Study Investigating the Safety, Tolerability, PK and Food Effect of BEN8744.

Phase 1

Completed

Conditions: Healthy Volunteer Study

Interventions: Drug: BEN8744
Drug: Matching Placebo

Registration Number: NCT06118385

Lead Sponsor: BenevolentAI Bio

Brief Summary: BEN8744 is an experimental new medicine for treating inflammatory bowel diseases such as Ulcerative Colitis.

The study will test single and repeated oral doses of BEN8744 or placebo. BEN8744 is a first in human study, so will start with a small dose and the dose will be increased as the study progresses. The goal is to find out its side effects and blood levels when taken by mouth and whether food affects the blood levels.

This is a 3-part study (Parts A, B and C) in up to 108 healthy people, aged 18-65.

Part A, will include up to 64 participants, single doses of BEN8744 or placebo. They'll take about 2 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row and make 2 outpatient visits.

Part B, will include up to 12 participants, single doses of BEN8744 with and without food. They'll take up to 3 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row on 2 occasions, and make 2 outpatient visits.

Part C will include up to 32 participants repeat doses of the BEN8744 or placebo for 14 days. They'll take about 4 weeks to complete the study, stay on the ward for 17 nights and 18 days in a row and make 2 outpatient visits.

Detailed Description: This first time in human, study will investigate the safety, tolerability, pharmacokinetics (PK) of BEN8744 after single and multiple ascending oral doses in healthy subjects, in both the fed and fasted state. The results of this study will be used to select doses for subsequent studies in patients. This is an exploratory study in healthy volunteers, with no anticipated therapeutic benefit to the participants; involvement of patients, service users or members of the public in the design of the trial is not appropriate.

Primary objectives Part A: To assess the safety and tolerability of single ascending oral doses of BEN8744 in healthy subjects Part B: To characterise the effect of food on the pharmacokinetic profile of at least 1 dose of BEN8744 Part C: To assess the safety and tolerability of multiple ascending oral doses of BEN8744 in healthy subjects

Secondary objectives Part A: To assess the PK profile of BEN8744 after single oral doses in healthy subjects Part B: To assess the safety and tolerability of a single dose of BEN8744 following high-fat food intake relative to fasting conditions in healthy subjects Part C: To assess the PK profile of BEN8744 after repeated oral doses in healthy subjects

Exploratory objective

Part B (and optional in Part C):

To measure BEN8744 in urine and determine renal clearance in healthy subjects. Exploratory characterisation of BEN8744 and its metabolites in plasma, urine, and faeces.

For part A

* Up to 64 subjects, 5 cohorts + 3 optional, 6 active, 2 placebo.

* Subjects will receive a single dose of BEN8744 or placebo, as capsules, after an overnight fast of at least 10 h.

* At each dose level, 6 subjects will receive BEN8744 and 2 will receive matching placebo in an overall ratio of 3:1.

* The starting dose for Group 1 is 2 mg BEN8744 or placebo. It is intended that subsequent cohorts will receive higher doses. The planned doses are:

A1- 2mg A2- 6mg A3- 20mg A4- 60mg A5- 100mg A6 (optional) - 120mg

For Part B

* Up to 12 subjects, 1 cohorts + 1 optional, 2 sessions fasted/fed.

* Each subject in Part B will have 2 study sessions (Sessions 1 and 2), in which they will receive a single dose of BEN8744, by mouth.

* Each subject will receive BEN8744 after an overnight fast of at least 10 h in one session, and after an FDA high-fat breakfast (1,013 kcal, 59.2 g fat \[of which 28.1 g saturated fat) in the other session; the order will be randomised 1:1.

* A subject's doses will be separated by a washout of at least 7 days (or 5 half-lives as determined in Part A, whichever is longer).

* Subjects dosed on the same day may be dosed at intervals of at least 10 min.

For Part C:

* Up 32 subjects, 3 cohorts + 1 optional, 6 active, 2 placebo.

* Each subject will receive daily doses of BEN8744 or placebo, by mouth, for 14 days.

* Doses will be taken once or twice daily in the fasted state, unless emerging data indicate they should be taken in the fed state.

