To Evaluate the Food Effect and the Absorption Profile of Ibuprofen Modified-Release Tablets 800 mg

An Open-label, Randomized, 3-way Crossover Study to Evaluate the Pharmacokinetics of Investigational Product Ibuprofen Modified-Release Tablets 800 mg Compared to Ibuprofen Tablets 800 mg in Healthy Volunteers

An open-label, randomized, 3-way crossover study to evaluate the pharmacokinetics of investigational product "Ibuprofen Modified-Release Tablets 800 mg" in comparison to the reference standard "Ibuprofen Regular-Release Tablets 600 mg/800 mg" in normal healthy volunteers

Primary objective:

To evaluate the food effect of IBUMR and its bioavailability of single and multiple doses compared with reference drugs in normal healthy volunteers.

Secondary objectives:

1. To determine and compare the single and multiple dose PK profiles of IBUMR and reference drugs.
2. To identify the effect duration for IBUMR after dose administration by detecting ibuprofen concentrations in plasma.
3. To evaluate the safety profile of single and multiple doses of IBUMR.

Study Overview

• Status: Completed
• Conditions: Chronic Pain
• Intervention / Treatment: Drug: Ibuprofen Tablets

Detailed Description

This study consists of 3 treatment periods as below. For Treatment A and Treatment B, single- and multiple-dose stages are included.

Treatment A:

One tablet of IBUMR will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBUMR every 12 hours for a total of 8 doses.

Treatment B:

One tablet of IBURed-800mg will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBURed-600mg every 8 hours for a total of 12 doses.

Treatment C:

Single dose of IBUMR will be given to the subjects under fed condition (a standard high-fat, high calorie breakfast should be consumed within 30 minutes prior to dosing).

A minimum of 3-day washout interval will be introduced across the 3 treatment periods. Subjects will be required to be fasted for at least 10 hours prior to the administration of morning doses.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Taiwan, China
    • Taipei Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects whose body mass index (BMI) at screening is within a range of ≥18.5 kg/m2 and <25.0 kg/m2.

BMI = Body Weight (kg) / [Height (m)]2 And body weight is not less than 50 kg and 45 kg for males and females, respectively.

• Subject's medical history shows no contraindication to the test medications (hypersensitivity to ibuprofen or any component of test and reference products) and non-steroidal anti-inflammatory drugs (NSAIDs).
• Subjects who are judged to be in good health by the investigator based upon the results of physical examination (PE), vital signs, and routine laboratory tests.
• The female subject shows negative pregnancy test results within 30 days prior to the first dose of the study.
• The subject did not take any of the following medications in the specified durations:
• Any systemically absorbed medication within 14 days (excluding vitamins, food supplements and hormone contraceptives not ibuprofen drug interactions) prior to the first dose of the study
• Any enzyme inducer/inhibitor and/or known hepatic or renal clearance-altering agents (e.g., erythromycin, cimetidine, barbiturates, phenothiazine, clarithromycin, troleandomycin, ketoconazole, miconazolem fluconazole, itraconazole) within 30 days prior to the first dose of the study.
• Subjects are willing to comply with protocol-stated requirements, instructions and restrictions, followed by understanding and signing the written informed consent form by the subject or legal representative if he/she is under the statutory age of consent as per the local authority.

Exclusion Criteria:

