Bioequivalence Study Between SKF101804 Cefixime 200 Milligram (mg)/5 Milliliter (mL) Suspension Versus Cefixime 200 mg/5 mL Suspension Reference Product in Healthy Adult Subjects Under Fasting Conditions

Study Overview
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Brief Summary
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This study is open-label, randomized two-way cross-over study to determine if cefixime 200 mg/5 mL powder for suspension (test formulation: SKF101804) is bioequivalent to cefixime 200 mg/5 mL suspension reference formulation. Study will be conducted in 28 healthy adult subjects under fasting conditions. There will be two treatment periods and each subject will participate in both periods. The washout period between both treatment periods will be 7-14 days. Subjects will be randomized to either of treatment sequences of reference followed by test or test followed by reference to receive a single dose of test or reference formulation on Day 1 in each treatment period. The study will last for 5 to 7 weeks.

Official Title
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An Open-label, Randomised, Single-dose, Two-period Cross-over Study to Evaluate Bioequivalence of SKF101804 Cefixime 200 mg/5 mL Suspension Versus Cefixime 200 mg/5 mL Suspension Reference Product in Healthy Adult Participants Under Fasting Conditions

Conditions
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Infections, Bacterial

Intervention / Treatment
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* Drug: Test formulation A
* Drug: Reference formulation B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent. Subject must be healthy, non-smoker, as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the normal reference range for the population being studied may be included at investigator discretion in consultation with the Medical Monitor if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Subject with a body weight 50 kilogram (kg) and body mass index (BMI) within the range 19-30 kilogram per meter square (kg/m^2) (inclusive). A healthy male subject must agree to use contraception during the treatment period and for at least 5 days after the last dose of study treatment and refrain from donating sperm during this period. A female subject is eligible to participate if she is not pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days after the last dose of study treatment. A subject should be capable of giving signed informed consent. Exclusion Criteria: Subject with history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data. Subjects with any other condition that is capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data. Subject with abnormal renal function, as determined by creatinine clearance and considered as clinically significant by the investigator will be excluded. Subject with abnormal blood pressure (BP) as determined by the investigator. Subject with lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. Subject who had breast cancer within the past 10 years. ALT >1.5 times upper limit of normal (ULN). Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Subject with current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Subject with history of colitis Subject with history of cephalosporin induced hemolytic anemia. QT interval corrected for heart rate according to Bazett's formula (QTcB) >450 milliseconds (msec). Subjects with a known risk of QT prolongation will be excluded. Past or intended use of over-the-counter or prescription medication including herbal medications, within 14 days prior to dosing unless in the opinion of the investigator and sponsor, the medication will not interfere with the study. Participation in the study would result in loss of blood or blood products in excess of 500 mL within 90 days. Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Current enrolment or past participation within the last 90 days before signing of consent in this or any other clinical study involving an investigational study treatment or any other type of medical research. Presence of Hepatitis B surface antigen (HBsAg) at screening. Positive Hepatitis C antibody test result at screening. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained. Positive pre-study drug/alcohol screen. Positive human immunodeficiency virus (HIV) antibody test. Regular use of known drugs of abuse. Subjects with regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. Subjects with urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening. Subjects who are sensitive to heparin or heparin-induced thrombocytopenia. Subjects with known sensitivity to any drugs from the class of cephalosporin, or components thereof. Subjects with known sensitivity to any drugs from the class of penicillin, or components thereof. Subjects with known sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test followed by Reference Formulation<br>Subjects will be randomized to receive single dose of Test formulation (SKF101804: cefixime 200 mg/ 5 mL) on Day 1 of the treatment period 1 and Reference formulation (cefixime 200 mg/5 mL) on Day 1 of the treatment period 2. There will be wash out period of 7-14 days between the two treatment periods. | Drug: Test formulation A<br>* Test formulation: SKF101804 will be available as oral suspension supplied as powder for reconstitution (Off-white to cream coloured powder). Subjects will receive single dose of 5 mL of suspension thus receiving 200 mg dose of cefixime. The suspension is a white to off white viscous suspension with a fruit flavor and odor.<br>Drug: Reference formulation B<br>* Reference formulation will be available as oral suspension supplied as powder for reconstitution (Off-white to cream coloured powder). Subjects will receive single dose of 5 mL of suspension thus receiving 200 mg dose of cefixime. The suspension is a white to off white viscous suspension with a strawberry flavor and odor.<br>|
| Experimental: Reference followed by Test Formulation<br>Subjects will be randomized to receive single dose of Reference formulation (cefixime 200 mg/5 mL) on Day 1 of the treatment period 1 and Test formulation (SKF101804: cefixime 200 mg/ 5 mL) on Day 1 of the treatment period 2. There will be wash out period of 7-14 days between the two treatment periods. | Drug: Test formulation A<br>* Test formulation: SKF101804 will be available as oral suspension supplied as powder for reconstitution (Off-white to cream coloured powder). Subjects will receive single dose of 5 mL of suspension thus receiving 200 mg dose of cefixime. The suspension is a white to off white viscous suspension with a fruit flavor and odor.<br>Drug: Reference formulation B<br>* Reference formulation will be available as oral suspension supplied as powder for reconstitution (Off-white to cream coloured powder). Subjects will receive single dose of 5 mL of suspension thus receiving 200 mg dose of cefixime. The suspension is a white to off white viscous suspension with a strawberry flavor and odor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments (AUC [0-t]) for Cefixime | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of cefixime under fasted state. Pharmacokinetic analysis of cefixime was conducted using non-compartmental methods. Pharmacokinetic Population comprised of participants who completed the study and for whom primary pharmacokinetic parameters could be calculated for all treatment periods were included in the statistical pharmacokinetic analysis of the study. | Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 8.0, 10.0, 12.0, 16.0 and 20.0 hours post dose on Day 1, 24.00 hours post dose on Day 2 of each treatment period | 
