A Study to Investigate the Pharmacokinetics of Midazolam After Repeated Doses of Camizestrant (AZD9833) and to Investigate the Pharmacokinetics of Camizestrant When Administered Alone and in Combination With Carbamazepine in Healthy Post-Menopausal Female Participants

A Phase I, Open-label, 2 Part, Fixed Sequence Study to Assess the Effect of Co-administration of Camizestrant (AZD9833) on the Pharmacokinetics of Midazolam Exposure (CYP3A4/5 Substrate) and of Carbamazepine (CYP3A4/5 Inducer) on Camizestrant Exposure in Healthy Post Menopausal Female Participants

This study will be conducted in order to determine the effect of repeated oral doses of camizestrant on the pharmacokinetics (PK) of midazolam and to determine the effect of repeated oral titrated doses of carbamazepine on the PK of camizestrant in healthy post-menopausal female participants.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: Midazolam; Drug: Camizestrant; Drug: Carbamazepine

Detailed Description

This is an open-label, fixed sequence, 2-part (Part A and Part B), drug-drug interaction study in healthy post-menopausal female participants. Participants enrolled in Part A may subsequently also participate in Part B.

Part A of the study will assess the effect of repeated oral doses of camizestrant on the PK of a single oral dose of midazolam. It will comprise:

• A Screening Period of maximum 28 days.

• Three Treatment Periods during which participants will be resident at the Clinical Unit from the day before study intervention administration (Day -1) until after the last camizestrant PK sample on Day 8.

  1. Period 1: participants will receive a single oral dose of midazolam (Day 1).
  2. Period 2: participants will receive an oral once daily (OD) dose of camizestrant (Day 2 to Day 6).
  3. Period 3: participants will receive a single oral dose of midazolam and camizestrant (Day 7).
• A Follow-up Visit, for which the participant will return to the Clinical Unit 7 (± 2) days after the last camizestrant PK sample in Period 3.

Part B of the study will assess the effect of multiple oral doses of carbamazepine on the PK of a single oral dose of camizestrant. It will comprise:

• A Screening Period of maximum 28 days.

• Two Treatment Periods during which participants will be resident at the Clinical Unit from the day before study intervention administration (Day -1) until after the last camizestrant PK sample on Day 16.

  1. Period 1: participants will receive a single oral dose of camizestrant (Day 1) with PK sampling on Day 1 to Day 4.
  2. Period 2: participants will receive low oral doses (Dose 1) of carbamazepine twice a day (BID) on Day 4 to Day 6, mid oral doses (Dose 2) of carbamazepine BID on Day 7 to Day 9, and high oral doses (Dose 3) of carbamazepine BID on Day 10 to Day 15. On Day 13, participants will receive a single oral dose of camizestrant.
• A Follow-up Visit, for which the participant will return to the Clinical Unit 7 (± 2) days after the last camizestrant PK sample in Period 2.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Harrow, United Kingdom, HA1 3UJ
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy post-menopausal female participants with suitable veins for cannulation or repeated venipuncture.
• Female participants must be post-menopausal as confirmed at the Screening Visit. Post-menopausal defined as amenorrhoea for at least 12 months or more without an alternative medical or surgical cause and confirmed by a follicle stimulating hormone (FSH) result of ≥ 30 Internation units/liter (IU/L).
• Have a body mass index between 19 and 35 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
• Must agree to not use warfarin or phenytoin (and other coumarin-derived vitamin K antagonist anticoagulants) during the study, and for 2 weeks after last administration of study intervention.

Exclusion Criteria:

