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

Phase 1

Completed

• Conditions: Infections, Bacterial
• Interventions: Drug: Test formulation A; Drug: Reference formulation B

• Registration Number: NCT03408392
• Lead Sponsor: GlaxoSmithKline

Brief Summary

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-01-17
• Study First Submitted QC: 2018-01-17
• Study First Posted: 2018-01-24
• Study Start: 2018-02-06
• Primary Completion: 2018-03-13
• Study Completion: 2018-03-13
• Results First Submitted: 2018-12-11
• Results First Submitted QC: 2018-12-11
• Results First Posted: 2019-03-22
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-17
• Last Update Posted: 2020-02-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Reference followed by Test Formulation	Test formulation A	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.
Test followed by Reference Formulation	Reference formulation B	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.
Test followed by Reference Formulation	Test formulation A	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.
Reference followed by Test Formulation	Reference formulation B	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.

Primary Outcome Measures

Name	Time	Method
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	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	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.
Maximum Observed Plasma Concentration (Cmax) Within a Participant Across All Treatments of Cefixime	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	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.

Secondary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to (AUC [0-infinity]) Across All Treatments for Cefixime	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	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.
Terminal Phase Half-life (T1/2) for Cefixime	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	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.
Mean Corpuscular Hemoglobin (MCH) at Indicated Time-points	Day -1 and Day 2 of each treatment period	Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of MCH.
Blood Urea Nitrogen (BUN) at Indicated Time-points	Day -1 and Day 2 of each treatment period	Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of BUN.
Total Protein at Indicated Time-points	Day -1 and Day 2 of each treatment period	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.
Mean Corpuscular Volume (MCV) at Indicated Time-points	Day -1 and Day 2 of each treatment period	Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of MCV.
Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), and Aspartate Aminotransferase (AST) at Indicated Time-points	Day -1 and Day 2 of each treatment period	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.
Erythrocyte Count at Indicated Time-points	Day -1 and Day 2 of each treatment period	Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of erythrocyte count.
Number of Participants With Potential Clinical Importance (PCI) Abnormal Findings for Urinalysis	Day -1 and Day 2 of each treatment period	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.
Time of Occurrence of Cmax (Tmax) for Cefixime	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	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.
Percentage of AUC(0-infinity) Obtained by Extrapolation (%AUCex) for Cefixime	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	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.
Calcium, Glucose, Potassium and Sodium at Indicated Time-points	Day -1 and Day 2 of each treatment period	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.
Total Bilirubin (Total Bil), Direct Bilirubin (Direct Bil) and Creatinine (Creat) at Indicated Time-points	Day -1 and Day 2 of each treatment period	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.
Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points	Day -1 and Day 2 of each treatment period	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.
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time-points	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	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.
Number of Participants With Non-serious Adverse Events (AE) and Serious Adverse Events (SAE)	Up to Day 16 in each treatment period	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.
Hematocrit at Indicated Time-points	Day -1 and Day 2 of each treatment period	Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of hematocrit.
Percent Reticulocytes at Indicated Time-points	Day -1 and Day 2 of each treatment period	Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of percent reticulocytes.
Respiratory Rate at Indicated Time-points	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	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.
Body Temperature at Indicated Time-points	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 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.
Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Hb) at Indicated Time-points	Day -1 and Day 2 of each treatment period	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.
Pulse Rate at Indicated Time-points	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 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.

Trial Locations

Locations (1)

GSK Investigational Site; 🇿🇦 Bloemfontein, Free State, South Africa