Steady State (Vss) Following an IV Dose in Treatment A | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Characterize the IV dose of Treatment A by Vss, which is defined as the apparent volume of distribution at steady state |
| Relative Bioavailability (Frel) Based on Ratios of Cmax | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Point estimates and 90% CI for the ratio of geometric means for Cmax will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment. Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. Cmax is defined as the maximum observed plasma concentration. |
| Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Point estimates and 90% CI for the ratio of geometric means for AUC(0-T) and AUC(INF) will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment. Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity. |
| Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Food effect analysis of the high and low dose SDD capsules based on ratios of Cmax. The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment. Cmax is defined as the maximum observed plasma concentration. |
| Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | Food effect with low and high dose SDD capsules based on ratios of AUC(0-T) and AUC(INF). The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment. AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity. |
| Renal Clearance (CLR) | Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks) | CLR is defined as the volume of plasma completely cleared of a substance by the kidneys per unit of time, in this case by hour. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence 1: ABCED On Day 1 of Treatment Period 1 all participants will receive the (A) milvexian oral solution in the fasted state, followed 1 hour later by the intravenous (IV) \[14C\]milvexian microdose infused over 15 minutes. On Day 1 for Treatment Periods 2 to 5, participants will receive (B) milvexian SDD high dose capsules in the fasted state, (C) milvexian SDD low dose capsules in the fed state, (E) milvexian SDD high dose capsules in the fed state, and (D) milvexian SDD low dose capsules in the fasted state with a minimum of 72 hour washout in between each treatment period. | 4 |
| Treatment Sequence 2: ACDBE On Day 1 of Treatment Period 1 all participants will receive the (A) milvexian oral solution in the fasted state, followed 1 hour later by the intravenous (IV) \[14C\]milvexian microdose infused over 15 minutes. On Day 1 for Treatment Periods 2 to 5, participants will receive (C) milvexian SDD low dose capsules in the fed state, (D) milvexian SDD low dose capsules in the fasted state, (B) milvexian SDD high dose capsules in the fasted state, and (E) milvexian SDD high dose capsules in the fed state with a minimum of 72 hour washout in between each treatment period. | 5 |
| Treatment Sequence 3: ADECB On Day 1 of Treatment Period 1 all participants will receive the (A) milvexian oral solution in the fasted state, followed 1 hour later by the intravenous (IV) \[14C\]milvexian microdose infused over 15 minutes. On Day 1 for Treatment Periods 2 to 5, participants will receive (D) milvexian SDD low dose capsules in the fasted state, (E) milvexian SDD high dose capsules in the fed state, (C) milvexian SDD low dose capsules in the fed state, (B) milvexian SDD high dose capsules in the fasted state with a minimum of 72 hour washout in between each treatment period. | 4 |
| Treatment Sequence 4: AEBDC On Day 1 of Treatment Period 1 all participants will receive the (A) milvexian oral solution in the fasted state, followed 1 hour later by the intravenous (IV) \[14C\]milvexian microdose infused over 15 minutes. On Day 1 for Treatment Periods 2 to 5, participants will receive (E) milvexian SDD high dose capsules in the fed state, (B) milvexian SDD high dose capsules in the fasted state, (D) milvexian SDD low dose capsules in the fasted state, (C) milvexian SDD low dose capsules in the fed state with a minimum of 72 hour washout in between each treatment period. | 4 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Other reasons | 1 | 0 | 0 | 0 |
| Overall Study | Participant withdrew consent | 0 | 1 | 0 | 0 |
| Overall Study | Poor/Non-compliance | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Sequence 1: ABCED | Treatment Sequence 2: ACDBE | Treatment Sequence 3: ADECB | Treatment Sequence 4: AEBDC | Total |
|---|---|---|---|---|---|
| Age, Continuous | 40.0 Years STANDARD_DEVIATION 14.5 | 45.4 Years STANDARD_DEVIATION 10.1 | 45.8 Years STANDARD_DEVIATION 15 | 37.3 Years STANDARD_DEVIATION 16.2 | 42.3 Years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 4 Participants | 4 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 2 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 14 |
| other Total, other adverse events | 8 / 17 | 2 / 15 | 2 / 15 | 0 / 15 | 2 / 14 |
| serious Total, serious adverse events | 0 / 17 | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 14 |
Outcome results
Primary
Absolute Bioavailability (F)
Absolute bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose. Treatment A (milvexian oral solution with IV microdose) was assessed versus each treatment phase of milvexian administered as: a oral solution (fasted), high dose SDD (Spray-Dried Dispersion) capsule (fed and fasted) and low dose SDD capsule (fed and fasted).
