The primary purpose of this study is to demonstrate the bioequivalence of new formulation Advil Dual Action (ADA) liquid filled capsules (Test) compared to the currently marketed ADA Caplet (Reference) under fasted conditions and to assess the relative bioavailability of ADA liquid filled capsules (Test) under fed conditions compared to ADA liquid filled capsules (Reference) under fasted conditions.
This is a single center, single oral dose, open-label, randomized, four-treatment, four period, four sequence, crossover, bioequivalence study of ADA liquid filled capsules (125 milligrams \[mg\] ibuprofen/250 mg acetaminophen) (Treatment A) versus (vs.) ADA Caplets (125 mg ibuprofen/250 mg acetaminophen) (Treatment B) in healthy adult participants under fasted conditions. The study also includes a bioavailability assessment of ADA liquid filled capsules (125 mg ibuprofen/250 mg acetaminophen) under fed conditions (Treatment C) and Advil Liqui-Gels (200 mg ibuprofen) under fasted conditions (Treatment D). A sufficient number of male and female participants will be screened to randomize approximately 54 to ensure at least 48 evaluable participants complete the entire study. Participants will be randomly assigned to 1 of the 4 treatment sequences and receive a single oral dose of the investigational products per the randomization in each period following a crossover design. There will be a wash-out period of 3 days between investigational product administrations. Blood will be sampled regularly at scheduled times for 24 hours following treatment in each period to assess the pharmacokinetic parameters.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
54
ADA liquid filled capsules containing 125 mg ibuprofen and 250 mg acetaminophen.
ADA Caplets containing 125 mg ibuprofen and 250 mg acetaminophen.
Advil Liqui-gels containing 200 mg ibuprofen.
Spaulding Clinical
West Bend, Wisconsin, United States
Maximum Observed Post-dose Concentration (Cmax) for Ibuprofen Under Fasted Conditions (ADA Liquid Filled Capsules [Treatment A] vs. ADA Caplet [Treatment B])
Cmax is defined as the maximum observed post-dose concentration for ibuprofen obtained without interpolation. Blood samples will be collected at indicated timepoints for the analysis of Cmax.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Area Under the Plasma Concentration Versus Time Curve Calculated from Time 0 to the Last Measurable Sampling Time Point, t (AUC[0-t]) for Ibuprofen Under Fasted Conditions (ADA Liquid Filled Capsules [Treatment A] vs. ADA Caplet [Treatment B])
AUC(0-t) is defined as the area under the plasma concentration versus time curve calculated from time 0 to the last measurable sampling time point, t, computed using the linear trapezoidal rule. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-t).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days
Cmax for Acetaminophen Under Fasted Conditions (ADA Liquid Filled Capsules [Treatment A] vs. ADA Caplet [Treatment B])
Cmax is defined as the maximum observed post-dose concentration for acetaminophen obtained without interpolation. Blood samples will be collected at indicated timepoints for the analysis of Cmax.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-t) for Acetaminophen Under Fasted Conditions (ADA Liquid Filled Capsules [Treatment A] vs. ADA Caplet [Treatment B])
AUC(0-t) is defined as the area under the plasma concentration versus time curve calculated from time 0 to the last measurable sampling time point, t, computed using the linear trapezoidal rule. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-t).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Cmax for Ibuprofen (ADA Liquid Filled Capsules Under Fed Conditions [Treatment C] vs. ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A])
Cmax is defined as the maximum observed post-dose concentration for ibuprofen obtained without interpolation. Blood samples will be collected at indicated timepoints for the analysis of Cmax.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-t) for Ibuprofen (ADA Liquid Filled Capsules Under Fed Conditions [Treatment C] vs. ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A])
AUC(0-t) is defined as the area under the plasma concentration versus time curve calculated from time 0 to the last measurable sampling time point, t, computed using the linear trapezoidal rule. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-t).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Area Under the Plasma Concentration Versus Time Curve Calculated From Time 0 to Infinity (AUC[0-inf]) for Ibuprofen (ADA Liquid Filled Capsules Under Fed Conditions [Treatment C] vs. ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A])
