Sensitivity of Pharmacokinetics to Differences in Aerodynamic Particle Size Distribution

NCT01966692 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: IRB201400464-need FDA approval00079088HHSF223401610099COCR15966
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

When a drug company first develops a drug, the company has to show the Food and Drug Administration (FDA) that the drug is safe and effective. If FDA concludes that the drug is safe and effective, FDA approves the drug. The company can then sell the drug, which the company does using "trade name." Only the drug company that developed the "trade name" drug is allowed to sell it. However, other drug companies can create their own version of the "trade name" drug, which usually happens after the patents for the "trade name" product run out. These drugs, often called "generic drugs," potentially will be less expensive for the patient. In order to sell generic drugs, drug companies must show that their generic version is the same as the "trade name" drug in a number of ways. For example, they generally have to show that their product is intended to be used to treat the same diseases or conditions, that it has the same label, and that the product has the same active ingredient as the "trade name" drug. The generic company also has to show that generic product is "bioequivalent" to the trade name drug, meaning that the generic product gets to the part of the body where the drug works at the same rate that the trade name drug does. How to show how much drug gets to the part of the body where it works, and how fast, depends on the type of product the drug is. The primary aim of this research study is to aid the FDA in finding methods to ensure that the versions of generic drugs that are inhaled (for example, drugs used to treat asthma) are bioequivalent to the trade name drug. As a part of the research study, pharmacokinetic (PK) studies (studies measuring drug levels in the blood over time after inhalation) will be done using three different versions of fluticasone propionate (FP, a drug routinely used in asthmatic patients) administered using a dry powder inhaler (DPI, an inhalation device that delivers the drug as a dry powder). The results from this study will help FDA ensure that generic products are the same as the trade name drugs.

Conditions

Asthma

Keywords

Bioequivalence; Fluticasone Propionate

Outcome Measures

Primary Outcomes (2)

• Area Under the Plasma Concentration-time Profile From Time 0 the Last Quantifiable Concentration (AUC0-last) With Dose Normalization

  Area under the plasma concentration versus time curve from time zero (pre-dose) to the last quantifiable concentration after pulmonary dose (estimated from anatomical throats) normalization; measured as picograms multiplied by hours divided by milliliters (pg\*h/mL).

  Day 1 of Periods 1, 2, 3, and 4: pre-dose (15 minutes prior to the dosing), and 5, 10, 15, 20, 30, 45, 60 minutes, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours (+/- 1 hour) post-dose

• Maximum Plasma Concentration (Cmax) With Dose Normalization

  Cmax measured as picograms divided by milliliters (pg/mL) after pulmonary dose (estimated from anatomical throats) normalization.

  Day 1 of Periods 1, 2, 3, and 4: pre-dose (15 minutes prior to the dosing), and 5, 10, 15, 20, 30, 45, 60 minutes, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours (+/- 1 hour) post-dose

Secondary Outcomes (3)

• Time to Reach Maximum Observed Plasma Concentration (Tmax)

  Day 1 of Periods 1, 2, 3, and 4: pre-dose (15 minutes prior to the dosing), and 5, 10, 15, 20, 30, 45, 60 minutes, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours (+/- 1 hour) post-dose

• Mean Residence Time (MRT)

  Day 1 of Periods 1, 2, 3, and 4: pre-dose (15 minutes prior to the dosing), and 5, 10, 15, 20, 30, 45, 60 minutes, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours (+/- 1 hour) post-dose

• Elimination Half Life (t1/2)

  Day 1 of Periods 1, 2, 3, and 4: pre-dose (15 minutes prior to the dosing), and 5, 10, 15, 20, 30, 45, 60 minutes, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours (+/- 1 hour) post-dose

Study Arms (4)

