Clinical trial NCT06547164: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Healthy Participants
Keywords: Midazolam
Camizestrant
Carbamazepine
Post-menopausal
Estrogen receptor (ER) positive disease
Breast Cancer
Cytochrome P450, family 3, subfamily A (CYP3A)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2024-08-09
Enrollment: 50
Sex: FEMALE
Minimum age (years): 50
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part A: Area under concentration-time curve from time 0 to infinity (AUCinf) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part A: Area under concentrationcurve from time 0 to the last quantifiable concentration (AUClast) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part A: Maximum observed plasma (peak) drug concentration (Cmax) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part B: Area under concentration-time curve from time 0 to infinity (AUCinf) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
measure: Part B: Area under concentrationcurve from time 0 to the last quantifiable concentration (AUClast) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
measure: Part B: Maximum observed plasma (peak) drug concentration (Cmax) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
Secondary outcomes:
measure: Part A: Time to reach maximum observed concentration (tmax) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part A: Terminal elimination half-life (t½λz) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part A: Terminal rate constant (λz) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part A: Apparent total body clearance (CL/F) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part A: Apparent volume of distribution based on the terminal phase (Vz/F) of midazolam
timeFrame: Period 1 (Day 1) and Period 3 (Day 7 to Day 8)
measure: Part A: Plasma concentration of camizestrant
timeFrame: Period 3: Pre-dose and 3 hours post-dose of Day 7 and Day 8
measure: Part B: Time to reach maximum observed concentration (tmax) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
measure: Part B: Terminal elimination half-life (t½λz) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
measure: Part B: Terminal rate constant (λz) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
measure: Part B: Apparent total body clearance (CL/F) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
measure: Part B: Apparent volume of distribution based on the terminal phase (Vz/F) of camizestrant
timeFrame: Period 1 (Day 1 to Day 4), Period 2 (Day 22 to Day 25)
measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: 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
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
References: