Community-acquired Infection
Conditions
Keywords
pharmacokinetics, bronchoalveolar lavage, GSK2251052, pulmonary, healthy volunteer, antimicrobial
Brief summary
GSK2251052 is a member of a novel mechanistic and structural class of antibiotics that inhibits the bacterial enzyme leucyl tRNA synthetase (LeuRS) by forming a boron adduct with tRNA and is currently in development for the treatment of hospital acquired Gram-negative infections (including E. coli, K. pneumoniae, and Enterobacter spp.). This is an open-label, randomized, single period, parallel-cohort pharmacokinetic study to evaluate serum and pulmonary pharmacokinetics following single dose and multiple dose administration of intravenous GSK2251052. In Cohort 1, approximately 15 healthy adult subjects will be randomized to receive a single IV dose of GSK2251052 1500 mg in the fasted state. Following the dose, bronchoalveolar lavage (BAL) fluid and serial plasma samples will be collected for determination of GSK2251052 parent and metabolite concentrations. In Cohort 2, approximately 15 healthy adult subjects will receive GSK2251052 1500 mg IV BID x 5 doses (Cohort 2). Following the last dose in the fasted state, bronchoalveolar lavage (BAL) fluid and serial plasma samples will be collected for determination of GSK2251052 parent and metabolite concentrations. Vital signs, ECGs, and adverse events will be monitored throughout the study. A follow up visit will occur 10 to 14 days after the last dose of study drug.
Interventions
DRUGGSK2251052
1500 mg (dosing detailed in Arm description)
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* AST, ALT, alkaline phosphatase and bilirubin \< or = 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). Abnormal LFT tests may be repeated once at the discretion of the Investigator. If an abnormality is repeated, the subject would not be eligible for inclusion. * Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECGs. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Male or female between 18 and 55 years of age inclusive, at the time of signing the informed consent. * A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. A follicle stimulating hormone (FSH) will be performed for confirmation. For this study, FSH level \> 40 MlU/ml is confirmatory\]. * Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until the follow-up visit. * Body weight \> or = 50 kg for men and \> or = 45 kg for women and BMI within the range 18.5-30.0 kg/m2 (inclusive). * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * QTcB or QTcF \<450 msec or QTcB or QTcF \<480 msec in subjects with Bundle Branch Block.
Exclusion criteria
* Deviations from
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Epithelial lining fluid (ELF)/ plasma ratios for GSK2251052 at early, mid, and late dosing interval timepoints following intravenous administration of 1500 mg q12h. | up to 3 days |
| Alveolar macrophage (AM)/ plasma ratios for GSK2251052 at early, mid, and late dosing interval timepoints following intravenous administration of 1500 mg q12h. | up to 3 days |
Secondary
| Measure | Time frame |
|---|---|
| Plasma AUC (0-t), Cmax, CL, Vss, and t½, following intravenous administration of GSK2251052, as permitted by the data. | up to 3 days |
| GSK2251052 concentrations in urine following single and repeat dose administration | up to 3 days |
| Safety and tolerability parameters, including adverse event, concurrent medication, clinical laboratory, cardiac monitoring, and vital signs assessments. | up to 14 days |
Countries
United States
Outcome results
None listed