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: Evaluable PK population-all participants who received at least one dose of study drug and had any available concentration-time data with adequate PK profiles for accurate estimation of PK parameters
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Absolute Bioavailability (F) | 105 Percentage of drug |
| Treatment B: High Dose SDD Fasted | Absolute Bioavailability (F) | 54.2 Percentage of drug |
| Treatment C: Low Dose SDD Fed | Absolute Bioavailability (F) | 44.3 Percentage of drug |
| Treatment D: Low Dose SDD Fasted | Absolute Bioavailability (F) | 58.2 Percentage of drug |
| Treatment E: High Dose SDD Fed | Absolute Bioavailability (F) | 75.6 Percentage of drug |
Secondary
Apparent Clearance of Drug After Extravascular Administration (CLT/F)
CLT/F is defined as the apparent clearance of drug after extravascular administration.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Apparent Clearance of Drug After Extravascular Administration (CLT/F) | 6.36 Liters/hour |
| Treatment B: High Dose SDD Fasted | Apparent Clearance of Drug After Extravascular Administration (CLT/F) | 12.1 Liters/hour |
| Treatment C: Low Dose SDD Fed | Apparent Clearance of Drug After Extravascular Administration (CLT/F) | 15.9 Liters/hour |
| Treatment D: Low Dose SDD Fasted | Apparent Clearance of Drug After Extravascular Administration (CLT/F) | 12.1 Liters/hour |
| Treatment E: High Dose SDD Fed | Apparent Clearance of Drug After Extravascular Administration (CLT/F) | 8.89 Liters/hour |
Secondary
Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F)
Vz/F is defined as the apparent volume of distribution at terminal phase after extravascular administration.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) | 121 Liters |
| Treatment B: High Dose SDD Fasted | Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) | 243 Liters |
| Treatment C: Low Dose SDD Fed | Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) | 344 Liters |
| Treatment D: Low Dose SDD Fasted | Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) | 245 Liters |
| Treatment E: High Dose SDD Fed | Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) | 159 Liters |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)]
AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity following single administration in the fed and fasted states to healthy participants
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)] | 31435 ng.h/mL |
| Treatment B: High Dose SDD Fasted | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)] | 16464 ng.h/mL |
| Treatment C: Low Dose SDD Fed | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)] | 1569 ng.h/mL |
| Treatment D: Low Dose SDD Fasted | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)] | 2061 ng.h/mL |
| Treatment E: High Dose SDD Fed | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)] | 22496 ng.h/mL |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)]
AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration following single administration in the fed and fasted states to healthy participants.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 30844 ng.h/mL |
| Treatment B: High Dose SDD Fasted | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 15855 ng.h/mL |
| Treatment C: Low Dose SDD Fed | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 1603 ng.h/mL |
| Treatment D: Low Dose SDD Fasted | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 2183 ng.h/mL |
| Treatment E: High Dose SDD Fed | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 21972 ng.h/mL |
Secondary
Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E
Food effect with low and high dose SDD capsules based on ratios of AUC(0-T) and AUC(INF). The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment. AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of Treatment B, C, D, or E with evaluable concentration-time data
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Treatment A: Oral Solution With IV | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(0-T) | 15871 ng.h/mL |
| Treatment A: Oral Solution With IV | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(INF) | 16480 ng.h/mL |
| Treatment B: High Dose SDD Fasted | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(INF) | 1545 ng.h/mL |
| Treatment B: High Dose SDD Fasted | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(0-T) | 1592 ng.h/mL |
| Treatment C: Low Dose SDD Fed | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(0-T) | 2170 ng.h/mL |
| Treatment C: Low Dose SDD Fed | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(INF) | 2069 ng.h/mL |
| Treatment D: Low Dose SDD Fasted | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(0-T) | 22171 ng.h/mL |
| Treatment D: Low Dose SDD Fasted | Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E | AUC(INF) | 22774 ng.h/mL |
Secondary
Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E