* Part C will not start until at least 3 dose levels have been completed in Part A and may also be conducted in parallel with Part B.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 76

Inclusion Criteria

Male or female healthy volunteer in good health
Aged 18-65 years
Body mass index 18.0-30.9 and weight ≥ 50 kg

Exclusion Criteria

Woman who is pregnant or lactating, or pre-menopausal woman who is sexually active and not using a reliable method of contraception

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part A Dose 2	BEN8744	Part A Dose 2 Single dose of 6 mg BEN8744
Part B Dose 2 Fasted	BEN8744	Part B Dose 2 Fasted Single dose of BEN8744 after 10 hours fasting (Dose 50mg QD)
Part C Dose 1	BEN8744	Part C Dose 1 14 daily doses of BEN8744 (Dose 30mg BID)
Part A Dose 3	BEN8744	Part A Dose 3 Single dose of 20 mg BEN8744
Part A Dose 4	BEN8744	Part A Dose 4 Single dose of 60 mg BEN8744
Part A placebo	Matching Placebo	Part A placebo Single dose of placebo
Part C placebo	Matching Placebo	Part C placebo 14 daily doses of placebo
Part A Dose 1	BEN8744	Part A Dose 1 Single dose of 2 mg BEN8744
Part A Dose 5	BEN8744	Part A Dose 5 Single dose of 100 mg BEN8744
Part A Dose 6	BEN8744	Part A Dose 6 Single dose of 120 mg BEN8744
Part B Dose 1 fed	BEN8744	Part B Dose 1 Fed Single dose of BEN8744 after high-fat meal (Dose 30mg QD)
Part B Dose 1 Fasted	BEN8744	Part B Dose 1 Fasted Single dose of BEN8744 after 10 hours fasting (Dose 30mg QD)
Part B Dose 2 Fed	BEN8744	Part B Dose 2 Fed Single dose of BEN8744 after high-fat meal (Dose 50mg QD)
Part C Dose 2	BEN8744	Part C Dose 2 14 daily doses of BEN8744 (Dose 50mg BID)

Primary Outcome Measures

Name	Time	Method
AUC72 (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Area under the plasma concentration-time curve from time 0 to 72 hours postdose. Calculated from plasma concentrations at time points below.
%AUCextrap (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Percentage of AUCinf extrapolated from time of last measurable concentration to infinity. Calculated from plasma concentrations collected at time points below.
Change From Baseline in Visual Analogue Scale (VAS) (Part C)	From Baseline (predose on Day 1) through 48 hours postdose	The participant graded level of alertness by placing a mark on a linear scale from 0 (very alert) to 100 (very drowsy). Negative change is a better outcome; positive change is a worse outcome.
Columbia-Suicide Severity Rating Scale (C-SSRS) (Part C)	Completed during screening and on Days 17 and 24	The C-SSRS is a questionnaire completed by the Investigator, who asks yes/no questions of the participant It I used to categorise risk levels based on the responses.
AUCinf (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Area under the plasma concentration-time curve from time 0 to infinity. Calculated from plasma concentrations at time points below.
t1⁄2 (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Terminal half-life. Calculated from plasma concentrations at time points below.
Terminal Rate Constant (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Calculated from plasma concentrations at time points below.
Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part A)	From Baseline (predose on Day 1) through 72 hours postdose	The investigator/designee scored the participant's level of alertness on a scale of 0 (absence of response to stimulus) to 5 (readily responsive to the subject's name in a normal tone) in each of 4 components (responsiveness, speech, facial expression, eyes). The composite score corresponds to the lowest score for any component. The sum is the sum of the 4 component scores, ranging from 9 to 20. Positive change in composite score or sum is a better outcome; negative change is a worse outcome.
Change From Baseline in Visual Analogue Scale (VAS) (Part A)	From Baseline (predose on Day 1) through 72 hours postdose	The participant graded level of alertness by placing a mark on a linear scale from 0 (very alert) to 100 (very drowsy). Negative change is a better outcome; positive change is a worse outcome.
Cmax (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Maximum (peak) plasma concentration. Calculated from plasma concentrations at time points below.
Tmax (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Time to reach maximum (peak) plasma concentration. Calculated from plasma concentrations at time points below.
AUC24 (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose in each of the 2 treatment periods (fasted and fed)	Area under the plasma concentration-time curve from time 0 to 24 hours postdose. Calculated from plasma concentrations at time points below.
AUClast (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Area under the plasma concentration-time curve from time zero to time of last measurable concentration. Calculated from plasma concentrations at time points below.
VZ/F (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Apparent volume of distribution relative to absolute bioavailability. Calculated from plasma concentrations at time points below.
CL/F (PK Part B)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)	Systemic clearance relative to absolute bioavailability. Calculated from plasma concentrations at time points below.
Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part C)	From Baseline (predose on Day 1) through 48 hours postdose	The investigator/designee scored the participant's level of alertness on a scale of 0 (absence of response to stimulus) to 5 (readily responsive to the subject's name in a normal tone) in each of 4 components (responsiveness, speech, facial expression, eyes). The composite score corresponds to the lowest score for any component. The sum is the sum of the 4 component scores, ranging from 9 to 20. Positive change in composite score or sum is a better outcome; negative change is a worse outcome.

