A Three-Part Phase I, Open-Label, Single Ascending Dose, and A Single-Blind, Placebo-Controlled, Repeat Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Relative Bioavailability of Intravenous and Oral GSK1322322 in Healthy Volunteers and Healthy Male Japanese Subjects
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Composite of PK parameters for single oral dose of GSK1322322 in Part A
研究概览
简要总结
The primary objectives of this study are to assess the safety, tolerability and pharmacokinetics of GSK1322322 following intravenous (IV) and oral administration. GSK1322322 shows broad spectrum antibacterial activity against pathogens involved in respiratory tract infections as well as methicillin-resistant S. Aureus (MRSA).
This study consists of three parts (Part A, Part B and Part C). The results from Part A of this study will enable use of large-scale, commercial tablets produced for administration to patients in pivotal clinical trials of GSK1322322. The results from Parts B and C will support enrolment of Japanese subjects in future clinical studies. Additionally, the results will support the dose selection for further clinical development of GSK1322322 in hospitalized patients with severe bacterial infections in Japan and other Asian populations.
In Part A, subjects will undergo screening, 4 treatment periods receiving single dose of each of: 1500 mg Initial, fit-for-purpose tablet (product code AP), 1500 mg Over granulated tablet (product code AR), and the 1500 mg and 2000 mg of intended commercial tablets (product code AU).
In Part B of the study subjects will undergo screening, and be randomized to receive 3 doses of GSK1322322 oral cohort (100 mg, 1500 mg and 2000 mg) or IV cohort (600 mg, 900 mg and 1200 mg) each in 3 treatment periods.
Part C will be a single-blind, placebo-controlled, repeat dose study of GSK1322322 in healthy Japanese male subjects. GSK1322322 will be administered (fasted) via IV for 4 days BID, followed by administration of GSK1322322 orally (fed) for 6 days BID. A follow-up evaluation will be conducted 7-10 days following last dose of for each subjects in each Part of the study.
Approximately 12 subjects will be enrolled in each part of the study such that approximately 8, 6, and 9 subjects complete dosing and critical assessments in part A,B, and C respectively.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Part A GSK1322322 single dose Arm
Subjects will receive single dose of one of the following 4 GSK1322322 treatments in 4 treatment periods (one per period) with an aqueous suspension of a low dose of GSK1322322F (stable isotope labeled drug substance) PO in a fed condition: 1500 mg (fit for purpose formulation), 1500 mg (intended commercial formulation), 1500 mg (over granulated formulation), and 2000 mg (intended commercial formulation)
干预措施: GSK1322322 Initial fit for purpose tablets (Drug)
Part A GSK1322322 single dose Arm
Subjects will receive single dose of one of the following 4 GSK1322322 treatments in 4 treatment periods (one per period) with an aqueous suspension of a low dose of GSK1322322F (stable isotope labeled drug substance) PO in a fed condition: 1500 mg (fit for purpose formulation), 1500 mg (intended commercial formulation), 1500 mg (over granulated formulation), and 2000 mg (intended commercial formulation)
干预措施: GSK1322322 over granulated tablets (Drug)
Part A GSK1322322 single dose Arm
Subjects will receive single dose of one of the following 4 GSK1322322 treatments in 4 treatment periods (one per period) with an aqueous suspension of a low dose of GSK1322322F (stable isotope labeled drug substance) PO in a fed condition: 1500 mg (fit for purpose formulation), 1500 mg (intended commercial formulation), 1500 mg (over granulated formulation), and 2000 mg (intended commercial formulation)
干预措施: GSK1322322 intended commercial tablets (Drug)
Part A GSK1322322 single dose Arm
Subjects will receive single dose of one of the following 4 GSK1322322 treatments in 4 treatment periods (one per period) with an aqueous suspension of a low dose of GSK1322322F (stable isotope labeled drug substance) PO in a fed condition: 1500 mg (fit for purpose formulation), 1500 mg (intended commercial formulation), 1500 mg (over granulated formulation), and 2000 mg (intended commercial formulation)
干预措施: 13C-GSK1322322 stable isotope powder (Drug)
Part B Cohort 1- GSK1322322 Oral Arm
Subjects in this part will receive single dose of GSK1322322 on Day 1 of each of the three treatment periods. Subjects in Cohort 1 will receive following GSK1322322 (intended commercial formulation) doses po in fed state: 1000 mg, 1500 mg and 2000 mg
干预措施: GSK1322322 intended commercial tablets (Drug)
Part B Cohort 2 -GSK1322322 IV Arm
Subjects in this part will receive single dose of GSK1322322 on Day 1 of each of the three treatment periods. Subjects in Part B Cohort 2 will receive following GSK1322322 IV fasted doses (one per period): 600 mg, 900 mg and 1200 mg
干预措施: GSK1322322 for injection (Drug)
Part C GSK1322322 Arm
Subjects in this arm will receive repeat doses of GSK1322322 as following: GSK1322322 1200 mg IV fasted for 4 days twice a day (BID), followed by GSK1322322 2000 mg orally fed for 6 days BID