• History of any clinically important disease or disorder.
• History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• History of any clinically significant cardiovascular, chronic respiratory disease, haematological, neurological or psychiatric disorder.
• History of acute pulmonary insufficiency marked neuromuscular respiratory weakness, obsessional states, phobic states, sleep apnoea syndrome, and unstable myasthenia gravis.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
• Any clinically important abnormalities in clinical chemistry, haematology, or urinalysis results.
• Any relevant history or known risk factors of QT prolongation or have received drugs known to prolong QT interval.
• Any positive result for serum Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV).
• History of or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to camizestrant or the formulation excipients.
• Presence of any contraindication to the probe substrate carbamazepine.
• Presence of any contraindication to midazolam.
• Have any active indication for therapeutic anticoagulation, and/or having taken an anticoagulant within 14 days of Screening Visit.
• Part B only: Participants identified to carry human leukocyte antigen (HLA)-A*3101 and/or HLA-B*1502 allele.
• Participants with bone marrow suppression or a history of bone marrow suppression or aplastic anaemia.
• History of or ongoing clinically significant visual disturbances including but not limited to visual hallucinations, migraine with visual symptoms, blurred vision, frequent floaters/flashes associated with other symptoms such as dizziness.
• Participants with family history of glaucoma or closed angle glaucoma or participants who are currently on anticholinergic medications.
• Participants with an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the participation in the study.
• Vulnerable participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Midazolam + Camizestrant; Participants will receive a single oral dose of midazolam on Day 1 in Period 1, followed by oral dose of camizestrant OD from Day 2 to Day 6 in Period 2, and then single oral dose of midazolam with camizestrant on Day 7 with PK sampling on Day 7 to Day 8 in Period 3.	Drug: Midazolam; Midazolam will be administered orally.; Drug: Camizestrant; Camizestrant will be administered orally.; Other Names: AZD9833
Experimental: Part B: Camizestrant + Carbamazepine; Participants will receive a single oral dose of camizestrant on Day 1 with PK sampling on Day 1 to Day 4 in Period 1, followed by low oral doses of carbamazepine BID on Day 4 to Day 6, mid oral doses of carbamazepine BID on Day 7 to Day 9 and high oral doses of carbamazepine BID on Day 10 to Day 15 with single oral dose of camizestrant on Day 13 with PK sampling on Day 16 in Period 2.	Drug: Camizestrant; Camizestrant will be administered orally.; Other Names: AZD9833; Drug: Carbamazepine; Carbamazepine will be administered orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Area under concentration-time curve from time 0 to infinity (AUCinf) of midazolam	To determine the effect of repeated oral doses of camizestrant on the key PK parameters of a single oral dose of midazolam in healthy postmenopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part A: Area under concentrationcurve from time 0 to the last quantifiable concentration (AUClast) of midazolam	To determine the effect of repeated oral doses of camizestrant on the key PK parameters of a single oral dose of midazolam in healthy postmenopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part A: Maximum observed plasma (peak) drug concentration (Cmax) of midazolam	To determine the effect of repeated oral doses of camizestrant on the key PK parameters of a single oral dose of midazolam in healthy postmenopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part B: Area under concentration-time curve from time 0 to infinity (AUCinf) of camizestrant	To determine the effect of repeated oral titrated doses of carbamazepine on the PK of a single oral dose of camizestrant in healthy postmenopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Part B: Area under concentrationcurve from time 0 to the last quantifiable concentration (AUClast) of camizestrant	To determine the effect of repeated oral titrated doses of carbamazepine on the PK of a single oral dose of camizestrant in healthy postmenopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Part B: Maximum observed plasma (peak) drug concentration (Cmax) of camizestrant	To determine the effect of repeated oral titrated doses of carbamazepine on the PK of a single oral dose of camizestrant in healthy postmenopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Time to reach maximum observed concentration (tmax) of midazolam	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part A: Terminal elimination half-life (t½λz) of midazolam	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part A: Terminal rate constant (λz) of midazolam	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part A: Apparent total body clearance (CL/F) of midazolam	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part A: Apparent volume of distribution based on the terminal phase (Vz/F) of midazolam	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
Part A: Plasma concentration of camizestrant	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 3: Pre-dose and 3 hours post-dose of Day 7 and Day 8
Part B: Time to reach maximum observed concentration (tmax) of camizestrant	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Part B: Terminal elimination half-life (t½λz) of camizestrant	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Part B: Terminal rate constant (λz) of camizestrant	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Part B: Apparent total body clearance (CL/F) of camizestrant	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Part B: Apparent volume of distribution based on the terminal phase (Vz/F) of camizestrant	To further characterise the effect of camizestrant on the PK of midazolam, and the effect of carbamazepine on the PK of camizestrant, in healthy post-menopausal female participants.	Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Number of participants with adverse events (AEs) and serious adverse events (SAEs)	To evaluate the safety and tolerability of camizestrant, alone and in combination with midazolam and carbamazepine, respectively, in healthy post-menopausal female participants.	For SAEs - Part A: From screening (Day -28 to Day -2) to 7 weeks; Part B: From screening (Day -28 to Day -2) to 9 weeks. For AEs: Part A: From Day 1 to 7 weeks; Part B: From Day 1 to 9 weeks

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2024
• Primary Completion (Actual): August 20, 2025
• Study Completion (Actual): August 20, 2025

Study Registration Dates

• First Submitted: August 7, 2024
• First Submitted That Met QC Criteria: August 7, 2024
• First Posted (Actual): August 9, 2024

Study Record Updates

• Last Update Posted (Estimated): September 4, 2025
• Last Update Submitted That Met QC Criteria: September 3, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Breast Cancer; Post-menopausal; Midazolam; Carbamazepine; Camizestrant; Estrogen receptor (ER) positive disease; Cytochrome P450, family 3, subfamily A (CYP3A)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzazepines; Benzodiazepines; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Midazolam; Carbamazepine; AZD9833
• Other Study ID Numbers: D8532C00006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

"Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No