Secondary Outcome Measures

Name	Time	Method
Tmax (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Time to reach maximum (peak) plasma concentration. Calculated from plasma concentrations at time points below.
AUC72 (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Area under the plasma concentration-time curve from time 0 to 72 hours postdose. Calculated from plasma concentrations at time points below.
Terminal Rate Constant (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Calculated from plasma concentrations at time points below.
Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part B)	From Baseline (predose on Day 1) through 72 hours postdose	The investigator/designee scored the participant's level of alertness on a scale of 0 (absence of response to stimulus) to 5 (readily responsive to the subject's name in a normal tone) in each of 4 components (responsiveness, speech, facial expression, eyes). The composite score corresponds to the lowest score for any component. The sum is the sum of the 4 component scores, ranging from 9 to 20. Positive change in composite score or sum is a better outcome; negative change is a worse outcome.
Ctrough (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Trough plasma concentration. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
AUClast (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Area under the plasma concentration-time curve from time 0 to time of last measurable concentration. Calculated from plasma concentrations at time points below.
%AUCextrap (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Percentage of AUCinf extrapolated from time of last measurable concentration to infinity. Calculated from plasma concentrations at time points below.
t1⁄2 (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Terminal half-life. Calculated from plasma concentrations at time points below.
Cmax (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Maximum (peak) plasma concentration. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
Cmax (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Maximum (peak) plasma concentration. Calculated from plasma concentrations at time points below.
AUC24 (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours postdose	Area under the plasma concentration-time curve from time 0 to 24 hours postdose. Calculated from plasma concentrations at time points below.
AUCinf (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Area under the plasma concentration-time curve from time 0 to infinity. Calculated from plasma concentrations at time points below.
CL/F (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Systemic clearance relative to absolute bioavailability. Calculated from plasma concentrations at time points below.
VZ/F (PK Part A)	Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Apparent volume of distribution relative to absolute bioavailability. Calculated from plasma concentrations at time points below.
Tmax (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Time to reach maximum (peak) plasma concentration. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
Change From Baseline in Visual Analogue Scale (VAS) (Part B)	From Baseline (predose on Day 1) through 72 hours postdose	The participant graded level of alertness by placing a mark on a linear scale from 0 (very alert) to 100 (very drowsy). Negative change is a better outcome; positive change is a worse outcome.
AUCtau (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Area under the concentration-time curve across a dosing interval. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
AUClast (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Area under the concentration-time curve from time 0 to the last measurable timepoint. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
AUC72 (PK Part C)	At 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14	Area under the plasma concentration-time curve from time 0 to 72 hours postdose. Calculated from plasma concentrations measured at the time points below.
t1⁄2 (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Terminal half-life. Maximum (peak) plasma concentration. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
AUCinf (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Area under the plasma concentration-time curve from time 0 to infinity. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
%AUCextrap (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Percentage of AUCinf extrapolated from time of last measurable concentration to infinity. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
Terminal Rate Constant (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
CLSS/F (PK Part C)	Plasma concentrations measured at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14	Systemic clearance relative to bioavailability at steady state (Day 14). Calculated from plasma concentrations measured at the time points below.
VZ/F (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Apparent volume of distribution relative to absolute bioavailability (Day 14). Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
Rac(AUCtau) (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Area under the concentration-time curve over the dosing interval on Day 14/area under the concentration-time curve over the dosing interval on Day 1 in AM. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
Rac(Cmax) (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Maximum observed plasma concentration on Day 14/maximum observed plasma concentration on Day 1 in AM. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.
SR(AUC) (PK Part C)	Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)	Area under the concentration-time curve across a dosing interval on Day 14/area under the concentration-time curve from time 0 to infinity. Calculated from plasma concentrations measured before the morning dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20 and 24 hours after the morning dose on Day 1; before the morning dose on Days 3, 5, 7, 9, 11, and 13; and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14.