A Phase I Study to Assess PK of AZD7986 Alone & With Verapamil, Itraconazole or Diltiazem in Healthy Subjects

NCT02653872 | Completed Phase 1 Results

• 1 other identifier: D6190C00003
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 1, non-randomized, fixed sequence, 3-period, drug-drug interaction study to assess the pharmacokinetics (PK) of AZD7986 in healthy subjects when administered alone and in combination with multiple doses of verapamil and itraconazole or diltiazem

Conditions

Healthy Subjects

Keywords

Non-randomized; Verapamil; Itraconazole; Diltiazem; Safety; Tolerability; Pharmacokinetics

Outcome Measures

Primary Outcomes (9)

• Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax).

  To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC).

  To assess the effect of verapamil and itraconazole on the PK of AZD7986.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]).

  To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz).

  To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax)

  To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F).

  To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F).

  To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole.

  To assess the area under the plasma concentration-time curve from time over the dosing interval tau (24 hours) of Verapamil, itraconazole and OH-itraconazole (a metabolite of Itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

• Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole.

  To assess the time to reach maximum observed concentration of Verapamil, Itraconazole and OH-itraconazole (a metabolite of itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.

  Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Study Arms (4)

AZD7986 (alone) Treatment period 1

EXPERIMENTAL

AZD7986 (15 mg/mL) 25 mg dosage administered alone

Drug: AZD7986

Verapamil (with AZD7986) Treatment period 2

ACTIVE COMPARATOR

Daily administration of verapamil (240 mg, extended release formulation) on Days 1 to 10 plus administration of single dose AZD7986 (25 mg) on Day 5

Drug: AZD7986; Drug: Verapamil

Itraconazole (with AZD7986) Treatment Period 3

ACTIVE COMPARATOR

Itraconazole (200 mg, oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily Days 2 to 11 plus single dose AZD7986 (25 mg, tbc) on Day 6

Drug: AZD7986; Drug: Itraconazole

Diltiazem (with AZD7986) Treatment period 3

ACTIVE COMPARATOR

Diltiazem (360 mg, extended release formulation) administered Days 1 to 13 plus single dose AZD7986 (25 mg) on Day 8

Drug: AZD7986; Drug: Diltiazem

Interventions

AZD7986 DRUG

Oral solution, single dose, dilution from concentrate

AZD7986 (alone) Treatment period 1; Diltiazem (with AZD7986) Treatment period 3; Itraconazole (with AZD7986) Treatment Period 3; Verapamil (with AZD7986) Treatment period 2

Verapamil DRUG

Extended release tablet for oral use

Verapamil (with AZD7986) Treatment period 2

Itraconazole DRUG

Oral solution

Itraconazole (with AZD7986) Treatment Period 3

Diltiazem DRUG

Extended release capsule

Diltiazem (with AZD7986) Treatment period 3

Eligibility Criteria

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

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male and/or female subjects aged 18 to 55 years (inclusive) with suitable veins for cannulation or repeated venepuncture.
• Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria:
• Post-menopausal 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 post menopausal range(\> 40 milli-International unit \[mIU\]/mL).
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation.
• Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive.
• Provision of signed, written and dated informed consent for optional genetic/biomarker research.
• Hormone replacement therapy is not allowed for females to exclude any drug drug interaction between the hormone replacement therapy and AZD7986.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
• History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of AZD7986.
• Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator.
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
• Any clinically significant abnormal findings in vital signs after at least 10 minutes of rest, defined as the following:
• Systolic blood pressure \< 100 mmHg or \> 140 mmHg;
• Diastolic blood pressure \< 50 mmHg or \> 90 mmHg; or
• Pulse rate \< 50 or \> 85 beats per minute.
• Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12 Lead ECG as considered by the investigator that may interfere with the interpretation of ECG interval measured from the onset of the QRS complex (electrical activity or ventricular contraction on the ECG where Q represents the downward deflection, R represents upward deflection and S represents a downward one) to the end of the T wave corrected for heart rate (QTc) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.
• Prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF) \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome.
• PR (PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
• PR (PQ) interval prolongation \> 200 ms, intermittent second or third degree atrioventricular (AV) block (Wenckebach block while asleep is not exclusive), or AV dissociation.
• Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 110 ms. Subjects with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.
• Known or suspected history of drug abuse, as judged by the investigator.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

London, United Kingdom

Location

MeSH Terms

Interventions

brensocatib; Verapamil; Itraconazole; Diltiazem

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: AZD7986 Global Clinical Leader
• Organization: AstraZeneca AB

ClinicalTrialTransparency@astrazeneca.com

+46317761000

Study Officials

• Annelize Koch, MBChB, FFPM

  Parexel

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

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: January 11, 2016
• First Posted: January 12, 2016
• Study Start: January 22, 2016
• Primary Completion: April 13, 2016
• Study Completion: April 13, 2016
• Last Updated: February 23, 2018
• Results First Posted: February 23, 2018

Record last verified: 2017-07

Locations

GB (1)