AUC(0-inf) is defined as the area under the plasma concentration versus time curve calculated from time 0 to infinity. AUC(0-inf) = AUC(0-t) + C(t)/λz where C(t) is the concentration at the last measurable sampling time point and λz is the terminal elimination rate constant. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-inf).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Cmax for Acetaminophen (ADA Liquid Filled Capsules Under Fed Conditions [Treatment C] vs. ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A])
Cmax is defined as the maximum observed post-dose concentration for acetaminophen obtained without interpolation. Blood samples will be collected at indicated timepoints for the analysis of Cmax.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-t) for Acetaminophen (ADA Liquid Filled Capsules Under Fed Conditions [Treatment C] vs. ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A])
AUC(0-t) is defined as the area under the plasma concentration versus time curve calculated from time 0 to the last measurable sampling time point, t, computed using the linear trapezoidal rule. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-t).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-inf) for Acetaminophen (ADA Liquid Filled Capsules Under Fed Conditions [Treatment C] vs. ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A])
AUC(0-inf) is defined as the area under the plasma concentration versus time curve calculated from time 0 to infinity. AUC(0-inf) = AUC(0-t) + C(t)/λz where C(t) is the concentration at the last measurable sampling time point and λz is the terminal elimination rate constant. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-inf).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex) for Ibuprofen (Treatment A, Treatment C, Treatment B and Treatment D)
%AUCex is defined as the percentage of AUC(0-inf) obtained by extrapolation, calculated as (1-\[AUC0-t/AUC0-inf\]) \*100. Blood samples will be collected at indicated timepoints for the analysis of %AUCex.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-inf) for Ibuprofen (Treatment A, Treatment C, Treatment B and Treatment D)
AUC(0-inf) is defined as the area under the plasma concentration versus time curve calculated from time 0 to infinity. AUC(0-inf) = AUC(0-t) + C(t)/λz where C(t) is the concentration at the last measurable sampling time point and λz is the terminal elimination rate constant. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-inf).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Terminal Elimination Rate Constant (λz) for Ibuprofen (Treatment A, Treatment C, Treatment B and Treatment D)
λz is defined as the terminal elimination rate constant computed as the negative of the slope of the regression line of ln(C\[t\]) on time. Blood samples will be collected at indicated timepoints for the analysis of λz.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Time of the Maximum Observed Post-dose Concentration (tmax) for Ibuprofen (Treatment A, Treatment C, Treatment B and Treatment D)
Blood samples will be collected at indicated timepoints for the analysis of tmax.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
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Elimination Half-life (t1/2) for Ibuprofen (Treatment A, Treatment C, Treatment B and Treatment D)
t1/2 is defined as the elimination half-life computed as t1/2 = ln(2)/λz where λz is the terminal elimination rate constant. Blood samples will be collected at indicated timepoints for the analysis of t1/2.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Apparent Volume of Distribution (Vz/F) for Ibuprofen (Treatment A, Treatment C, Treatment B and Treatment D)
Vz/F is defined as the apparent volume of distribution, as calculated by the dose administered/(λz \*AUC0-inf) where λz is the terminal elimination rate constant and AUC(0-inf) is the area under the plasma concentration versus time curve calculated from time 0 to infinity. Blood samples will be collected at indicated timepoints for the analysis of Vz/F.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Apparent Total Clearance (Cl/F) for Ibuprofen (Treatment A, Treatment C, Treatment B and Treatment D)
Cl/F is defined as the apparent total clearance, as calculated by the dose administered/AUC0-inf where AUC(0-inf) is the area under the plasma concentration versus time curve calculated from time 0 to infinity. Blood samples will be collected at indicated timepoints for the analysis of Cl/F.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
%AUCex for Acetaminophen (Treatment A, Treatment C, Treatment B and Treatment D)
%AUCex is defined as the percentage of AUC(0-inf) obtained by extrapolation, calculated as (1-\[AUC0-t/AUC0-inf\]) \*100. Blood samples will be collected at indicated timepoints for the analysis of %AUCex.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-inf) for Acetaminophen (Treatment A, Treatment C, Treatment B and Treatment D)
