A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ESN364 in Healthy Japanese Male and Pre- and Post-menopausal Female Subjects

Healthy Subjects Clinical Trial

Official title:

Phase 1 Study of ESN364 - Placebo-controlled, Single and Multiple Oral Dose Study in Healthy Japanese Male and Healthy Japanese Pre- and Postmenopausal Female Subjects -

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03436849
• Other study ID #: 2693-CL-0020
• Status: Completed
• Phase: Phase 1
• Start date: February 22, 2018
• Est. completion date: May 23, 2018

Study information

• Verified date: April 2019
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and tolerability of single and multiple oral doses of ESN364 in healthy Japanese male and pre- and post-menopausal female subjects. This study will also evaluate the pharmacokinetics (PK) of ESN364 and its metabolite, and the pharmacodynamics (PD) of ESN364 after single and multiple oral doses administration in healthy Japanese male and pre- and post-menopausal female subjects.

Description:

This study consists of two parts. Part 1; Single Dose (SD) and Part 2; Single and Multiple Dose (SD and MD).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: May 23, 2018
• Est. primary completion date: May 23, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 64 Years

Eligibility

Inclusion Criteria:

• Male subject between 20 to < 45 years of age, or female subject between 20 to < 65 years of age.

• Body weight at screening: = 50.0 kg and < 80.0 kg for male, = 40.0 kg and < 70.0 kg for female.

• Body mass index (BMI) at screening: range of = 17.6 kg/m2 and < 26.4 kg/m2 [BMI = Body weight (kg) ÷ {Body height (m)2}].

Exclusion Criteria:

• Subjects who participated or are scheduled to participate in any clinical trials or post-marketing studies within 84 days prior to screening.

• Subject has had previous exposure with ESN364.

• Subject has any clinically significant history of allergic conditions prior to study drug administration.

• Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy.

• Subject has contracted pyretic or symptomatic viral, bacterial, or fungal infection within 7 days prior to hospital admission.

• Any deviation from the normal range of blood pressure, pulse, body temperature, or routine 12-lead ECG at screening or on the day of hospital admission.

• Subjects who has any significantly abnormal results of laboratory tests at screening or on the day of hospital admission.

• Subjects who are positive for any of urinary drug abuse test or serology test at screening.

• Subject took a drug or underwent therapy within 2 weeks prior to hospital admission.

• Subjects used a drug or underwent therapy that affects sex hormones within 3 months prior to hospital admission.

• Subjects who had bilateral orchiectomy.

• Subject has used any inducer of metabolism in the 3 months prior to hospital admission.

• Subject has a history of smoking more than 10 cigarettes per day within 3 months prior to screening test.

• Subject consumes, on average, more than approximately 500 mg/day of caffeine

• Subject has a history of consuming more than 30 units of alcoholic beverages per week within 6 months prior to screening or has a history of alcoholism or drug/chemical/ substance abuse within past 2 years prior to screening.

• Subjects who conducted or is scheduled to conduct any blood donation or blood drawing.

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• ESN364
ESN364 will be administered orally.
• Placebo
Placebo will be administered orally.

