A Bioequivalence Study of a New Paracetamol Oral Suspension 24mg/ml Compared to the Marketed Paracetamol Oral Suspension (Panadol Baby and Infant 24mg/ml) in Healthy Adult Subjects

Study Overview
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Brief Summary
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The objective of the study is to compare the bioequivalence of a New Paracetamol Oral Suspension 24 milligram/milliliter (mg/ml) with that of an already approved Paracetamol (24 mg/ml) Oral Suspension (Panadol Baby & Infant) when administered to healthy volunteers under fasting condition. Pharmacokinetic parameters will be calculated from plasma concentration data. The rate and extent of absorption of the formulations will be compared.

Detailed Description
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This will be a 2-arm, single center, single dose, open-label, randomized, two-sequence, two period crossover, bioequivalence study in healthy adult participants. Participants will be screened for eligibility within 15 days prior to dosing. Participants will receive each of the two study treatments in fasted state during a 6-day (5-overnight stay) residential period at the study site. Participants will receive both treatment regimens in a randomized order with a 72-hour washout period between each dose. During each treatment period, a total of 21 blood samples will be collected which will include a pre-dose blood sample 1 hour before dosing and 20 post-dose blood samples at 5, 10, 20, 30, 40, 50, 60, 80, 90, 120, 150, 180 minutes, 4, 5, 6, 8, 10, 12, 14, 16 hours, for bioanalytical analyses of paracetamol. Vital signs, clinical safety laboratory tests and monitoring of adverse events will be used to assess the safety and tolerability of the study products.

Official Title
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A Randomized, Open Label, Single Center, Single Dose, Two Period, Two Sequence, Crossover Bioequivalence Study of Paracetamol in a New Pediatric Paracetamol Oral Suspension Compared to a Marketed Paracetamol Oral Suspension (Panadol Baby & Infant) in Healthy Adult Subjects

Conditions
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Pain

Intervention / Treatment
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* Drug: New Paracetamol Oral Suspension (24 mg/ml)
* Drug: Panadol B&I Oral Suspension (24 mg/ml paracetamol)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant provision of a signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study before any assessment is performed. A participant who is willing and able to comply with scheduled visits, treatment plan, laboratory tests, study restrictions and other study procedures. A participant in good general and mental health with, in the opinion of the investigator or medically qualified designee, as determined by medical evaluation, including medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG or clinical laboratory tests. A participant with a Body Mass Index (BMI) of 18.5 to 30.0 kg/m^2; and a total body weight >50 kg Female participants of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for 7 days after the last dose of assigned treatment. Participant with two consecutive negative tests for active COVID-19, separated by > 24 hours. Czech citizenship Exclusion Criteria: A participant who is an employee of the investigational site, either directly involved in the conduct of the study or a member of their immediate family; or an employee of the investigational site otherwise supervised by the investigator; or, a GSKCH employee directly involved in the conduct of the study or a member of their immediate family. A participant who has participated in other studies (including non-medicinal studies) involving investigational product(s) within 30 days before dosing. A participant with, in the opinion of the investigator or medically qualified designee, an acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator or medically qualified designee, would make the participant inappropriate for entry into this study. A participant who is pregnant as confirmed by a positive hCG laboratory test or intending to become pregnant over the duration of the study. A participant who is breastfeeding. A participant with known or suspected intolerance or hypersensitivity to the study materials (or closely related compounds) or any of their stated ingredients. This includes paracetamol and excipients in the products e.g. sorbitol, maltitol glycerol etc. A participant unwilling or unable to comply with Lifestyle Considerations. Diagnosis of long QT syndrome or QTc > 450 msec for males and > 470 msec for females at screening. A participant with evidence or history of clinically significant laboratory abnormality, hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease within the last 5 years that may increase the risk associated with study participation. Any surgical or medical condition which may significantly alter the absorption, distribution, metabolism or excretion of any drug substance but not limited to any of the following: History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling or gastric banding (note: this is not applicable for minor abdominal surgery without significant tissue resection, e.g., appendectomy and herniorrhaphy) History of inflammatory bowel disease History or current evidence of renal disease or impaired renal function at screening as indicated by abnormal levels of serum creatinine (≥ 123 μmol/l) or urea (≥ 8.9 mmol/L) or the presence of clinically significant abnormal urinary constituents (e.g. albuminuria); History or current evidence of ongoing hepatic disease or impaired hepatic function at screening. A candidate will be excluded if more than one of the following lab value deviations are found: 1) AST/SGOT (≥ 1.2 ULN), ALT/SGPT (≥ 1.2 ULN), 2) GGT (≥ 1.2 ULN), ALP (≥ 1.2 ULN), 3) bilirubin (≥ 1.2 ULN) or CK (≥ 3 ULN). A single deviation from the above values is acceptable and will not exclude the candidate, unless specifically advised by the Investigator; Evidence of urinary obstruction or difficulty in voiding at screening. History or clinical evidence at screening of pancreatic injury or pancreatitis A participant with history of regular alcohol consumption exceeding 18 g (women) or 35 g (men) of pure alcohol per day, i.e. 1 drink/day for women or 2 drinks/day for men (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor) within 6 months of screening Participant reported regular consumption of > 5 cups of coffee or tea per day (or equivalent consumption of ≥ 500 mg xanthine per day using other products) Positive results in any of the virology tests for HIV-Ab, HCV-Ab, HBsAg and HBc-Ab (IgG + IgM) Allergy to skin disinfecting agents, tape, or latex rubber, whenever appropriate substitutions cannot be applied or in the Investigator's opinion may pose a risk to the candidate. Any condition not identified in the protocol that in the opinion of the Investigator would confound the evaluation and interpretation of the study data or may put the participant at risk A participant who has previously been enrolled in this study. A participant who, in the opinion of the investigator or medically qualified designee, should not participate in the study Use of any medication (including over-the-counter medications, vitamins, herbal remedies, dietary supplements) within 2 weeks prior to admission to the unit or within less than 10 times the elimination half-life of the respective drug (whichever is longer) or is anticipated to require any concomitant medication during that period or at any time throughout the study. Allowed treatments are: systemic contraceptives and hormone replacement therapy, as long as female participant is on stable treatment for at least 3 months and continues treatment throughout the study; occasional use of ibuprofen 200 mg (up to 1200 mg daily) or equivalent analgesic Participant reports consumption of any drug metabolizing enzyme (e.g. CYP3A4 or other cytochrome P450 enzymes) inducing or inhibiting aliments, beverages or food supplements (e.g. broccoli, Brussels sprouts, grapefruit, grapefruit juice, star fruit, St. John's Wort etc.) within 2 weeks prior to admission to the unit Sitting blood pressure after a minimum of 5 minutes of rest is out of the range of 90-140 mmHg for systolic BP and/or 60-90 mmHg for diastolic BP and/or heart rate out of the range of 50-100 bpm during the screening procedure. Body temperature is consistently out of the range of 35.4-37.3°C at screening, at check-in or during the study. Clinically relevant chronic or acute infectious illnesses or febrile infections within 2 weeks prior to screening till admission to the unit A participant with a positive urine drug screen, alcohol breath test at screening and on day of admission to the unit Smokers, defined as the use of tobacco products during the 3 months prior to screening till admission to the unit or a positive urine cotinine test at screening Performance of strenuous physical exercise (body building, high performance sports) from 2 weeks prior to admission to the unit Donation or loss of at least 500 mL of blood within 90 days or any donation of plasma or platelets from 2 weeks prior to admission to the unit Getting a tattoo, body piercing or any cosmetic treatment involving skin penetration within 90 days before the screening till admission to the unit, unless evaluated by Investigator as non-significant for inclusion in the study Participant with signs and symptoms suggestive of COVID-19 (i.e. fever, cough, etc.) from 2 weeks prior to screening till admission to the unit Participant with known COVID-19 positive contacts in the past from 2 weeks prior to screening till admission to the unit Participants who were hospitalized for COVID-19 related reasons