• Subjects with any properly diagnosed disease within 30 days prior to the first dose of the study.
• Subjects with a clinically significant hematological, endocrine, cardiovascular, hepatic, renal, gastrointestinal, and/or pulmonary disorder; subjects with any predisposing condition that might interfere with the absorption, distribution, metabolism and excretion of drugs; subjects who has had any previous gastrointestinal surgery or coronary artery bypass graft.
• Subjects who require treatment with any medications, either prescription or non-prescription (excluding vitamins and food supplements), within 30 days prior to the first dose of the study
• Subjects have participated in investigational drug trials and took any investigational drug within 60 days prior to the first does of the study.
• Subjects had blood donation more than 250 and 500 mL within 60 and 90 days, respectively prior to the first dose of the study.
• Subjects had a history of drug abuse or alcohol abuse according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria.
• Subjects cannot stop smoking and caffeine-intakes for 48 hours prior to the first dose of the study and during the entire study period.
• Subjects who are pregnant or lactating.
• Subjects who have been tested positive for the following tests:
• Human immunodeficiency virus (HIV)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Treponema pallidum (STS test)
• For enrollment of female subjects with child-bearing potential, the subject must be practicing sexual abstinence or be using and willing to continue to use a medically acceptable form of birth control for at least 30 days prior to screening (that period will extend to 3 months for oral contraceptive use) and for at least 30 days after the last dose of study drug. For a subject to be considered not to be of child-bearing potential, she must have been amenorrheic for at least 2 years, or must have had a hysterectomy, a bilateral tubal ligation, and/or a bilateral oophorectomy (as determined by the medical history). The male partner of a female study subject with childbearing potential must use a condom and ensure that his partner uses a suitable method of contraception as outlined above.
• Subjects with underlying medical, mental, psychological, or other inappropriate conditions that would impair treatment compliance, or in the opinion of the investigator would not permit to participate in the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment ABC; Receive the investigational product and active comparator in a sequence of treatment A, treatment B and treatment C.	Drug: Ibuprofen Tablets; Treatment A: One tablet of IBUMR will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBUMR every 12 hours for a total of 7 doses. Treatment B: One tablet of IBURed will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBURed every 8 hours for a total of 10 doses. Treatment C: Single dose of IBUMR will be given to the subjects under fed condition (a standard high-fat, high calorie breakfast should be consumed within 30 minutes prior to dosing).
Experimental: Treatment ACB; Receive the investigational product and active comparator in a sequence of treatment A, treatment C and treatment B.	Drug: Ibuprofen Tablets; Treatment A: One tablet of IBUMR will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBUMR every 12 hours for a total of 7 doses. Treatment B: One tablet of IBURed will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBURed every 8 hours for a total of 10 doses. Treatment C: Single dose of IBUMR will be given to the subjects under fed condition (a standard high-fat, high calorie breakfast should be consumed within 30 minutes prior to dosing).
Experimental: Treatment BAC; Receive the investigational product and active comparator in a sequence of treatment B, treatment A and treatment C.	Drug: Ibuprofen Tablets; Treatment A: One tablet of IBUMR will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBUMR every 12 hours for a total of 7 doses. Treatment B: One tablet of IBURed will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBURed every 8 hours for a total of 10 doses. Treatment C: Single dose of IBUMR will be given to the subjects under fed condition (a standard high-fat, high calorie breakfast should be consumed within 30 minutes prior to dosing).
Experimental: Treatment BCA; Receive the investigational product and active comparator in a sequence of treatment B, treatment C and treatment A.	Drug: Ibuprofen Tablets; Treatment A: One tablet of IBUMR will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBUMR every 12 hours for a total of 7 doses. Treatment B: One tablet of IBURed will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBURed every 8 hours for a total of 10 doses. Treatment C: Single dose of IBUMR will be given to the subjects under fed condition (a standard high-fat, high calorie breakfast should be consumed within 30 minutes prior to dosing).
Experimental: Treatment CAB; Receive the investigational product and active comparator in a sequence of treatment C, treatment A and treatment B.	Drug: Ibuprofen Tablets; Treatment A: One tablet of IBUMR will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBUMR every 12 hours for a total of 7 doses. Treatment B: One tablet of IBURed will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBURed every 8 hours for a total of 10 doses. Treatment C: Single dose of IBUMR will be given to the subjects under fed condition (a standard high-fat, high calorie breakfast should be consumed within 30 minutes prior to dosing).
