Evaluation of Pharmacokinetics and Safety of A006 in Healthy Volunteers (A006-D)

Evaluation of Pharmacokinetics and Safety of A006 in Healthy Volunteers (A Randomized, Double- or Evaluator-blinded, Single-dose, Four-arm, Crossover Pharmacokinetics (PK) Study in Healthy Adults)

The objective of this study is to evaluate the pharmacokinetics (PK) and safety profiles of A006, an Albuterol dry powder inhaler (DPI), following a single dose of 110 mcg (T1) or 220 mcg (T2), in healthy male and female adult volunteers.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: A006 DPI; Drug: A006 DPI; Drug: Proventil® MDI; Drug: Proventil® MDI

Detailed Description

This study is a randomized, double or evaluator-blinded, single dose, four-arm, crossover PK study in eighteen (18) healthy volunteers, both male and female adults, at 18-40 years of age.

All candidates will be screened and only those who satisfy all enrollment criteria will be enrolled into this study. Each study subject will participate in a screening visit and four (4) study visits with one (1) randomized study treatment given in each visit.

PK samples will be analyzed with an established LC/MS/MS method. An End-of-Study (EOS) safety evaluation will be conducted at the end of Study Visit-4.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Cypress, California, United States, 90630
      • Amphastar Site 0035

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Generally healthy, male and female adults, 18-40 years of age at Screening;
• Having no clinically significant respiratory, cardiovascular and other systemic or organic illnesses;
• Body weight ≥ 50 kg for men and ≥ 45 kg for women, and BMI within the range of 18.5 - 30.0 kg/m2 inclusive;
• Sitting blood pressure ≤ 135/90 mmHg;
• Demonstrating negative HIV, HBsAg and HCV tests, alcohol and nine panel urine drug screen tests;
• Demonstrating proficiency in the use of DPI and MDI or able to be trained in the proper use of these devices;
• Demonstrating Peak Inspiratory Flow Rate (PIF) within 80-150 L/min (after training), for at least 2 times consecutively, with a maximum of 5 attempts;
• Having no known hypersensitivity to any ingredients of A006 and Proventil® MDI (Albuterol, sulfate, lactose, milk protein, HFA-134a, oleic acid, or ethanol). (Subjects must be able to tolerate at least one teaspoon of milk);
• Women of child-bearing potential must be non-pregnant, non-lactating, and practicing a clinically acceptable form of birth control; and
• Having properly consented and satisfied all other inclusion/exclusion criteria as required for this protocol.

Exclusion Criteria:

