A Phase I Study in Healthy Volunteers to Assess the Effect of Cytochrome3A4 (CYP3A4) Inhibitors (Diltiazem and Itraconazole) on the Pharmacokinetics (PK) of AZD3293 and the Effects of AZD3293 on the Pharmacokinetics of Midazolam, a Cytochrome 3A4 and Cytochrome 3A5 (CYP3A4/CYP3A5) Substrate

NCT02010970 | Completed Phase 1

• 1 other identifier: D5010C00004
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a single-center, open-label, 3-group, fixed-sequence drug-drug interaction study to assess the effect of coadministration of multiple-dose itraconazole or diltiazem on the single-dose PK of AZD3293 and the effects of coadministration of single- and multiple-dose AZD3293 on the single-dose PK of midazolam. The study will also evaluate the safety and tolerability of single and multiple oral doses of AZD3293, alone and in combination with itraconazole, diltiazem, and midazolam in healthy young subjects.AZD3293 is being developed for the treatment of Alzheimer's disease

Conditions

Healthy Volunteers; Pharmacologic Action

Keywords

phase I; healthy volunteers; AZD3293; itraconazole; diltiazem; medazolam; drug interactions; Pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• The effect of multiple-dose co-administration of CYP3A4 inhibitors on the single-dose PK of AZD3293 measured by assessment of area under the curve over the time (AUC) and maximum concentration

  In Group 1, serial blood samples for AZD3293 plasma concentrations will be collected from predose to 96 hours after administration of AZD3293 on Day 1 and from predose to 144 hours after study drug administration on Day 8. Sparse blood samples for itraconazole plasma concentrations will be collected at predose (prior to administration of AZD3293) on Day 1 and 2 hours after the morning dose of itraconazole on Day 5 through Day 13. In Group 2, serial blood samples for AZD3293 plasma concentrations will be collected from predose to 96 hours after administration of AZD3293 on Day 1 and from predose to 144 hours after study drug administration on Day 8. Sparse blood samples for diltiazem plasma concentrations will be collected at predose (prior to administration of AZD3293) on Day 1 and 3 hours after diltiazem administration on Day 5 through Day 13.

  up to day 13

• The effect of multiple-dose AZD3293 administration (including the reversibilityof any of its effects) on the single-dose PK of a CYP3A4/CYP3A5 substrate (midazolam) by assessment of area under the curve over the time (AUC) and maximum concentration

  Serial blood samples for midazolam plasma concentrations will be collected from predose to 24 hours after administration of midazolam on Day 1 and Day 17 and for 48 hours after administration of midazolam on Day 8. Sparse blood samples for AZD3293 plasma concentrations will be collected at predose (prior to administration of midazolam) on Day 1 and 2 hours after AZD3293 administration on Day 2 through Day 10.

  up to day 17

Secondary Outcomes (6)

• Safety profile in terms of Adverse events assessment

  from Baseline and up to day 18

• Safety and tolerability in terms of lab tests assessment (hematology, chemistry, urinalysis)

  from Baseline and up to day 18

• Safety and tolerability in terms of vital signs assessment (blood pressure, pulse and body temperature) and physical exams

  from baseline and up till day 18

• Safety and tolerability by assessing changes in electrocardiogram (ECG) parameters

  from Baseline and up to day 18

• Safety and tolerability by assessing telemetry records

  from baseline and up to day 13

Study Arms (3)

Group 1 AZD3293-itraconazole

EXPERIMENTAL

Subjects from Group 1 will receive a single dose of AZD3293 as an oral solution on Day 1 . In Group 1, itraconazole will be administered orally twice daily starting on Day 5 for 9 consecutive days (Days 5 to 13). On Day 8, a single dose of AZD3293 will be coadministered as an oral solution after the morning dose of itraconazole. Group 1 subjects will be discharged on Day 14.

Drug: Group 1 AZD3293; Drug: Group 1 Itraconazole

Group 2 AZD3293-diltiazem

EXPERIMENTAL

Subjects from Group 2 will receive a single dose of AZD3293 as an oral solution on Day 1 . In Group 2, diltiazem will be administered orally once daily starting on Day 5, for 9 consecutive days (Days 5 to 13). On Day 8, a single dose of AZD3293 will be coadministered as an oral solution after the diltiazem dose. Group 2 subjects will be discharged on Day 14.

Drug: Group 2 AZD3293; Drug: Group 2 Diltiazem

Group 3 AZD3293-midazolam

EXPERIMENTAL

Subjects from Group 3 will receive a single dose of midazolam on Day 1 . AZD3293 will be administered as an oral solution once daily starting on Day 2 for 9 consecutive days (Days 2 to 10) followed by a 7 day wash-out period. On Day 8 and Day 17 a single dose of midazolam will be administered. Group 3 subjects will be discharged on Day 18

Drug: Group 3 AZD3293; Drug: Group 3 Midazolam

Interventions

Group 1 AZD3293 DRUG

AZD3293 oral solution

Also known as: beta secretase inhibitor

Group 1 AZD3293-itraconazole

Group 2 AZD3293 DRUG

AZD3293 oral solution

Also known as: beta secretase inhibitor

Group 2 AZD3293-diltiazem

Group 3 AZD3293 DRUG

AZD3293 oral solution

Also known as: beta secretase inhibitor

Group 3 AZD3293-midazolam

Group 1 Itraconazole DRUG

itraconazole capsule

Also known as: azole antifungal

Group 1 AZD3293-itraconazole

Group 2 Diltiazem DRUG

Diltiazem ER tablet

Also known as: calcium channel blocker

Group 2 AZD3293-diltiazem

Group 3 Midazolam DRUG

midazolam syrup

Also known as: benzodiazepine

Group 3 AZD3293-midazolam

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed, written, and dated informed consent prior to any study-specific procedures Male and nonfertile female healthy subjects, aged 18 to 55 years at the time of consent
• Body weight ≥50 to ≤100 kg and body mass index (BMI) ≥19 to ≤30 kg/m2
• Clinically normal findings on physical examination in relation to age, as judged by the Investigator
• Male healthy subjects must be willing to use barrier contraception, ie, condoms, even if their partners are post-menopausal, surgically sterile, or using accepted contraceptive methods, from the first day of dosing until 3 months after the last dose of investigational product (IP)

You may not qualify if:

• Participation in any prior study of AZD3293
• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may put the subject at risk because of participation in the study, may influence the results, or may limit the subject's ability to participate in the 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
• History of previous or ongoing psychiatric disease/condition including psychosis, affective disorder, anxiety disorder, borderline state and personality disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV), as assessed by the Mini-International Neuropsychiatric Interview (MINI)

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Cypress, California, United States

Location

MeSH Terms

Interventions

Calcium Channel Blockers; Benzodiazepines

Intervention Hierarchy (Ancestors)

Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Cardiovascular Agents; Therapeutic Uses; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Apinya Vutikullird, DO

  WCCT Global

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2013
• First Posted: December 13, 2013
• Study Start: December 1, 2013
• Primary Completion: February 1, 2014
• Study Completion: February 1, 2014
• Last Updated: April 28, 2014

Record last verified: 2014-04

Locations

US (1)