Food effect analysis of the high and low dose SDD capsules based on ratios of Cmax. The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment. Cmax is defined as the maximum observed plasma concentration.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of Treatment B, C, D, or E with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E | 1197 ng/mL |
| Treatment B: High Dose SDD Fasted | Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E | 128 ng/mL |
| Treatment C: Low Dose SDD Fed | Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E | 185 ng/mL |
| Treatment D: Low Dose SDD Fasted | Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E | 1709 ng/mL |
Secondary
Half-life (T-HALF)
T-HALF is defined as the time required for half the quantity of a drug to be metabolized or eliminated by normal biological processes.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Oral Solution With IV | Half-life (T-HALF) | 13.3 Hours | Standard Deviation 2.02 |
| Treatment B: High Dose SDD Fasted | Half-life (T-HALF) | 14.3 Hours | Standard Deviation 4.08 |
| Treatment C: Low Dose SDD Fed | Half-life (T-HALF) | 15.8 Hours | Standard Deviation 6.13 |
| Treatment D: Low Dose SDD Fasted | Half-life (T-HALF) | 14.5 Hours | Standard Deviation 4.1 |
| Treatment E: High Dose SDD Fed | Half-life (T-HALF) | 12.8 Hours | Standard Deviation 3.65 |
Secondary
Maximum Observed Plasma Concentration (Cmax)
Cmax is defined as the maximum observed plasma concentration following single administration in the fed and fasted states to healthy participants.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Maximum Observed Plasma Concentration (Cmax) | 2929 ng/mL |
| Treatment B: High Dose SDD Fasted | Maximum Observed Plasma Concentration (Cmax) | 1200 ng/mL |
| Treatment C: Low Dose SDD Fed | Maximum Observed Plasma Concentration (Cmax) | 130 ng/mL |
| Treatment D: Low Dose SDD Fasted | Maximum Observed Plasma Concentration (Cmax) | 185 ng/mL |
| Treatment E: High Dose SDD Fed | Maximum Observed Plasma Concentration (Cmax) | 1696 ng/mL |
Secondary
Mean Residence Time (MRT) Following an IV Dose in Treatment A
Mean residence time (MRT) represents the average time the drug stays in the body and is evaluated for the IV dose of Treatment A only.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of Treatment A with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Mean Residence Time (MRT) Following an IV Dose in Treatment A | 14.8 Hours |
Secondary
Number of Participants Experiencing Abnormal Vital Sign Measurements
Occurrence of abnormalities in vital sign measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include: Heart Rate(bpm) Value \> 100 and change from baseline \> 30, or Value \< 55 and change from baseline \< -15 Systolic Blood Pressure(mmHg) Value \> 140 and change from baseline \> 20, or Value \< 90 and change from baseline \< -20 Diastolic Blood Pressure(mmHg) Value \> 90 and change from baseline \> 10, or Value \< 55 and change from baseline \< -10 Respiratory Rate(breaths/min) Value \> 16 or change from baseline \> 10 Temperature (°C) Value \> 38.3°C or change from baseline \> 1.6°C
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value > 100 and change from baseline > 30 | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value < 55 and change from baseline < -15 | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value > 140 and change from baseline > 20 | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value < 90 and change from baseline < -20 | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value > 90 and change from baseline > 10 | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value < 55 and change from baseline < -10 | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Respiratory Rate (breaths/min) Value > 16 or change from baseline > 10 | 13 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Abnormal Vital Sign Measurements | Temperature (°C)Value > 38.3°C or change from baseline > 1.6°C | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value > 140 and change from baseline > 20 | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value < 55 and change from baseline < -10 | 2 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value > 100 and change from baseline > 30 | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value < 90 and change from baseline < -20 | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value < 55 and change from baseline < -15 | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Temperature (°C)Value > 38.3°C or change from baseline > 1.6°C | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value > 90 and change from baseline > 10 | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Respiratory Rate (breaths/min) Value > 16 or change from baseline > 10 | 10 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Respiratory Rate (breaths/min) Value > 16 or change from baseline > 10 | 10 