| Maximum Observed Plasma Concentration (Cmax) Within a Participant Across All Treatments of Cefixime | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of cefixime under fasted state. Pharmacokinetic analysis of cefixime was conducted using non-compartmental methods. | Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 8.0, 10.0, 12.0, 16.0 and 20.0 hours post dose on Day 1, 24.00 hours post dose on Day 2 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to (AUC [0-infinity]) Across All Treatments for Cefixime | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of cefixime under fasted state. Pharmacokinetic analysis of cefixime was conducted using non-compartmental methods. | Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 8.0, 10.0, 12.0, 16.0 and 20.0 hours post dose on Day 1, 24.00 hours post dose on Day 2 of each treatment period | 
| Time of Occurrence of Cmax (Tmax) for Cefixime | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of cefixime under fasted state. Pharmacokinetic analysis of ciprofloxacin was conducted using non-compartmental methods. Tmax of cefixime was analyzed using a nonparametric test to compute point estimate of the median and full range. | Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 8.0, 10.0, 12.0, 16.0 and 20.0 hours post dose on Day 1, 24.00 hours post dose on Day 2 of each treatment period | 
| Percentage of AUC(0-infinity) Obtained by Extrapolation (%AUCex) for Cefixime | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of cefixime under fasted state. Pharmacokinetic analysis of cefixime was conducted using non-compartmental methods. | Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 8.0, 10.0, 12.0, 16.0 and 20.0 hours post dose on Day 1, 24.00 hours post dose on Day 2 of each treatment period | 
| Terminal Phase Half-life (T1/2) for Cefixime | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of cefixime under fasted state. Pharmacokinetic analysis of cefixime was conducted using non-compartmental methods. | Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0 8.0, 10.0, 12.0, 16.0 and 20.0 hours post dose on Day 1, 24.00 hours post dose on Day 2 of each treatment period | 
| Number of Participants With Non-serious Adverse Events (AE) and Serious Adverse Events (SAE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/ incapacity, is a congenital anomaly/ birth defect or other situations. The analysis was performed on Safety Population which comprised of all randomized participants who received at least 1 dose of study treatment. Participants were analyzed according to the treatment they actually received. | Up to Day 16 in each treatment period | 
| Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), and Aspartate Aminotransferase (AST) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of clinical chemistry parameters including ALT, ALP and AST. | Day -1 and Day 2 of each treatment period | 
| Blood Urea Nitrogen (BUN) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of BUN. | Day -1 and Day 2 of each treatment period | 
| Calcium, Glucose, Potassium and Sodium at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of clinical chemistry parameters including calcium, glucose, potassium and sodium. | Day -1 and Day 2 of each treatment period | 
| Total Bilirubin (Total Bil), Direct Bilirubin (Direct Bil) and Creatinine (Creat) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of clinical chemistry parameters including total bil, direct bil and creat. | Day -1 and Day 2 of each treatment period | 
| Total Protein at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of total Protein. | Day -1 and Day 2 of each treatment period | 
| Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of hematology parameters including platelets, neutrophils, monocytes, lymphocytes, leucocyte, eosinophils and basophils. | Day -1 and Day 2 of each treatment period | 
| Mean Corpuscular Volume (MCV) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of MCV. | Day -1 and Day 2 of each treatment period | 
| Mean Corpuscular Hemoglobin (MCH) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of MCH. | Day -1 and Day 2 of each treatment period | 
| Erythrocyte Count at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of erythrocyte count. | Day -1 and Day 2 of each treatment period | 
| Hematocrit at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of hematocrit. | Day -1 and Day 2 of each treatment period | 
| Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Hb) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of hematology parameters including MCHC and Hb. | Day -1 and Day 2 of each treatment period | 
| Percent Reticulocytes at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of percent reticulocytes. | Day -1 and Day 2 of each treatment period | 
| Number of Participants With Potential Clinical Importance (PCI) Abnormal Findings for Urinalysis | Urine samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2. PCI ranges for urinalysis parameters were as follows: specific gravity 1.001 to 1.035 kilogram per liter, blood negative (0 to 9) RBC per microliter, pH 4.6 to 8.0, protein negative (0.0 to 0.14) gram per liter, glucose negative (0 to 5.49) millimoles per liter, ketones negative (0.0 to 0.49) millimoles per liter, urobilinogen (0.0 to 1.0) milligrams per deciliter, urine leucocytes negative (0 to 14) leucocytes per microliter, Urine WBC, RBC and epithelial cells 0 to 5 high power per field. | Day -1 and Day 2 of each treatment period | 
| Respiratory Rate at Indicated Time-points | Respiratory rate of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. | Day 1 Pre-dose 1.5 hours, Day 1 post-dose 2, 4, and 6 hours and Day 2 post-dose 24 hours of each treatment period | 
| Pulse Rate at Indicated Time-points | Pulse rate of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. | Day 1 Pre-dose 1.5 hours, Day 1 post-dose 2, 4, and 6 hours and Day 2 post-dose 24 hours of each treatment period | 
| Body Temperature at Indicated Time-points | Body temperature of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. | Day 1 Pre-dose 1.5 hours, Day 1 post-dose 2, 4, and 6 hours and Day 2 post-dose 24 hours of each treatment period | 
| Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time-points | Blood pressure of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. | Day 1 Pre-dose 1.5 hours, Day 1 post-dose 2, 4, and 6 hours and Day 2 post-dose 24 hours of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Single dose, Oral suspension, Bioequivalence, Cefixime, Two-way crossover