干预措施: GSK1322322 intended commercial tablets (Drug)
Part C GSK1322322 Arm
Subjects in this arm will receive repeat doses of GSK1322322 as following: GSK1322322 1200 mg IV fasted for 4 days twice a day (BID), followed by GSK1322322 2000 mg orally fed for 6 days BID
干预措施: GSK1322322 for injection (Drug)
Part C Placebo Arm
Subjects in this arm will receive repeat doses of Placebo IV fasted for 4 days BID, followed by placebo po fed for 6 days BID
干预措施: Placebo tablets (Drug)
Part C Placebo Arm
Subjects in this arm will receive repeat doses of Placebo IV fasted for 4 days BID, followed by placebo po fed for 6 days BID
干预措施: Placebo injection (Drug)
结局指标
主要结局
Composite of PK parameters for single oral dose of GSK1322322 in Part A
时间窗: Up to 16 days in Part A. Collection will be done for each period at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose
PK parameters include: area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC\[0-t\]), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0-infinite\]), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2)
AUC(0-infinite) comparison for bioavailability assessment for three formulations of GSK1322322 in Part A
时间窗: Up to 16 days in Part A. Collection will be done for each period at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose
To evaluate the relative oral bioavailability, the AUC (0-infinite) of the three formulations (Initial fit-for-purpose tablets, Over-granulated tablets, and Intended commercial tablets) will be compared. Bioavailability is defined as the amount of drug available at the site of action after administration
Composite of PK parameters to assess dose proportionality of the GSK1322322 Over-granulated formulation tablets of 1500 mg and 2000 mg
时间窗: Up to 16 days in Part A. Collection will be done for each period at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose
PK parameters include: AUC (0-infinite) and Cmax. to demonstrate similar or different bioavailability across the two dose levels in Part A
Composite of PK parameters for single oral dose of GSK1322322 in healthy Japanese subjects in Part B
时间窗: Up to 12 days in Part B. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post dose
PK parameters include: AUC(0-t), AUC (0-infinite), Cmax, tmax, and t1/2
Composite of PK parameters for single intravenous (IV) dose of GSK1322322 in healthy Japanese subjects in Part B
时间窗: Up to 12 days in Part B. Collection will be done at pre-dose 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post infusion start
PK parameters include: AUC(0-t), AUC (0-infinite), Cmax, volume of distribution at steady state (Vss), mean residence time intravenous (MRTiv), t1/2, and systemic clearance of parent drug (CL)
Composite of PK parameters for repeat IV dose of GSK1322322 in healthy Japanese subjects in Part C
时间窗: Up to 10 days in Part C. Collection will be done at pre-dose 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post dose on Day 1, Day 4 and Day 10
In Part C, on Day 1 after the morning IV dose, area under the concentration-time curve from time zero (pre-dose) to 12 hours after dosing \[AUC(0-12)\] and Cmax will be computed; on Day 4 after the morning IV dose, area under the concentration-time curve over the dosing interval \[AUC(0-tau)\], Cmax, and systemic clearance at steady state (CLss) will be computed; on Day 10, after the oral morning dose, AUC(0-tau), Cmax, tmax, will be computed
次要结局
- Safety and tolerability of single oral dose of GSK1322322 in healthy subjects assessed by the collection of adverse events (AEs) in Part A(Up to 23 days)
- Collection of AEs to assess safety and tolerability of single oral and IV GSK1322322 doses in healthy Japanese male subjects in Part B(Up to19 days)
- Collection of AEs to assess safety and tolerability of repeat oral and IV GSK1322322 doses in healthy Japanese male Subjects in Part C(Up to18 days)
- Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, electrocardiogram (ECG) intervals, ECG rhythm in healthy subjects in Part A(Up to 23 days)
- Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, ECG intervals, ECG rhythm in healthy Japanese male Subjects in Part B(Up to 19 days)
- Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, ECG intervals, ECG rhythm in healthy Japanese male Subject in Part C(Up to 18 days)
- Dose proportionality of GSK1322322 following IV and oral single dose in Part B(Up to 12 days. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post dose)
- GSK1322322 accumulation ratio following repeat IV administration in Part C(Day 1 and Day 4. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post infusion start)
- The potential relationship of CL/CLss following single IV dose versus body weight in Part B(Up to 12 days. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post infusion start)
- The potential relationship of CL/CLss following repeat IV doses versus body weight in Part C(Up to 10 days. Collection will be done at pre-dose 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post infusion)