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Temperature (°C)Value > 38.3°C or change from baseline > 1.6°C | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value < 90 and change from baseline < -20 | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value < 55 and change from baseline < -10 | 1 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value > 140 and change from baseline > 20 | 1 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value < 55 and change from baseline < -15 | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value > 100 and change from baseline > 30 | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value > 90 and change from baseline > 10 | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value < 55 and change from baseline < -15 | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value > 140 and change from baseline > 20 | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value < 90 and change from baseline < -20 | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value > 90 and change from baseline > 10 | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value < 55 and change from baseline < -10 | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Temperature (°C)Value > 38.3°C or change from baseline > 1.6°C | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value > 100 and change from baseline > 30 | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Abnormal Vital Sign Measurements | Respiratory Rate (breaths/min) Value > 16 or change from baseline > 10 | 9 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value < 90 and change from baseline < -20 | 1 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Temperature (°C)Value > 38.3°C or change from baseline > 1.6°C | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure (mmHg) Value > 140 and change from baseline > 20 | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Respiratory Rate (breaths/min) Value > 16 or change from baseline > 10 | 7 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value > 100 and change from baseline > 30 | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value < 55 and change from baseline < -10 | 1 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate (bpm) Value < 55 and change from baseline < -15 | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure (mmHg) Value > 90 and change from baseline > 10 | 0 Participants |
Secondary
Number of Participants Experiencing Adverse Events (AEs)
The number of participants experiencing AEs following single oral and IV administration. AEs are defined as any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Adverse Events (AEs) | Total participants with an adverse event | 8 Participants |
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Adverse Events (AEs) | Adverse events leading to discontinuation | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Adverse Events (AEs) | Total participants with an adverse event | 2 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Adverse Events (AEs) | Adverse events leading to discontinuation | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Adverse Events (AEs) | Total participants with an adverse event | 2 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Adverse Events (AEs) | Adverse events leading to discontinuation | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Adverse Events (AEs) | Adverse events leading to discontinuation | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Adverse Events (AEs) | Total participants with an adverse event | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Adverse Events (AEs) | Total participants with an adverse event | 2 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Adverse Events (AEs) | Adverse events leading to discontinuation | 0 Participants |
Secondary
Number of Participants Experiencing Serious Adverse Events (SAE)
The number of participants experiencing SAEs following single oral and IV administration. SAEs are defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or causes prolongation of existing hospitalization.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A: Oral Solution With IV | Number of Participants Experiencing Serious Adverse Events (SAE) | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants Experiencing Serious Adverse Events (SAE) | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants Experiencing Serious Adverse Events (SAE) | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants Experiencing Serious Adverse Events (SAE) | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants Experiencing Serious Adverse Events (SAE) | 0 Participants |
Secondary
Number of Participants With Abnormal Electrocardiograms (ECGs)