Experimental: Treatment CBA; Receive the investigational product and active comparator in a sequence of treatment C, treatment B and treatment A.	Drug: Ibuprofen Tablets; Treatment A: One tablet of IBUMR will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBUMR every 12 hours for a total of 7 doses. Treatment B: One tablet of IBURed will be administered to the subjects under fasted condition, followed by a minimum of 72-hour washout interval. After the washout period, subjects will receive 1 × IBURed every 8 hours for a total of 10 doses. Treatment C: Single dose of IBUMR will be given to the subjects under fed condition (a standard high-fat, high calorie breakfast should be consumed within 30 minutes prior to dosing).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of single-dose and multiple-dose bioavailability between IBUMR and IBURed	Comparison of single-dose and multiple-dose bioavailability between IBUMR and IBURed in log-transformed values of area under the curve from time 0 to the last measurable concentration (AUCL)	After collecting blood samples from the last participant, up to 30 days
Comparison of single-dose and multi-dose bioavailability of IBUMR and IBURed	Comparison of single-dose and multiple-dose bioavailability between IBUMR and IBURed in log-transformed values of the peak concentration (Cmax)	After collecting blood samples from the last participant, up to 30 days
Comparison of single - and multi-dose bioavailability of IBUMR and IBURed	Comparison of single-dose and multiple-dose bioavailability between IBUMR and IBURed in log-transformed values of area under the curve from time 0 to infinity (AUCinf).	After collecting blood samples from the last participant, up to 30 days
To assess the food effect of IBUMR in the PK parameters	To assess the food effect of IBUMR in the PK parameters including Cmax	After collecting blood samples from the last participant, up to 30 days
To evaluate the food effect of IBUMR on PK parameters	To assess the food effect of IBUMR in the PK parameters including time to reach peak concentration (Tmax)	After collecting blood samples from the last participant, up to 30 days
To evaluate the food effects of IBUMR on PK parameters	To assess the food effect of IBUMR in the PK parameters including AUCL	After collecting blood samples from the last participant, up to 30 days
Evaluate the food effect of IBUMR in PK parameters	To assess the food effect of IBUMR in the PK parameters including AUCinf	After collecting blood samples from the last participant, up to 30 days
Determine the food effect of IBUMR in PK parameters	To assess the food effect of IBUMR in the PK parameters including elimination half-life (t1/2)	After collecting blood samples from the last participant, up to 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Single-dose PK measures	-- Time to reach peak concentration (Tmax)	After collecting blood samples from the last participant, up to 30 days
Single dose PK method	-- Area under the concentration-time curve within time span t1 to t2 (AUCt1→t2)	After collecting blood samples from the last participant, up to 30 days
Single dose PK	-- Area under the concentration-time curve extrapolated from the last detectable sampling time point to infinity as a percentage of total AUC (AUCextrap)	After collecting blood samples from the last participant, up to 30 days
Single dose PK step	-- Elimination half-life (t1/2)	After collecting blood samples from the last participant, up to 30 days
Single dose PK design	-- Apparent oral clearance (CL/F)	After collecting blood samples from the last participant, up to 30 days
Single dose PK moves	-- Apparent volume of distribution after oral administration (Vd/F)	After collecting blood samples from the last participant, up to 30 days
Multiple-dose PK measures	-- Peak concentration at steady state (Cmax,ss)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK	-- Plasma drug concentration at a specified time t steady state (Ct,ss)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK method	-- Average concentration at steady state (Cavg)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK steps	-- Trough plasma concentration at steady state (Ctrough)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK design	-- Time to reach peak concentration at steady state (Tmax,ss)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK plan	-- Area under the concentration-time curve within time span t1 to t2 at steady state (AUCt1→t2,ss)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK program	-- AUC in 1 dosing interval (AUCτ) at steady state	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK process	-- Terminal half-life at steady state (t1/2,ss)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK arrangement	-- Apparent oral clearance at steady state (CL/Fss)	After collecting blood samples from the last participant, up to 30 days
Multiple - dosed PK planning	-- Apparent volume of distribution after oral administration at steady state (Vd/Fss)	After collecting blood samples from the last participant, up to 30 days
Assessment of effect duration for IBUMR	-- For the plasma ibuprofen concentration of IBUMR at steady state, the time to drop to the Ctrough of IBURed-600mg will be calculated.	After collecting blood samples from the last participant, up to 30 days
Evaluation of duration of IBUMR effect	-- Percentage of the test drug-treated subjects with higher or equal plasma ibuprofen concentrations at 12-hour at steady state (C12,ss) compared to the Ctrough of IBURed-600mg will be calculated.	After collecting blood samples from the last participant, up to 30 days
Incidence of treatment-emergent adverse events (safety and tolerability)	Incidence of AEs and SAEs	After collecting blood samples from the last participant, up to 60 days
safety and tolerability	incidence of abnormal Physical examination	After collecting blood samples from the last participant, up to 60 days
Incidence of treatment-emergent adverse events	abnormal Vital signs	After collecting blood samples from the last participant, up to 60 days
Incidence of sudden adverse events (safety and tolerability)	abnormal laboratory tests results	After collecting blood samples from the last participant, up to 60 days
Incidence of treatment-induced adverse events (safety and tolerability)	abnormal 12-lead ECG exams	After collecting blood samples from the last participant, up to 60 days

