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Antimicrobial penetration can be assessed through evaluation of antimicrobial concentrations in various lung compartments, including bronchial mucosal tissue, epithelial lining fluid (ELF), and alveolar macrophages (AM). Antimicrobial concentrations determined in ELF and alveolar macrophages represent an ideal estimate of concentrations at the site of infection and can be accessed via bronchoalveolar lavage (BAL). However sampling of antimicrobial concentrations via BAL is not routine in clinical practice due to its complex methodology and poor patient tolerability. This study will evaluate intrapulmonary and plasma pharmacokinetics of GSK2140944 after single IV dose in adult healthy volunteers. This is a Phase I, open-label study to evaluate plasma and pulmonary pharmacokinetics following intravenous administration of GSK2140944 in healthy adult participants. Part A will evaluate the single dose PK profiles. Part B is optional and will only be conducted if necessary. Each part will consist of a maximum of 6 cohorts. In Part A, only 4 of the 6 cohorts will be dosed initially; cohorts 5 and 6 are optional and will only be dosed if additional time-points are necessary to adequately model the pulmonary pharmacokinetic profile.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A(Cohort1) | Experimental | Study BTZ116666 has two parts. Each part will consist of a maximum of 6 cohorts. Part A will be initiated with 4 initial cohorts/timepoints in order to minimize the number of healthy volunteers that undergo bronchoscopy in this study. After review of data from Cohorts 1 through 4 of Part A, the study team will determine if additional cohorts are needed to be studied in Part A and/ or if Part B is needed. If the study team determines that additional cohorts are needed, then only the necessary cohorts in Parts A and/or B will be executed. In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 2 hours x 1 dose |
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| Part A (Cohort2) | Experimental | In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 4 hours x 1 dose |
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| Part A (Cohort3) | Experimental | In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 8 hours x 1 dose |
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| Part A (Cohort4) | Experimental | In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 12 hours x 1 dose |
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| Part A (Cohort5) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GSK2140944 (Single dose) | Drug | A lyophilized formulation, pale yellow to grayish yellow cake containing 750 mg of GSK2140944 (as free base) per vial, Administered intravenously as a single dose. |
| Measure | Description | Time Frame |
|---|---|---|
| Pulmonary pharmacokinetics of GSK2140944 following intravenous single-dose administration. | Blood samples will be collected assessment of PK parameters including Epithelial Lining Fluid (ELF) and Alveolar Macrophages (AM) (AUC[0- Ï„]), 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]), Maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax), ELF and AM/plasma ratios for GSK2140944 at the early, mid and late dosing interval timepoints, and AUCELF/AUC plasma and AUCAM/AUC plasma ratios, as data permit. | Day 1, Day 2, Day 3 |
| Plasma pharmacokinetics of GSK2140944 following intravenous single-dose administration. | Blood sample will be collected for estimation of relative bioavailability and assessment of PK parameters including maximum observed concentration; Cmax, area under the concentration-time curve from time 0 to time t; AUC (0-t) and area under the concentration-time curve from time 0 to infinity; AUC(0-infinity), Systemic clearance of parent drug (CL), Volume of distribution at steady state of parent drug after intravascular (e.g., IV) administration (Vdss) and Terminal phase half-life (t½). | Day 1, Day 2, Day 3 |
| Pulmonary pharmacokinetics of GSK2140944 following repeat daily multiple intravenous dose administration. | Blood samples will be collected assessment of PK parameters including ELF and AM AUC(0- Ï„)), AUC(0-t), Cmax, tmax, ELF and AM/plasma ratios for GSK2140944 at the early, mid and late dosing interval timepoints, and AUCELF/AUC plasma and AUCAM/AUC plasma ratios, as data permit. | Day1, Day 2, Day 3, Day 4, Day 5 |
| Plasma pharmacokinetics of GSK2140944 following repeat daily multiple intravenous dose administration. | Blood sample will be collected for estimation of relative bioavailability and assessment of PK parameters including maximum observed concentration; Cmax, area under the concentration-time curve from time 0 to time t; AUC (0-t) and area under the concentration-time curve from time 0 to infinity; AUC(0-infinity), Systemic clearance of parent drug (CL), Volume of distribution at steady state of parent drug after intravascular (e.g., IV) administration (Vdss) and Terminal phase half-life (t½). |
| Measure | Description | Time Frame |
|---|---|---|