The number of participants with abnormal findings on ECGs following single oral and IV administration. Participants with ECG intervals outside of a pre-specified range and investigator identified ECG abnormalities will be listed. The following criteria will be used to determine ECG results that are outside of a pre-specified range: PR (msec)-Value \> 200; QRS (msec)-Value \> 120; QT (msec)-Value \> 500 or change from baseline \> 30; QTcF (msec)-Value \> 450 or change from baseline \> 30
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A: Oral Solution With IV | Number of Participants With Abnormal Electrocardiograms (ECGs) | 2 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants With Abnormal Electrocardiograms (ECGs) | 2 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants With Abnormal Electrocardiograms (ECGs) | 1 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants With Abnormal Electrocardiograms (ECGs) | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants With Abnormal Electrocardiograms (ECGs) | 1 Participants |
Secondary
Number of Participants With Abnormal Physical Examinations
The number of participants with abnormal findings on physical examinations following single oral and IV administration.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A: Oral Solution With IV | Number of Participants With Abnormal Physical Examinations | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants With Abnormal Physical Examinations | 2 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants With Abnormal Physical Examinations | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants With Abnormal Physical Examinations | 1 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants With Abnormal Physical Examinations | 0 Participants |
Secondary
Number of Participants With Clinical Laboratory Test Abnormalities
Number of participants with abnormalities in clinical lab test measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include: Alanine transaminase \> 3 × upper limit of normal (ULN) Aspartate transaminase \> 3 × ULN Alkaline phosphatase \> 1.5 × ULN Total bilirubin \> 2 × ULN
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Oral Solution With IV | Number of Participants With Clinical Laboratory Test Abnormalities | Alanine transaminase > 3 × upper limit of normal (ULN) | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants With Clinical Laboratory Test Abnormalities | Aspartate transaminase > 3 × ULN | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants With Clinical Laboratory Test Abnormalities | Alkaline phosphatase > 1.5 × ULN | 0 Participants |
| Treatment A: Oral Solution With IV | Number of Participants With Clinical Laboratory Test Abnormalities | Total bilirubin > 2 × ULN | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Alanine transaminase > 3 × upper limit of normal (ULN) | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Total bilirubin > 2 × ULN | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Aspartate transaminase > 3 × ULN | 0 Participants |
| Treatment B: High Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Alkaline phosphatase > 1.5 × ULN | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Total bilirubin > 2 × ULN | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Aspartate transaminase > 3 × ULN | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Alkaline phosphatase > 1.5 × ULN | 0 Participants |
| Treatment C: Low Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Alanine transaminase > 3 × upper limit of normal (ULN) | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Alanine transaminase > 3 × upper limit of normal (ULN) | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Aspartate transaminase > 3 × ULN | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Total bilirubin > 2 × ULN | 0 Participants |
| Treatment D: Low Dose SDD Fasted | Number of Participants With Clinical Laboratory Test Abnormalities | Alkaline phosphatase > 1.5 × ULN | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Total bilirubin > 2 × ULN | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Alkaline phosphatase > 1.5 × ULN | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Aspartate transaminase > 3 × ULN | 0 Participants |
| Treatment E: High Dose SDD Fed | Number of Participants With Clinical Laboratory Test Abnormalities | Alanine transaminase > 3 × upper limit of normal (ULN) | 0 Participants |
Secondary
Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF)
Point estimates and 90% CI for the ratio of geometric means for AUC(0-T) and AUC(INF) will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment. Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Treatment A: Oral Solution With IV | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(0-T) | NA ng.h/mL |
| Treatment A: Oral Solution With IV | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(INF) | NA ng.h/mL |
| Treatment B: High Dose SDD Fasted | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(0-T) | 0.513 ng.h/mL |
| Treatment B: High Dose SDD Fasted | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(INF) | 0.522 ng.h/mL |