Collaborators and Investigators

• Sponsor: Overseas Pharmaceuticals, Ltd.
• Investigators: Principal Investigator: Ming-Che Liu, M.D, Taipei Medical University Hospital

Publications and helpful links

General Publications

• Davies NM. Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin Pharmacokinet. 1998 Feb;34(2):101-54. doi: 10.2165/00003088-199834020-00002.
• Albert KS, Gernaat CM. Pharmacokinetics of ibuprofen. Am J Med. 1984 Jul 13;77(1A):40-6. doi: 10.1016/s0002-9343(84)80017-0.
• Albert KS, Gillespie WR, Wagner JG, Pau A, Lockwood GF. Effects of age on the clinical pharmacokinetics of ibuprofen. Am J Med. 1984 Jul 13;77(1A):47-50. doi: 10.1016/s0002-9343(84)80018-2.
• Barkin RL, Buvanendran A. Focus on the COX-1 and COX-2 agents: renal events of nonsteroidal and anti-inflammatory drugs-NSAIDs. Am J Ther. 2004 Mar-Apr;11(2):124-9. doi: 10.1097/00045391-200403000-00007.
• Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011 Oct 6;11:770. doi: 10.1186/1471-2458-11-770.
• Legg T, Paluch E, Jayawardena S. Single- and Multiple-Dose Pharmacokinetics of Immediate-Release/Extended-Release Ibuprofen Tablets. Clin Pharmacol Drug Dev. 2017 Jan;6(1):36-43. doi: 10.1002/cpdd.288. Epub 2016 Sep 22.
• Devarakonda K, Kostenbader K, Giuliani MJ, Young JL. Single- and multiple-dose pharmacokinetics of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) compared with immediate-release hydrocodone bitartrate/ibuprofen and immediate-release tramadol HCl/acetaminophen. J Pain Res. 2015 Sep 30;8:647-56. doi: 10.2147/JPR.S83416. eCollection 2015.
• O'Connor TP, Anderson AM, Lennox B, Muldoon C. A novel sustained-release formulation of ibuprofen provides effective once-daily therapy in the treatment of rheumatoid arthritis and osteoarthritis. Br J Clin Pract. 1993 Jan-Feb;47(1):10-3.
• Varrassi G, Pergolizzi JV, Dowling P, Paladini A. Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review. Adv Ther. 2020 Jan;37(1):61-82. doi: 10.1007/s12325-019-01144-9. Epub 2019 Nov 8.
• Volans G, Hartley V, McCrea S, Monaghan J. Non-opioid analgesic poisoning. Clin Med (Lond). 2003 Mar-Apr;3(2):119-23. doi: 10.7861/clinmedicine.3-2-119. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): December 24, 2020
• Primary Completion (Actual): February 6, 2021
• Study Completion (Actual): July 18, 2021

Study Registration Dates

• First Submitted: February 4, 2021
• First Submitted That Met QC Criteria: April 7, 2022
• First Posted (Actual): April 15, 2022

Study Record Updates

• Last Update Posted (Actual): April 15, 2022
• Last Update Submitted That Met QC Criteria: April 7, 2022
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: pain relief; Ibuprofen Modified-Release Tablets; Overseas Pharmaceuticals
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Chronic Pain; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; 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; Ibuprofen
• Other Study ID Numbers: OVEIBUA20181121

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