Assessing the Effect of Multiple Doses of Zibotentan on the Pharmacokinetics of Single Doses of Combined Oral Contraceptives in Healthy Female Participants of Non-childbearing Potential.

NCT05505162 | Completed Phase 1 FDA Drug

• 1 other identifier: D4325C00006
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

A study to assess the Pharmacokinetics (PK) of combined oral ethinyl estradiol (EE) and levonorgestrel (LNG) in healthy female participants of non-child-bearing potential, when administered alone and in combination with multiple oral doses of zibotentan.

Conditions

Healthy Female Participants

Keywords

Ethinyl estradiol; Levonorgestrel; Zibotentan; Chronic Kidney Disease; Non-Child-Bearing Potential; Drug-drug interaction

Outcome Measures

Primary Outcomes (7)

• Area under plasma concentration time curve from zero to infinity (AUCinf)

  The effect of multiple doses of zibotentan on the PK of a single dose of combined oral EE and LNG in healthy female volunteers of non-child-bearing potential will be assessed.

  Day 1 and Day 15

• Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

  The effect of multiple doses of zibotentan on the PK of a single dose of combined oral EE and LNG in healthy female volunteers of non-child-bearing potential will be assessed.

  Day 1 and Day 15

• Maximum observed plasma (peak) drug concentration (Cmax)

  The effect of multiple doses of zibotentan on the PK of a single dose of combined oral EE and LNG in healthy female volunteers of non-child-bearing potential will be assessed.

  Day 1 and Day 15

• Terminal elimination half-life (t1/2λz)

  The effect of multiple doses of zibotentan on the PK of a single dose of combined oral EE and LNG in healthy female volunteers of non-child-bearing potential will be assessed.

  Day 1 and Day 15

• Time to reach maximum observed concentration (tmax)

  The effect of multiple doses of zibotentan on the PK of a single dose of combined oral EE and LNG in healthy female volunteers of non-child-bearing potential will be assessed.

  Day 1 and Day 15

• Apparent total body clearance of drug from plasma (CL/F)

  The effect of multiple doses of zibotentan on the PK of a single dose of combined oral EE and LNG in healthy female volunteers of non-child-bearing potential will be assessed.

  Day 1 and Day 15

• Apparent volume of distribution based on terminal phase (Vz/F)

  The effect of multiple doses of zibotentan on the PK of a single dose of combined oral EE and LNG in healthy female volunteers of non-child-bearing potential will be assessed.

  Day 1 and Day 15

Secondary Outcomes (4)

• Area under plasma concentration-time curve in the dose interval (AUCtau)

  Day 15

• Maximum observed plasma (peak) drug concentration (Cmax)

  Day 15

• Time to reach maximum observed concentration (tmax)

  Day 15

• Number of participants with adverse events

  Until Follow up visit (7 days +/-2 days after last PK sample)

Study Arms (1)

Zibotentan and EE/LNG

EXPERIMENTAL

Participants will receive two tablets of combined oral EE/LNG on Day 1 with PK samples obtained from pre-dose on Day 1 until post-dose on Day 6. Participants will receive two capsules of zibotentan orally QD from Day 6 to Day 14. From Day 15 until Day 19 participants will continue to receive two capsules of zibotentan QD administered orally. On Day 15, participants will receive two tablets of combined oral EE and LNG with PK samples obtained pre-dose on Day 15 until post-dose (Day 20).

Drug: Zibotentan; Drug: EE/LNG

Interventions

Zibotentan DRUG

Participants will receive two capsules of Zibotentan orally QD from day 6-19.

Zibotentan and EE/LNG

EE/LNG DRUG

Participants will receive two tablets of EE and LNG once on Day 1 and Day 15 as a combined oral dose.

Zibotentan and EE/LNG

Eligibility Criteria

• Age: 35 Years - 75 Years
• Gender Eligibility Details: Only females are recruited
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the protocol.
• Healthy female participants aged 35 to 75 years (inclusive) at Day -1 with suitable veins for cannulation or repeated venipuncture.
• Females must have a negative pregnancy test at screening and within 24 hours prior to dosing with EE/LNG on Day 1 and Day 15, must not be lactating and must be of non childbearing potential, confirmed at screening by fulfilling one of the following criteria:
• (i) Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the postmenopausal range \[FSH \> 40 mIU/mL\].
• (ii) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
• Have a body mass index (BMI) between 18.5 and 35 kg/m2 inclusive at Day -1.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study. Clinically significant diseases or disorders also include, but are not limited to:
• (i) Undiagnosed abnormal uterine bleeding, (ii) Current diagnosis of, or history of breast cancer, which may be hormone sensitive, (iii) Liver tumors, benign or malignant, or liver disease. Acute viral hepatitis, or severe (decompensated) cirrhosis or use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations.
• Sex hormone therapy within 1 month before study.
• Current diagnosis or history of arterial or venous thrombosis (eg, deep vein thrombosis (DVT), pulmonary embolism (PE)), or known heredity risk factors (eg, activated protein C resistance), or coronary artery disease.
• Have inherited or acquired hypercoagulopathy.
• Participants treated with strong or moderate Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 3 months or longer (5 half-lives) prior to first administration of IMP in this study.
• History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any laboratory values with the following deviations:
• (i) Alanine aminotransferase \> Upper limit of normal (ULN) (ii) Aspartate aminotransferase \> ULN (iii) estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73 m2 (iv) Creatinine \> 1.5 ULN (v) White blood cell count \< 3.5 x 109/L (vi) Hemoglobin \< lower limit of normal (LLN)
• Prolonged QT interval (QTcF \> 470 ms) on ECG at check in into the clinical unit on Day 1 of Treatment Period 1, known congenital long QT syndrome or history of QT prolongation associated with other medications.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to zibotentan.
• Participants who have received zibotentan within 1 month prior to Day 1 dosing.
• Any of the following signs or confirmation of COVID-19 infection:
• (i) Positive COVID-19 test result on check in into the clinical unit on Day -1 and on Day 14.
• (ii) Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnoea, sore throat, and fatigue) on check in into the clinical unit on Day 1.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Brooklyn, Maryland, 21225, United States

Location

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

ZD4054

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 16, 2022
• First Posted: August 17, 2022
• Study Start: August 24, 2022
• Primary Completion: January 10, 2023
• Study Completion: January 10, 2023
• Last Updated: February 9, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Locations

US (1)