| Treatment C: Low Dose SDD Fed | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(0-T) | 0.425 ng.h/mL |
| Treatment C: Low Dose SDD Fed | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(INF) | 0.436 ng.h/mL |
| Treatment D: Low Dose SDD Fasted | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(INF) | 0.543 ng.h/mL |
| Treatment D: Low Dose SDD Fasted | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(0-T) | 0.570 ng.h/mL |
| Treatment E: High Dose SDD Fed | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(0-T) | 0.716 ng.h/mL |
| Treatment E: High Dose SDD Fed | Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF) | AUC(INF) | 0.720 ng.h/mL |
Secondary
Relative Bioavailability (Frel) Based on Ratios of Cmax
Point estimates and 90% CI for the ratio of geometric means for Cmax will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment. Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. Cmax is defined as the maximum observed plasma concentration.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Relative Bioavailability (Frel) Based on Ratios of Cmax | NA ng/mL |
| Treatment B: High Dose SDD Fasted | Relative Bioavailability (Frel) Based on Ratios of Cmax | 0.403 ng/mL |
| Treatment C: Low Dose SDD Fed | Relative Bioavailability (Frel) Based on Ratios of Cmax | 0.358 ng/mL |
| Treatment D: Low Dose SDD Fasted | Relative Bioavailability (Frel) Based on Ratios of Cmax | 0.510 ng/mL |
| Treatment E: High Dose SDD Fed | Relative Bioavailability (Frel) Based on Ratios of Cmax | 0.574 ng/mL |
Secondary
Renal Clearance (CLR)
CLR is defined as the volume of plasma completely cleared of a substance by the kidneys per unit of time, in this case by hour.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Renal Clearance (CLR) | 1.63 Liters/hour |
| Treatment B: High Dose SDD Fasted | Renal Clearance (CLR) | 1.68 Liters/hour |
| Treatment C: Low Dose SDD Fed | Renal Clearance (CLR) | 1.91 Liters/hour |
| Treatment D: Low Dose SDD Fasted | Renal Clearance (CLR) | 1.84 Liters/hour |
| Treatment E: High Dose SDD Fed | Renal Clearance (CLR) | 1.70 Liters/hour |
Secondary
Time of Maximum Observed Plasma Concentration (Tmax)
Tmax is defined as the time of maximum observed plasma concentration in the fed and fasted states to healthy participants.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Time of Maximum Observed Plasma Concentration (Tmax) | 1.27 Hours |
| Treatment B: High Dose SDD Fasted | Time of Maximum Observed Plasma Concentration (Tmax) | 4.00 Hours |
| Treatment C: Low Dose SDD Fed | Time of Maximum Observed Plasma Concentration (Tmax) | 4.00 Hours |
| Treatment D: Low Dose SDD Fasted | Time of Maximum Observed Plasma Concentration (Tmax) | 4.00 Hours |
| Treatment E: High Dose SDD Fed | Time of Maximum Observed Plasma Concentration (Tmax) | 5.00 Hours |
Secondary
Total Amount of Unchanged Drug Excreted Into the Urine (Ae)
Ae is defined as the total amount of unchanged drug excreted into the urine following single administration in the fed and fasted states to healthy participants
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Total Amount of Unchanged Drug Excreted Into the Urine (Ae) | 50.2 mg |
| Treatment B: High Dose SDD Fasted | Total Amount of Unchanged Drug Excreted Into the Urine (Ae) | 26.7 mg |
| Treatment C: Low Dose SDD Fed | Total Amount of Unchanged Drug Excreted Into the Urine (Ae) | 3.06 mg |
| Treatment D: Low Dose SDD Fasted | Total Amount of Unchanged Drug Excreted Into the Urine (Ae) | 4.01 mg |
| Treatment E: High Dose SDD Fed | Total Amount of Unchanged Drug Excreted Into the Urine (Ae) | 37.3 mg |
Secondary
Total Percent Urinary Recovery (%UR)
%UR is defined as a percent or absolute amount of dose that is recovered in the urine as the unchanged drug.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of study drug with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Total Percent Urinary Recovery (%UR) | 25.1 Percentage of milvexian recovered |
| Treatment B: High Dose SDD Fasted | Total Percent Urinary Recovery (%UR) | 13.3 Percentage of milvexian recovered |
| Treatment C: Low Dose SDD Fed | Total Percent Urinary Recovery (%UR) | 12.2 Percentage of milvexian recovered |
| Treatment D: Low Dose SDD Fasted | Total Percent Urinary Recovery (%UR) | 16.0 Percentage of milvexian recovered |
| Treatment E: High Dose SDD Fed | Total Percent Urinary Recovery (%UR) | 18.6 Percentage of milvexian recovered |
Secondary
Volume of Distribution at Steady State (Vss) Following an IV Dose in Treatment A
Characterize the IV dose of Treatment A by Vss, which is defined as the apparent volume of distribution at steady state
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Population: All participants who received at least one dose of Treatment A with evaluable concentration-time data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A: Oral Solution With IV | Volume of Distribution at Steady State (Vss) Following an IV Dose in Treatment A | 99.1 Liters |