Locations

Country	Name	City	State
Japan	Site JP00001	Fukuoka

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Inc

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety assessed by incidence of adverse events (AEs) in Part 1	AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA).	Up to Day 12 in Part 1
Primary	Safety assessed by incidence of AEs in Part 2	AEs will be coded using MedDRA.	Up to Day 24 in Part 2
Primary	Safety assessed by vital signs: Body temperature in Part 1	To assess vital signs as a criterion of safety variables.	Up to day 12 in Part 1
Primary	Safety assessed by vital signs: Body temperature in Part 2	To assess vital signs as a criterion of safety variables.	Up to Day 24 in Part 2
Primary	Safety assessed by vital signs: Blood pressure in Part 1	To assess vital signs as a criterion of safety variables.	Up to Day 12 in Part 1
Primary	Safety assessed by vital signs: Blood pressure in Part 2	To assess vital signs as a criterion of safety variables.	Up to Day 24 in Part 2
Primary	Safety assessed by vital signs: Pulse rate in Part 1	To assess vital signs as a criterion of safety variables.	Up to Day 12 in Part 1
Primary	Safety assessed by vital signs: Pulse rate in Part 2	To assess vital signs as a criterion of safety variables.	Up to Day 24 in Part 2
Primary	Safety assessed by laboratory test: Hematology in Part 1	To assess laboratory values as a criterion of safety variables. Potentially clinically significant laboratory values will be reported as AEs.	Up to Day 12 in Part 1
Primary	Safety assessed by laboratory test: Hematology in Part 2	To assess laboratory values as a criterion of safety variables. Potentially clinically significant laboratory values will be reported as AEs.	Up to Day 24 in Part 2
Primary	Safety assessed by laboratory test: Biochemistry in Part 1	To assess laboratory values as a criterion of safety variables. Potentially clinically significant laboratory values will be reported as AEs.	Up to Day 12 in Part 1
Primary	Safety assessed by laboratory test: Biochemistry in Part 2	To assess laboratory values as a criterion of safety variables. Potentially clinically significant laboratory values will be reported as AEs.	Up to Day 24 in Part 2
Primary	Safety assessed by laboratory test: Urinalysis in Part 1	To assess laboratory values as a criterion of safety variables. Potentially clinically significant laboratory values will be reported as AEs.	Up to Day 12 in Part 1
Primary	Safety assessed by laboratory test: Urinalysis in Part 2	To assess laboratory values as a criterion of safety variables. Potentially clinically significant laboratory values will be reported as AEs.	Up to Day 24 in Part 2
Primary	Safety assessed by standard 12-lead electrocardiogram (ECG) in Part 1	Subjects should keep rest for 5 minutes before evaluation. Any clinically significant adverse changes on the ECG will be reported as AEs.	Up to Day 12 in Part 1
Primary	Safety assessed by standard ECG in Part 2	Subjects should keep rest for 5 minutes before evaluation. Any clinically significant adverse changes on the ECG will be reported as AEs.	Up to Day 24 in Part 2
Primary	Safety assessed by ECG parameters: Heart rate in Part 1	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing in Part 1
Primary	Safety assessed by ECG parameters: Heart rate in Part 2	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing on Day 10 in multiple dose (MD) of Part 2
Primary	Safety assessed by ECG parameters: QT interval in Part 1	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing in Part 1
Primary	Safety assessed by ECG parameters: QT interval in Part 2	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing on Day 10 in MD of Part 2
Primary	Safety assessed by ECG parameters: RR interval in Part 1	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing in Part 1
Primary	Safety assessed by ECG parameters: RR interval in Part 2	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing on Day 10 in MD of Part 2
Primary	Safety assessed by ECG parameters: PR interval in Part 1	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing in Part 1
Primary	Safety assessed by ECG parameters: PR interval in Part 2	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing on Day 10 in MD of Part 2
Primary	Safety assessed by ECG parameters: QRS interval in Part 1	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing in Part 1
Primary	Safety assessed by ECG parameters: QRS interval in Part 2	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing on Day 10 in MD of Part 2
Primary	Safety assessed by ECG parameters: QTc interval corrected by Fridericia method (QTcF) in Part 1	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing in Part 1
Primary	Safety assessed by ECG parameters: QTcF in Part 2	To assess ECG parameters as a criterion of safety variables.	Up to 24 hr after dosing on Day 10 in MD of Part 2
Primary	Safety assessed by body weight in Part 1	To assess body weight as a criterion of safety variables	Up to Day 3 in Part 1
Primary	Safety assessed by body weight in Part 2	To assess body weight as a criterion of safety variables	Up to Day 15 in Part 2
Primary	Safety assessed by menstrual cycle in pre-menopausal females	To assess menstrual cycle as a criterion of safety variables	Up to an average of two weeks after last dosing
Secondary	Pharmacokinetics (PK) parameter for ESN364 and its metabolite: Area under the concentration-time curve (AUC) from the time of dosing to time 24 h (AUC24) in plasma	To assess the PK of ESN364 and its metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2
Secondary	PK parameter for ESN364 and its metabolite: AUC from the time of dosing extrapolated to time infinity (AUCinf) in plasma	To assess the PK of ESN364 and its metabolite4 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2
Secondary	PK parameter for ESN364 and its metabolite: Percentage of AUCinf (AUCinf(%extrap)) in plasma	To assess the PK of ESN364 and its metabolite in Part 1.	Up to 48 hr after dosing in Part 1
Secondary	PK parameter for ESN364 and its metabolite: AUC from the time of dosing to the last measurable concentration (AUClast) in plasma	To assess the PK of ESN364 and its metabolite in Part 1.	Up to 48 hr after dosing in Part 1
