Ibuprofen and Pseudoephedrine Comparative Pharmacokinetic Study

An Open-label, Randomised, Three-way Cross-over, Single Dose, Single Centre, Comparative Pharmacokinetic Study Between Ibuprofen and Pseudoephedrine Liquid Capsules (2x 200 mg Ibuprofen & 30 mg Pseudoephedrine) (Test), Ibuprofen and Pseudoephedrine Tablets (2x 200 mg Ibuprofen & 30 mg Pseudoephedrine) (Comparator 1), and Ibuprofen Liquid Capsules (2x 200 mg Solubilised Ibuprofen) (Comparator 2)

This comparative pharmacokinetic study is being conducted to provide supporting evidence for inclusion in dossiers to regulatory authorities for an Article 8(3) of Directive 2001/83/EC abridged application for ibuprofen and pseudoephedrine liquid capsules (200 mg ibuprofen & 30 mg pseudoephedrine).

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Test Nurofen Cold and Flu®, Ibuprofen and pseudoephedrine liquid capsules; Drug: Comparator 1 Nurofen Cold and Flu®, ibuprofen and pseudoephedrine tablets; Drug: Comparator 2 Nurofen Immedia 200 mg Weichkapseln, ibuprofen liquid capsules

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female subjects who have given written informed consent.
2. Age: ≥ 18 years ≤ 50 years.
3. Body Mass Index (BMI) of ≥ 20 and ≤ 30 kg/m2.
4. Healthy as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
5. Female subject of child bearing potential with a negative pregnancy test at the screening visit and willing to use an effective method of contraception unless of non-childbearing potential or where abstaining from sexual intercourse in line with the preferred and usual lifestyle of the subject from first dose until 3 months after the final dose of study medication.
6. Female subject of non-child bearing potential with negative pregnancy test at the screening visit.
7. Male subject willing to use an effective method of contraception unless anatomically sterile or where abstaining from sexual intercourse in line with the preferred and usual lifestyle of the subject from first dose until 3 months after the final dose of study medication.

Exclusion Criteria:

1. Pregnant or lactating females.
2. A history and/or presence of significant disease of any body system, including psychiatric disorders.
3. Any condition that may currently interfere with the absorption, distribution, metabolism or excretion of drugs.
4. A history of allergy or intolerance related to treatment with ibuprofen, aspirin, other NSAIDs, pseudoephedrine, other sympathomimetic or catecholamine derivative decongestant drugs or the excipients of the formulations.
5. A history of or active peptic or duodenal ulcers or gastro-intestinal bleed or upper gastro-intestinal bleed, or other significant gastro-intestinal disorders.
6. A history of hypertension or hypertension that is currently treated with antihypertensive medication.
7. A history of frequent dyspepsia, e.g. heartburn or indigestion.
8. A history of migraine.
9. Current smokers and ex-smokers who have smoked or used nicotine replacement products during the previous 6 months prior to first dosing.
10. A history of substance abuse (including alcohol).
11. High consumption of stimulating drinks (coffee, tea, cola, energy drinks etc.; total caffeine intake per day above 300 mg).
12. Those with positive screen/test for drugs of abuse and alcohol.
13. Those with a positive screen for ibuprofen.
14. Ingestion of a prescribed drug at any time in the 14 days before the first dose of study medication (excluding hormonal contraceptives and hormone replacement therapy), or consumption of enzyme inhibitors or inducers 30 days prior to the first dose of study medication.
15. Ingestion of an over-the-counter preparation within 7 days before the first dose of study medication, including herbal medications, vitamin/fish oil supplements, ibuprofen, other NSAIDs or decongestants.
16. Donation of blood in quantity > 400 ml e.g. to the blood transfusion service in the 12 weeks prior to the first dose of study medication
17. Known human immune deficiency virus (HIV) positive status, or a positive viral serology screen.
18. Topical use of ibuprofen within 7 days before the first dose of study medication.
19. Those previously randomised into this study.
20. Those who are an employee at the study site.
21. Those who are a partner or first degree relative of the Investigator.
22. Those who have participated in a clinical trial in the 12 weeks prior to the first dose of study medication.
23. Those unable in the opinion of the Investigator to comply fully with the study requirements.
24. Those who have consumed grapefruit or grapefruit juice, pummelo or Seville oranges in the 7 days prior to randomisation.
25. Those who are unwilling to consume gelatine of animal origin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Treatment Order: Test, Comparator 1, Comparator 2	Drug: Test Nurofen Cold and Flu®, Ibuprofen and pseudoephedrine liquid capsules; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 1 Nurofen Cold and Flu®, ibuprofen and pseudoephedrine tablets; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 2 Nurofen Immedia 200 mg Weichkapseln, ibuprofen liquid capsules; 2 x 200 mg solubilised ibuprofen
Experimental: 2; Treatment Order: Test, Comparator 2, Comparator 1	Drug: Test Nurofen Cold and Flu®, Ibuprofen and pseudoephedrine liquid capsules; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 1 Nurofen Cold and Flu®, ibuprofen and pseudoephedrine tablets; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 2 Nurofen Immedia 200 mg Weichkapseln, ibuprofen liquid capsules; 2 x 200 mg solubilised ibuprofen
Experimental: 3; Treatment Order: Comparator 1, Test, Comparator 2	Drug: Test Nurofen Cold and Flu®, Ibuprofen and pseudoephedrine liquid capsules; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 1 Nurofen Cold and Flu®, ibuprofen and pseudoephedrine tablets; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 2 Nurofen Immedia 200 mg Weichkapseln, ibuprofen liquid capsules; 2 x 200 mg solubilised ibuprofen
Experimental: 4; Treatment Order: Comparator 1, Comparator 2, Test	Drug: Test Nurofen Cold and Flu®, Ibuprofen and pseudoephedrine liquid capsules; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 1 Nurofen Cold and Flu®, ibuprofen and pseudoephedrine tablets; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 2 Nurofen Immedia 200 mg Weichkapseln, ibuprofen liquid capsules; 2 x 200 mg solubilised ibuprofen
Experimental: 5; Treatment Order: Comparator 2, Test, Comparator 1	Drug: Test Nurofen Cold and Flu®, Ibuprofen and pseudoephedrine liquid capsules; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 1 Nurofen Cold and Flu®, ibuprofen and pseudoephedrine tablets; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 2 Nurofen Immedia 200 mg Weichkapseln, ibuprofen liquid capsules; 2 x 200 mg solubilised ibuprofen
Experimental: 6; Treatment Order: Comparator 2, Comparator 1, Test	Drug: Test Nurofen Cold and Flu®, Ibuprofen and pseudoephedrine liquid capsules; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 1 Nurofen Cold and Flu®, ibuprofen and pseudoephedrine tablets; 2 x 200 mg ibuprofen & 30 mg pseudoephedrine; Drug: Comparator 2 Nurofen Immedia 200 mg Weichkapseln, ibuprofen liquid capsules; 2 x 200 mg solubilised ibuprofen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pseudoephedrine AUC0-t for Test vs. Comparator 1.	The Test and Comparator 1 will be considered similar if for pseudoephedrine, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator 1 ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%:	PK Analysis: 0-48hrs
Pseudoephedrine Cmax for Test vs. Comparator 1.	The Test and Comparator 2 will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator 2 ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%:	PK Analysis: 0-48hrs
Ibuprofen AUC0-t for Test vs. Comparator 2.	The Test and Comparator 2 will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator 2 ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%:	PK Analysis: 0-48hrs
Ibuprofen Cmax for Test vs. Comparator 2.	The Test and Comparator 2 will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator 2 ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%:	PK Analysis: 0-48hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ibuprofen AUC0-t for Test vs. Comparator 1.	The Test and Comparator 1 will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator 1 ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%: • Cmax for ibuprofen (in the context of the Test vs. Comparator 1 comparison)	PK Analysis: 0-48hrs
Ibuprofen Cmax for Test vs. Comparator 1.	The Test and Comparator 1 will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator 1 ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%:	PK Analysis: 0-48hrs
Assessment of how fast the ibuprofen from the Test product starts to be absorbed and how quickly it reaches the therapeutic level.	T8.4 - time to reach the therapeutic level (8.4 µg/ml) for ibuprofen.	PK Analysis: 0-48hrs
Pharmacokinetic parameters will be assessed as secondary endpoints.	Cn - the plasma concentration of an active at each planned nominal time-point.	PK Analysis: 0-48hrs
Pharmacokinetic parameters will be assessed as secondary endpoints.	AUC0-inf - Area under the plasma concentration-time curve from administration to infinity.	PK Analysis: 0-48hrs
Pharmacokinetic parameters will be assessed as secondary endpoints.	administration to infinity. AUCR - ratio AUC0-t / AUC0-inf.	PK Analysis: 0-48hrs
Pharmacokinetic parameters will be assessed as secondary endpoints.	Tmax -Time until Cmax is first achieved.	PK Analysis: 0-48hrs
Pharmacokinetic parameters will be assessed as secondary endpoints.	Kel - elimination rate constant.	PK Analysis: 0-48hrs
Pharmacokinetic parameters will be assessed as secondary endpoints.	T1/2 - plasma concentration half-life.	PK Analysis: 0-48hrs
Pharmacokinetic parameters will be assessed as secondary endpoints.	Tlag - time between administration and the beginning of absorption of ibuprofen. This will be calculated only for the Test.	PK Analysis: 0-48hrs

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The occurrence of Adverse Events.		Through study completion - Screening to study follow-up (Approx 8 weeks)
Change from baseline in oral temperature.	Measured in degrees Celcius	Through study completion - Screening to study follow-up (Approx 8 weeks)
Change from baseline in resting heart rate.	Measured in beats per minute	Through study completion - Screening to study follow-up (Approx 8 weeks)
Change from baseline in resting blood pressure.	Measured in mmHg	Through study completion - Screening to study follow-up (Approx 8 weeks)
Change from baseline in haematology testing.		Through study completion - Screening to study follow-up (Approx 8 weeks)
Change from baseline in biochemistry testing.		Through study completion - Screening to study follow-up (Approx 8 weeks)
Change from baseline in urinary testing.		Through study completion - Screening to study follow-up (Approx 8 weeks)

Collaborators and Investigators

• Sponsor: Reckitt Benckiser Healthcare (UK) Limited
• Collaborators: Simbec Research

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2016
• Primary Completion (Actual): January 30, 2017
• Study Completion (Actual): January 30, 2017

Study Registration Dates

• First Submitted: May 17, 2017
• First Submitted That Met QC Criteria: June 8, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: June 8, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Central Nervous System Stimulants; Sympathomimetics; Vasoconstrictor Agents; Nasal Decongestants; Ibuprofen; Ephedrine; Pseudoephedrine
• Other Study ID Numbers: NL1309

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No