AUC(0-inf) is defined as the area under the plasma concentration versus time curve calculated from time 0 to infinity. AUC(0-inf) = AUC(0-t) + C(t)/λz where C(t) is the concentration at the last measurable sampling time point and λz is the terminal elimination rate constant. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-inf).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
λz for Acetaminophen (Treatment A, Treatment C, Treatment B and Treatment D)
λz is defined as the terminal elimination rate constant computed as the negative of the slope of the regression line of ln(C\[t\]) on time. Blood samples will be collected at indicated timepoints for the analysis of λz.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
tmax for Acetaminophen (Treatment A, Treatment C, Treatment B and Treatment D)
Blood samples will be collected at indicated timepoints for the analysis of tmax.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
t1/2 for Acetaminophen (Treatment A, Treatment C, Treatment B and Treatment D)
t1/2 is defined as the elimination half-life computed as t1/2 = ln(2)/λz where λz is the terminal elimination rate constant. Blood samples will be collected at indicated timepoints for the analysis of t1/2.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Vz/F for Acetaminophen (Treatment A, Treatment C, Treatment B and Treatment D)
Vz/F is defined as the apparent volume of distribution, as calculated by the dose administered/(λz \*AUC0-inf) where λz is the terminal elimination rate constant and AUC(0-inf) is the area under the plasma concentration versus time curve calculated from time 0 to infinity. Blood samples will be collected at indicated timepoints for the analysis of Vz/F.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Cl/F for Acetaminophen (Treatment A, Treatment C, Treatment B and Treatment D)
Cl/F is defined as the apparent total clearance, as calculated by the dose administered/AUC0-inf where AUC(0-inf) is the area under the plasma concentration versus time curve calculated from time 0 to infinity. Blood samples will be collected at indicated timepoints for the analysis of Cl/F.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Cmax for Ibuprofen (ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A] vs. Advil Liqui-gel Under Fasted Conditions [Treatment D]
Cmax is defined as the maximum observed post-dose concentration for ibuprofen obtained without interpolation. Blood samples will be collected at indicated timepoints for the analysis of Cmax.
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-t) for Ibuprofen (ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A] vs. Advil Liqui-gel Under Fasted Conditions [Treatment D]
AUC(0-t) is defined as the area under the plasma concentration versus time curve calculated from time 0 to the last measurable sampling time point, t, computed using the linear trapezoidal rule. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-t).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
AUC(0-inf) for Ibuprofen (ADA Liquid Filled Capsules Under Fasted Conditions [Treatment A] vs. Advil Liqui-gel Under Fasted Conditions [Treatment D]
AUC(0-inf) is defined as the area under the plasma concentration versus time curve calculated from time 0 to infinity. AUC(0-inf) = AUC(0-t) + C(t)/λz where C(t) is the concentration at the last measurable sampling time point and λz is the terminal elimination rate constant. Blood samples will be collected at indicated timepoints for the analysis of AUC(0-inf).
Time frame: Pre-dose (within 1 hour prior to dosing) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 8,10,12,16,20, and 24 hours post dose on Day 1 in each treatment period (each period is of 3 days)
Number of Participants Reporting Ease of Swallowing: Categorical Response
Immediately after dosing, participants will be asked to evaluate the ease of swallowing to assess the acceptability of each treatment. Participants will be asked to provide a categorical response (Agree/Disagree) to the question "Do you agree or disagree that the product is Easy to swallow?". Number of participants providing response to the question will be reported.
Time frame: Post Dose on Day 1 in each treatment period (each period is of 3 days)
Number of Participants Reporting Ease of Swallowing on a 5-Point Ordinal Scale
Immediately after dosing, participants will be asked to rank the ease of swallowing of each product on a 5-point ordinal scale with scores ranging from 1 to 5 where 1=not easy to swallow; 2=somewhat easy to swallow; 3=average to swallow; 4=above average to swallow; 5=very easy to swallow. Higher score indicates more ease in swallowing.
Time frame: Post Dose on Day 1 in each treatment period (each period is of 3 days)