| Characterisation of the safety profile of GSK2140944 with adverse events (AEs) following intravenous single-dose administration | AE is defined as Any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Up to study day 15 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Baltimore | Maryland | 21225 | United States |
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| Label | URL |
|---|---|
| Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research. | View source |
| Results for study 116666 can be found on the GSK Clinical Study Register. | View source |
| ID | Type | URL | Comment |
|---|---|---|---|
| 116666 | Annotated Case Report Form | View IPD |
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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| ID | Term |
|---|---|
| D001424 | Bacterial Infections |
| ID | Term |
|---|---|
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C000612856 | gepotidacin |
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| Experimental |
In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| Part A (Cohort6) | Experimental | In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| Part B (Cohort1) | Experimental | In Part B, participants will receive GSK2140944 1000 mg IV infusion, q12h x 5 doses. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| Part B (Cohort2) | Experimental | In Part B, participants will receive GSK2140944 1000 mg IV infusion over, q12h x 5 doses. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| Part B (Cohort3) | Experimental | In Part B, participants will receive GSK2140944 1000 mg IV infusion over, q12h x 5 doses. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| Part B (Cohort4) | Experimental | In Part B, participants will receive GSK2140944 1000 mg IV infusion over q12h x 5 doses. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| Part B (Cohort5) | Experimental | In Part B, participants will receive GSK2140944 1000 mg IV infusion over, q12h x 5 doses. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| Part B (Cohort6) | Experimental | In Part B, participants will receive GSK2140944 1000 mg IV infusion over, q12h x 5 doses. Optional Cohort or Part and will only be used if necessary. Sampling times are to be determined based on the review of preliminary PK results from prior study parts and/or cohorts. |
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| GSK2140944 (Multiple dose) | Drug | A lyophilized formulation, pale yellow to grayish yellow cake containing 750 mg of GSK2140944 (as free base) per vial, Administered intravenously every 12 hours for 5 doses (3 days). |
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| Day1, Day 2, Day 3, Day 4, Day 5 |
| Characterisation of the safety profile of GSK2140944 with chemistry and haematology laboratory values following intravenous single-dose administration | Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) | Up to study day 15 |
| Characterisation of the safety profile of GSK140944 electrocardiograms (ECG) following intravenous single-dose administration | Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically calculates heart rate and measures PR, QRS, QT, RR and QTcB intervals. | Up to study day 15 |
| Characterisation of the safety profile of GSK2140944 with vital signs following intravenous single-dose administration | Vital sign measurements will include systolic and diastolic blood pressure, body temperature, pulse rate. | Up to study day 15 |
| Characterisation of the safety profile of GSK2140944 with adverse events (AEs) following repeat daily multiple intravenous dose administration | AE is defined as Any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Up to study day 18 |
| Characterisation of the safety profile of GSK2140944 with chemistry and haematology laboratory values following repeat daily multiple intravenous dose administration | Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) | Up to study day 18 |
| Characterisation of the safety profile of GSK140944 electrocardiograms (ECG) following repeat daily multiple intravenous dose administration | Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically calculates heart rate and measures PR, QRS, QT, RR and QTcB intervals. | Up to study day 18 |
| Characterisation of the safety profile of GSK2140944 with vital signs following repeat daily multiple intravenous dose administration | Vital sign measurements will include systolic and diastolic blood pressure, body temperature, pulse rate. | Up to study day 18 |
For additional information about this study please refer to the GSK Clinical Study Register |
| 116666 | Individual Participant Data Set | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116666 | Clinical Study Report | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116666 | Informed Consent Form | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116666 | Dataset Specification | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116666 | Statistical Analysis Plan | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116666 | Study Protocol | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |