Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of Topical GSK1278863 in Healthy Volunteers and Diabetic Patients, and Repeat Doses of GSK1278863 in Diabetic Patients for the Treatment of Diabetic Foot Ulcer

Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC(0-inf)] of GSK1278863 (Part A)

时间窗: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-inf) could not be determined as data was below the limit of quantification.

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)] of GSK1278863 (Part A)

时间窗: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hrs post-dose

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-t) could not be determined as data was below the limit of quantification.

Number of Participants With Abnormal Nurse/Physician Observation (Part B)

时间窗: Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])

A brief physical assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen) were planned to be performed by qualified licensed, medical professional (i.e., physician, physician assistant, or nurse practitioner) but was not performed. Since data was not collected, no analysis was performed.

AUC(0-inf) of GSK1278863 (Part B)

时间窗: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-inf) could not be determined as data was below the limit of quantification.

Number of Participants With AEs and SAEs Following Repeat Dose Administration (Part B)

时间窗: Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is 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; other important medical events; or is associated with liver injury and impaired liver function.

Number of Participants With Clinically Significant 12-lead ECG Measurement Following Repeat Dose Administrations (Part B)

时间窗: Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])

ECG measurements were taken with the participants in supine position for at least 5 minutes. The number of participants with clinically significant abnormal ECG measurement following single dose administration for worst case post-Baseline visit has been presented.

Number of Participants With Clinical Chemistry Values Outside the Clinical Concern Range (Part A)

时间窗: Day 1 (pre-dose and 48 hours) in period 1; Day 1 (48 hours) in period 2

Chemistry parameters assessed were: Blood urea nitrogen (BUN), creatinine, fasting glucose, sodium, creatine phosphokinase (CPK), potassium, chloride, total carbon dioxide (CO2), calcium, glycosylated hemoglobin (HbA1C), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gamma glutamyltransferase (GGT), Alkaline phosphatase (ALP), High sensitivity C-reactive protein (hsCRP), total and direct bilirubin, uric acid, albumin and total protein. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Following Single Dose Administration (Part A)

时间窗: Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is 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; other important medical events; or is associated with liver injury and impaired liver function.

Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Measurement Following Single Dose Administrations (Part A)

时间窗: Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])

ECG measurements were taken with the participants in supine position for at least 5 minutes. The number of participants with clinically significant abnormal ECG measurement following single dose administration for worst case post-Baseline visit has been presented.

Number of Participants With Vital Sign Data Outside Clinical Concern Range Following Single Dose Administration (Part A)

时间窗: Day 1 (pre-dose and 48 hours) of Periods 1 and 2

Vital sign measurements included systolic blood pressure (SBP) and diastolic blood pressure (DBP). Vital signs were measured after the participants rested in a supine or semi-supine position for 5 minutes prior to the procedure. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.

Number of Participants With Clinical Chemistry Values Outside the Clinical Concern Range (Part B)

时间窗: Days 1 and 7 (pre-dose) and Day 14 (24 hours)

Chemistry parameters assessed were: Blood urea nitrogen (BUN), creatinine, fasting glucose, sodium, creatine phosphokinase (CPK), potassium, chloride, total carbon dioxide (CO2), calcium, glycosylated hemoglobin (HbA1C), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gamma glutamyltransferase (GGT), Alkaline phosphatase (ALP), High sensitivity C-reactive protein (hsCRP), total and direct bilirubin, uric acid, albumin and total protein. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.

Maximum Observed Concentration (Cmax) of GSK1278863 (Part A)

时间窗: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hrs post-dose

The pharmacokinetic (PK) parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Cmax could not be determined as data was below the limit of quantification.

Cmax of GSK1278863 (Part B)

时间窗: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Cmax could not be determined as data was below the limit of quantification.

Time of Occurrence of Cmax (Tmax) of GSK1278863 (Part A)

时间窗: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tmax could not be determined as data was below the limit of quantification.

Apparent Terminal Elimination Half-life (t1/2) of GSK1278863 (Part A)

时间窗: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. t1/2 could not be determined as data was below the limit of quantification.

Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) (Part A)

时间窗: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tlag could not be determined as data was below the limit of quantification.

Number of Participants With Vital Sign Data Outside Clinical Concern Range Following Repeat Dose Administration (Part B)

时间窗: Days 1 and 7 (pre-dose), Day 14 (24 hours)

Vital sign measurements included systolic blood pressure (SBP) and diastolic blood pressure (DBP). Vital signs were measured after the participants rested in a supine or semi-supine position for 5 minutes prior to the procedure. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.

Number of Participants With Abnormal Nurse/Physician Observation (Part A)

时间窗: Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])

A brief physical assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen) were planned to be performed by qualified licensed, medical professional (i.e., physician, physician assistant, or nurse practitioner) but was not performed.Since data was not collected, no analysis was performed.

Number of Participants With Hematology Values Outside the Clinical Concern Range (Part A)

时间窗: Day 1 (pre-dose)

Hematology parameters assessed were: platelet count, red blood cell count, white blood cell count, hemoglobin, reticulocyte count, hematocrit, absolute neutrophil count (ANC), monocytes, lymphocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. When a high or low value was reported, all values are presented for that time point and parameter.

Number of Participants With Hematology Data Outside the Clinical Concern Range (Part B)

时间窗: Day 1 (pre-dose)

Hematology parameters assessed were: platelet count, red blood cell count, white blood cell count, hemoglobin, reticulocyte count, hematocrit, neutrophils, monocytes, lymphocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. When a high or low value was reported, all values are presented for that time point and parameter.

Tmax of GSK1278863 (Part B)

时间窗: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tmax could not be determined as data was below the limit of quantification.

t1/2 of GSK1278863 (Part B)

时间窗: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. t1/2 could not be determined as data was below the limit of quantification.

AUC(0-t) of GSK1278863 (Part B)

时间窗: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-t) could not be determined as data was below the limit of quantification.

Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) (Part B)

时间窗: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tlag could not be determined as data was below the limit of quantification.