• A smoking history of ≥ 5 pack-years, or having smoked within 6 months prior to Screening;
• Upper respiratory tract infections within 2 weeks, or lower respiratory tract infection within 4 weeks, prior to Screening;
• Previous history of asthma or COPD;
• Any current or recent respiratory conditions that, per investigator discretion, might significantly affect pharmacodynamic response to the study drugs, including cystic fibrosis, bronchiectasis, tuberculosis, emphysema, and other significant respiratory diseases;
• Concurrent clinically significant cardiovascular, hematological, renal, neurologic, hepatic, endocrine, psychiatric, malignant, or other illnesses that in the opinion of the investigator could impact on the conduct, safety and evaluation of the study;
• ECG at Screening and Visit-1 baseline expressed any single or multiple premature ventricular contractions (PVC);
• ECG at Screening and Visit-1 baseline with a QTc reading greater than 450ms;
• Use of prohibited drugs or failure to observe the drug washout restrictions; and
• Having been on other clinical drug/device studies or donated blood in the last 30 days prior to Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment T1; One inhalation of 110 mcg A006 DPI. Total 110 mcg	Drug: A006 DPI; Single dose 110 mcg, 1 inhalation; Other Names: Albuterol; Albuterol DPI; Drug: A006 DPI; Single dose 220 mcg, 1 inhalation; Other Names: Albuterol; Albuterol DPI
Experimental: Treatment T2; One inhalation of 220 mcg A006 DPI. Total 220 mcg.	Drug: A006 DPI; Single dose 110 mcg, 1 inhalation; Other Names: Albuterol; Albuterol DPI; Drug: A006 DPI; Single dose 220 mcg, 1 inhalation; Other Names: Albuterol; Albuterol DPI
Active Comparator: Treatment R1; One inhalation of 90 mcg Proventil® MDI. Total 90 mcg.	Drug: Proventil® MDI; Single dose 90 mcg, 1 inhalation; Other Names: Proventil®; Drug: Proventil® MDI; Single dose 90 mcg, 2 inhalations; Other Names: Proventil®
Active Comparator: Treatment R2; Two inhalations of 90 mcg Proventil® MDI. Total 180 mcg	Drug: Proventil® MDI; Single dose 90 mcg, 1 inhalation; Other Names: Proventil®; Drug: Proventil® MDI; Single dose 90 mcg, 2 inhalations; Other Names: Proventil®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve of Drug Concentration versus Time (AUC[0-t])	Subject PK blood samples will be taken prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period. PK samples will be analyzed using a validated test method. Area under the curve of the drug concentration versus time curve (AUC[0-t]) for each treatment period will be calculated using the trapezoidal rule.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
Peak Plasma Concentration (C[max])	Subject PK blood samples will be taken prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period. PK samples will be analyzed using a validated test method. Peak plasma concentration (C[max]) will be the highest concentration of Albuterol during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
Time to Reach Peak Plasma Concentration (t[max])	Subject PK blood samples will be taken prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period. PK samples will be analyzed using a validated test method. Time to reach peak plasma concentration (t[max]) will be the time it takes to reach the highest concentration of Albuterol during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
Plasma Albuterol Concentrations at All Time Points	Subject PK blood samples will be taken prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period. PK samples will be analyzed using a validated test method. Plasma Albuterol concentrations at these time points will be reported during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic Blood Pressure (SBP) at Screening	Subjects will have their vital signs, i.e., blood pressure and heart rate, measured during the Screening Visit to ensure they are generally healthy.	Within 14 days prior to Day 1 (Visit 1)
Systolic Blood Pressure (SBP)	Subject will have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
Diastolic Blood Pressure (DBP) at Screening	Subjects will have their vital signs, i.e., blood pressure and heart rate, measured during the Screening Visit to ensure they are generally healthy.	Within 14 days prior to Day 1 (Visit 1)
Diastolic Blood Pressure (DBP)	Subject will have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
Heart Rate (HR) at Screening	Subjects will have their vital signs, i.e., blood pressure and heart rate, measured during the Screening Visit to ensure they are generally healthy.	Within 14 days prior to Day 1 (Visit 1)
Heart Rate (HR)	Subject will have their vital signs, i.e., blood pressure and heart rate, measured prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
12-Lead ECG QT Intervals at Screening	12-Lead ECGs will be performed to measure QT and QTc intervals during the Screening Visit to ensure absence of overt cardiac illnesses.	Within 14 days prior to Day 1 (Visit 1)
12-Lead ECG QT Intervals	12-Lead ECGs will be performed to measure QT and QTc intervals prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
12-Lead ECG QTc Intervals at Screening	12-Lead ECGs will be performed to measure QT and QTc intervals during the Screening Visit to ensure absence of overt cardiac illnesses.	Within 14 days prior to Day 1 (Visit 1)
12-Lead ECG QTc Intervals	12-Lead ECGs will be performed to measure QT and QTc intervals prior to dosing and at multiple time points, up to 8 hours after dosing during each treatment period.	Within 30 minutes prior to dosing (baseline) to 8 hours post-dose
Complete Blood Count (CBC) at Screening	A CBC will be performed as part of the subject safety evaluations at screening.	Within 14 days prior to Day 1 (Visit 1)
Complete Blood Count (CBC) at End-of-Study	A CBC will be performed as part of the End-of-Study subject safety evaluations at end-of-study.	4 hours post-dose at Visit 4 (within 6 weeks after Day 1 (Visit 1))
Comprehensive Metabolic Panel (CMP) at Screening	A CMP will be performed as part of the subject safety evaluations at screening.	Within 14 days prior to Day 1 (Visit 1)
Comprehensive Metabolic Panel (CMP) at End-of-Study	A CMP will be performed as part of the End-of-Study subject safety evaluations at end-of-study.	4 hours post-dose at Visit 4 (within 6 weeks after Day 1 (Visit 1))
Urinalysis at Screening	Routine and microscopic urinalysis will be performed as part of the subject safety evaluations at screening.	Within 14 days prior to Day 1 (Visit 1)
Urinalysis at End-of-Study	Routine and microscopic urinalysis will be performed as part of the End-of-Study subject safety evaluations at end-of-study.	4 hours post-dose at Visit 4 (within 6 weeks after Day 1 (Visit 1))
Incidents of Pregnancy at Screening	A urinary pregnancy test will be performed for women of child-bearing potential as a part of the Screening Visit evaluations to determine the eligibility of the subject for the study.	Within 14 days prior to Day 1 (Visit 1)
Incidents of Pregnancy at End-of-Study	A urinary pregnancy test will be performed for women of child-bearing potential as a part of the End-of-Study safety evaluations to determine if a pregnancy had occurred during the study.	4 hours post-dose at Visit 4 (within 6 weeks after Day 1 (Visit 1))
Serious Adverse Events	Adverse drug events (ADEs), whether observed by investigators or reported by the subjects, will be documented, evaluated, followed up, and treated if deemed necessary. According to FDA guidelines, a serious ADE will refer to any adverse drug experience occurring at any dose that results in any of the following outcomes: 1) death; 2) a life-threatening adverse drug experience; 3) inpatient hospitalization or prolongation of existing hospitalization; 4) persistent or significant disability/incapacity; 5) congenital anomaly/birth defect; 6) other important medical events that may jeopardize the subject or may require medical or surgical intervention to prevent one of the outcomes listed in this definition. ADEs will be followed until stabilized/resolved or 30 days from the date the subject has finished the study, whichever is sooner.	Signing of Informed Consent at Screening Visit to End-of-Study Visit, an expected average of 7 Weeks
Other Adverse Events	Adverse drug events (ADEs), whether observed by investigators or reported by the subjects, will be documented, evaluated, followed up, and treated if deemed necessary. ADEs will be followed until stabilized/resolved or 30 days from the date the subject has finished the study, whichever is sooner.	Signing of Informed Consent at Screening Visit to End-of-Study Visit, an expected average of 7 Weeks