Fluticasone Propionate Formulation Sequence 1233*

ACTIVE COMPARATOR

Patients first received Fluticasone Propionate Drug formulation 1, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 2, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 3, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 3\*. All Fluticasone Propionate Drug formulations were administered via Plastiape Monodose Dry Powder Inhaler, 500mcg single dose. Mass Median Aerodynamic Diameter (MMAD) for formulation 1 is 4.5 µm. MMAD for formulation 2 is 3.8 µm MMAD for formulation 3 is 3.7 µm. MMAD for formulation 3\* is 3.7 µm. See Formulation Development in Detailed Description for details regarding differences in formulations

Drug: Fluticasone Propionate Formulation 1; Drug: Fluticasone Propionate Formulation 2; Drug: Fluticasone Propionate Formulation 3; Drug: Fluticasone Propionate Formulation 3*

Fluticasone Propionate Formulation Sequence 23*13

ACTIVE COMPARATOR

Patients first received Fluticasone Propionate Drug formulation 2, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 3\*, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 1, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 3. All Fluticasone Propionate Drug formulations were administered via Plastiape Monodose Dry powder Inhaler, 500mcg single dose. MMAD for formulation 1 is 4.5 µm. MMAD for formulation 2 is 3.8 µm. MMAD for formulation 3 is 3.7 µm. MMAD for formulation 3\* is 3.7 µm. See Formulation Development in Detailed Description for details regarding differences in formulations

Drug: Fluticasone Propionate Formulation 1; Drug: Fluticasone Propionate Formulation 2; Drug: Fluticasone Propionate Formulation 3; Drug: Fluticasone Propionate Formulation 3*

Fluticasone Propionate Formulation Sequence 313*2

ACTIVE COMPARATOR

Patients first received Fluticasone Propionate Drug formulation 3, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 1, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 3\*, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 2. All Fluticasone Propionate Drug formulations were administered via Plastiape Monodose Dry Powder Inhaler, 500mcg single dose. MMAD for formulation 1 is 4.5 µm. MMAD for formulation 2 is 3.8 µm MMAD for formulation 3 is 3.7 µm. MMAD for formulation 3\* is 3.7 µm. See Formulation Development in Detailed Description for details regarding differences in formulations

Drug: Fluticasone Propionate Formulation 1; Drug: Fluticasone Propionate Formulation 2; Drug: Fluticasone Propionate Formulation 3; Drug: Fluticasone Propionate Formulation 3*

Fluticasone Propionate Formulation Sequenct 3*321

ACTIVE COMPARATOR

Patients first received Fluticasone Propionate Drug formulation 3\*, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 3, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 2, after a washout period of at least 5 days, they then received Fluticasone Propionate Drug formulation 1. All Fluticasone Propionate Drug formulations were administered via Plastiape Monodose Dry powder Inhaler, 500mcg single dose. \* (The asterisk) A different set of capsules from the same batch of formulation 3 is given to the subject to assess the within-subject variability and to ensure that the study is sufficiently powered to show bioequivalence between two replicates of the same formulation. MMAD for formulation 1 is 4.5 µm. MMAD for formulation 2 is 3.8 µm MMAD for formulation 3 is 3.7 µm. MMAD for formulation 3\* is 3.7 µm.

Drug: Fluticasone Propionate Formulation 1; Drug: Fluticasone Propionate Formulation 2; Drug: Fluticasone Propionate Formulation 3; Drug: Fluticasone Propionate Formulation 3*

Interventions

Fluticasone Propionate Formulation 1 DRUG

Fluticasone Propionate dry powder inhaler Formulation 1

Fluticasone Propionate Formulation Sequence 1233*; Fluticasone Propionate Formulation Sequence 23*13; Fluticasone Propionate Formulation Sequence 313*2; Fluticasone Propionate Formulation Sequenct 3*321

Fluticasone Propionate Formulation 2 DRUG

Fluticasone Propionate dry powder inhaler Formulation 2

Fluticasone Propionate Formulation Sequence 1233*; Fluticasone Propionate Formulation Sequence 23*13; Fluticasone Propionate Formulation Sequence 313*2; Fluticasone Propionate Formulation Sequenct 3*321

Fluticasone Propionate Formulation 3* DRUG

Fluticasone Propionate dry powder inhaler Formulation 3\* \*(The asterisk) A different set of capsules from the same batch of formulation 3 is given to the subject to assess the within-subject variability and to ensure that the study is sufficiently powered to show bioequivalence between two replicates of the same formulation.