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a 2-arm, single center, single dose, open-label, randomized, two sequence, two-period crossover, bioequivalence study in healthy adult subjects, separated by one wash-out period of at least 72 hours.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test Drug<br>Participants will receive a single oral dose of either New Paracetamol Oral Suspension (24 mg/ml) or Panadol B&I Oral Suspension (24 mg/ml paracetamol) on Day 1 (Period 1) and Day 4 (Period 2) under fasting conditions as per the randomization schedule. A wash out period of at least 72-hour will be maintained between each treatment period. | Drug: New Paracetamol Oral Suspension (24 mg/ml)<br>* After an overnight fasting for at least 10 hours, New Paracetamol Oral Suspension (24 mg/ml) in a volume of 42 ml will be administered orally via a single use syringe by a trained study person to the study participants as per the randomization schedule in each period.<br>|
| Active Comparator: Reference Drug<br>Participants will receive a single oral dose of either New Paracetamol Oral Suspension (24 mg/ml) or Panadol B&I Oral Suspension (24 mg/ml paracetamol) on Day 1 (Period 1) and Day 4 (Period 2) under fasting conditions as per the randomization schedule. A wash out period of at least 72-hour will be maintained between each treatment period | Drug: Panadol B&I Oral Suspension (24 mg/ml paracetamol)<br>* After an overnight fasting for at least 10 hours, Panadol B&I Oral Suspension (24 mg/ml paracetamol) in a volume of 42 ml will be administered orally via a single use syringe by a trained study person to the study participants as per the randomization schedule in each period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve Calculated from Time 0 to the Last Measurable Sampling Time Point [AUC(0-tlast)] | AUC(0-tlast) = Area under the plasma concentration time curve from 0 to time of the last measurable sampling time point of both test and reference drug. | Predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.33, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours Post dose in each treatment period | 
| Time of the Maximum Observed Post-Dose Concentration (tmax) | Tmax = time (hours) to maximum plasma concentration (Cmax). | Predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.33, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours Post dose in each treatment period | 
| Maximum Observed Post-Dose Concentration (Cmax) | Cmax = maximum observed plasma concentration. | Predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.33, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours Post dose in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve Calculated From Time Zero to Infinity [AUC (0-inf)] | AUC0-inf = AUC0-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. | Predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.33, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours Post dose in each treatment period | 
| Percentage of Area Under the Plasma Concentration Versus Time Curve Calculated From Time Zero to Infinity [AUC (0-inf)] Obtained by Extrapolation | Percentage of AUC0-inf will be obtained by extrapolation, calculated as: (1- [AUC(0-t) /AUC (0-inf)]) ×100) | Predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.33, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours Post dose in each treatment period | 
| Terminal Elimination Rate Constant (λz) | λz computed as the slope of the regression line of ln [C(t)] on time. The regression should generally involve at least 3 consecutive measurable concentrations that decrease over time. | Predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.33, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours Post Dose in each treatment period |