Collaborators and Investigators

• Sponsor: Amphastar Pharmaceuticals, Inc.
• Investigators: Study Director: Safety Monitor, Amphastar Pharmeceuticals, Inc.

Publications and helpful links

General Publications

• Lipworth BJ, Clark DJ. Lung delivery of salbutamol given by breath activated pressurized aerosol and dry powder inhaler devices. Pulm Pharmacol Ther. 1997 Aug;10(4):211-4. doi: 10.1006/pupt.1997.0093.
• Ahrens RC. The role of the MDI and DPI in pediatric patients: "Children are not just miniature adults". Respir Care. 2005 Oct;50(10):1323-8; discussion 1328-30.
• Goldstein DA, Tan YK, Soldin SJ. Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers. Eur J Clin Pharmacol. 1987;32(6):631-4. doi: 10.1007/BF02456001.
• Hindle M, Newton DA, Chrystyn H. Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary albuterol (salbutamol) assay technique. Chest. 1995 Mar;107(3):629-33. doi: 10.1378/chest.107.3.629.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: October 20, 2014
• First Submitted That Met QC Criteria: October 20, 2014
• First Posted (Estimate): October 22, 2014

Study Record Updates

• Last Update Posted (Actual): April 19, 2017
• Last Update Submitted That Met QC Criteria: April 17, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Asthma; Albuterol
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: API-A006-CL-D