Fluticasone Propionate Formulation Sequence 1233*; Fluticasone Propionate Formulation Sequence 23*13; Fluticasone Propionate Formulation Sequence 313*2; Fluticasone Propionate Formulation Sequenct 3*321

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male or female subjects aged 18 to 50 years (inclusive).
• Females will be eligible only if they are currently non-lactating and demonstrate a negative urine pregnancy test. Female subjects must be willing to use highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly e.g. no sexual intercourse, an intrauterine device (IUD), using contraceptive foam AND a condom (double-barrier).
• Body weight ranging from 50 to 100 kg, corresponding to a BMI of 18-29 kg/m2.
• Non-smoker for at least 12 months prior to study screening and a maximum smoking history of less than ten-pack years (i.e. the equivalent of one-pack per day for ten years).
• Healthy and free of significant abnormal findings as determined by medical history, physical examination, vital signs, laboratory tests (including serum cortisol at screening), complete blood count (CBC) with differential, urinalysis and basic metabolic panel.
• Ability to read, comprehend and sign the consent form.
• Ability and willingness to comply with all study procedures, discontinue and/or withhold medications as specified in the protocol, and attend scheduled study visits.
• No history of respiratory disease.
• Normal baseline spirometry as predicted for age, sex and height, including forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC) \> 0.8.
• Healthy and without any pre-existing medical conditions.

You may not qualify if:

• Any history and/or conditions that might interfere with drug absorption, distribution, metabolism or excretion of FP, e.g., pre-existing lung and liver disease.
• Known or suspected sensitivity to Flonase (Fluticasone Propionate), Veramyst (Fluticasone Furoate), or related compounds in that class.
• Hypersensitivity to milk proteins or lactose (inactive ingredients in the formulation).
• Having a history and/or currently having the medical condition in the opinion of medically accountable investigator and hence taking any medication for the following (including but not limited to):
• Significant cardiac, dermatologic, gastrointestinal, hepatic, renal, hematological, neurological and psychiatric disease (determined by physical exam, CBC with differential, urinalysis, basic metabolic panel and medical history).
• Presence of glaucoma, cataracts, ocular herpes simplex or carcinoma (other than basal cell).
• Presence of tuberculosis and other respiratory diseases (including but not limited to intermittent or persistent asthma, emphysema and chronic bronchitis); or respiratory infection, common cold, sinusitis or ear infections.
• Current use of hormone replacement therapy (HRT), hormonal contraceptives and/or corticosteroid treatment within the last 2 months.
• Smoker during the last 1 year prior to study screening (self-report).
• Evidence of a positive pregnancy urine test for female volunteers or females who are pregnant or breast-feeding or are likely to become pregnant during the trial. Women of child-bearing potential may be included in the study if, in the opinion of the investigator, they are taking adequate contraceptive precautions as described above.
• Exposure to any investigational drug within 30 days of enrolment.
• Subjects who are unable to demonstrate proper inhalation of the test products.
• Subjects who have a history of anemia.
• Exposure to any medication that alters CYP3A4 activity within last 2 weeks (e.g.: azole antifungals, rifampin).
• Nausea, vomiting or diarrhoea within 7 days of dosing.

Sponsors & Collaborators

• University of Florida: lead
• Food and Drug Administration (FDA): collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32610, United States

Location

MeSH Terms

Conditions

Asthma

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Results Point of Contact

• Title: Dr Yuanyuan Jiao
• Organization: Unversity of Florida

yyjiao@cop.ufl.edu

(407) 313-7014

Study Officials

• Juergen Bulitta, PhD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2013
• First Posted: October 21, 2013
• Study Start: November 1, 2016
• Primary Completion: January 20, 2018
• Study Completion: January 20, 2018
• Last Updated: May 6, 2024
• Results First Posted: May 6, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share

Locations

US (1)