Secondary	PK parameter for ESN364 and its metabolite: Maximum concentration (Cmax) in plasma	To assess the PK of ESN364 and its metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: Apparent total clearance after extra-vascular dosing (CL/F) in plasma	To assess the PK of ESN364 and its metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: Time point prior to the time point corresponding to the first measurable (non-zero) concentration (tlag) in plasma	To assess the PK of ESN364 and its metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: Time of the maximum concentration: (tmax) in plasma	To assess the PK of ESN364 and its metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: Terminal elimination half-life (t1/2) in plasma	To assess the PK of ESN364 and its metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: volume of distribution during the terminal elimination phase after extra-vascular dosing (Vz/F) in plasma	To assess the PK of ESN364 and its metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 metabolite: Metabolite to parent ratio (MPR) in plasma	To assess the PK of ESN364 metabolite in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: AUC from the time of dosing to the start of the next dosing interval (AUCtau) in plasma	To assess the PK of ESN364 and its metabolite in Part 2.	Up to 48 hr after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: Peak-trough ratio (PTR) in plasma	To assess the PK of ESN364 and its metabolite in Part 2.	Up to 48 hr after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: Accumulation ratio calculated using AUC (Rac(AUC)) in plasma	To assess the PK of ESN364 and its metabolite in Part 2.	Up to 48 hr after dosing on Day 10 in MD part of Part 2
Secondary	PK parameter for ESN364 and its metabolite: Concentration immediately prior to dosing at multiple dosing (Ctrough) in plasma	To assess the PK of ESN364 and its metabolite in Part 2.	Before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Secondary	Pharmacodynamic (PD) endpoint for ESN364: Luteinizing hormone (LH) level in plasma	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC12 for LH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC24 for LH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC48 for LH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: Cmin for LH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: tmin for LH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC from the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) for LH level	To assess the PD of ESN364 in Part 2.	Before dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Cpredose for LH level	To assess the PD of ESN364 in Part 1 and Part 2.	Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Follicle stimulating hormone (FSH) level in plasma	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC12 for FSH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC24 for FSH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC48 for FSH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: Cmin for FSH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: tmin for FSH level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUCtau for FSH level	To assess the PD of ESN364 in Part 2.	Before dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Cpredose for FSH level	To assess the PD of ESN364 in Part 1 and Part 2.	Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Sex hormone binding globulin (SHBG) level in plasma	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC12 for SHBG level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC24 for SHBG level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC48 for SHBG level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: Cmin for SHBG level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: tmin for SHBG level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUCtau for SHBG level	To assess the PD of ESN364 in Part 2.	Before dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Cpredose for SHBG level	To assess the PD of ESN364 in Part 1 and Part 2.	Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Total testosterone (TT) level in plasma	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC24 for TT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC12 for TT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC48 for TT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: Cmin for TT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: tmin for TT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUCtau for TT level	To assess the PD of ESN364 in Part 2.	Before dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Cpredose for TT level	To assess the PD of ESN364 in Part 1 and Part 2.	Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Free testosterone (FT) level in plasma	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC12 for FT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC24 for FT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC48 for FT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
Secondary	PD endpoint for ESN364: Cmin for FT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: tmin for FT level	To assess the PD of ESN364 in Part 1 and Part 2.	Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUCtau for FT level	To assess the PD of ESN364 in Part 2.	Before dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Cpredose for FT level	To assess the PD of ESN364 in Part 1 and Part 2.	Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Estradiol (E) level in plasma	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC12 for E level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC24 for E level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC48 for E level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2.
Secondary	PD endpoint for ESN364: Cmin for E level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: tmin for E level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUCtau for E level	To assess the PD of ESN364 in female subjects in Part 2.	Before dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Cpredose for E level	To assess the PD of ESN364 in female subjects in Part 2.	Before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Progesterone (P) level in plasma	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUC12 for P level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC24 for P level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2.
Secondary	PD endpoint for ESN364: AUC48 for P level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2.
Secondary	PD endpoint for ESN364: Cmin for P level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: tmin for P level	To assess the PD of ESN364 in female subjects in Part 2.	Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: AUCtau for P level	To assess the PD of ESN364 in female subjects in Part 2.	Before dosing on Day 10 in MD part of Part 2
Secondary	PD endpoint for ESN364: Cpredose for P level	To assess the PD of ESN364 in female subjects in Part 2.	Before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2