This first time in human (FTIH) study will be the first administration of GSK1322322 as an intravenous formulation and will investigate safety, tolerability, and pharmacokinetics in healthy subjects. One cohort of subjects will undergo bronchoalveolar lavage (BAL) for determination of GSK1322322 concentrations in lung with simultaneous comparison to plasma concentrations to evaluate drug penetration in the lung. The study will evaluate the absolute bioavailability of an oral tablet formulation as compared to the IV formulation.In addition, Amendment 01 will enable the investigation of an improved IV formulation (GSK1322322J mesylate salt) in an additional repeat dosing cohort and the supra-therapeutic cohort.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
61
500mg IV
1000mg oral
1000mg IV
1500mg oral
1500mg IV
2000mg IV
3000mg IV
1000mg IV
GSK Investigational Site
Minneapolis, Minnesota, United States
GSK1322322 safety parameters including the number of subjects with adverse events (AEs)
Time frame: Cohort A up to 14 days; Cohort B and C up to 16 days
GSK1322322 safety parameters including absolute values and changes over time of clinical safety laboratory assessments.
Time frame: Cohort A up to 14 days; Cohort B and C up to 16 days
GSK1322322 safety parameters including the change from baseline in vital signs (blood pressure (BP) and heart rate)
Time frame: Cohort A up to 14 days; Cohort B and C up to 16 days
GSK1322322 safety parameters including change from baseline in electrocardiogram (ECG) parameters
Time frame: Cohort A up to 14 days; Cohort B and C up to 16 days
GSK1322322 pharmacokinetic parameters (PK) after single oral dose, area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)).
Time frame: Cohorts B and C on Day -2
GSK1322322 PK parameters after single oral dose area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-∞)).
Time frame: Cohorts B and C on Day -2
GSK1322322 PK parameters after single oral dose aximum observed concentration (Cmax).
Time frame: Cohorts B and C on Day -2
GSK1322322 PK parameters after single oral dose time of occurrence of Cmax (tmax).
Time frame: Cohorts B and C on Day -2
GSK1322322 PK parameters after single oral dose mean residence time (MRTpo)
Time frame: Cohorts B and C on Day -2
GSK1322322 PK parameters after single oral dose apparent clearance after oral administration (CL/F)
Time frame: Cohorts B and C on Day -2
GSK1322322 PK parameters after single oral dose apparent volume of distribution after oral administration (Vz/F)
Time frame: Cohorts B and C on Day -2
GSK1322322 PK parameters after single oral dose terminal phase half-life (t 1/2).
Time frame: cohort B and C on Day -2
GSK1322322 PK parameters after single IV dose area under the concentration-time curve from zero (pre-dose) to some fixed nominal time (12 hours) (AUC(0-12)).
Time frame: Cohorts A, B, C, D, E on Day 1
GSK1322322 PK parameters after single IV dose area under the concentration-time curve from zero (pre-dose) to some fixed nominal time (24 hours) AUC(0-24)
Time frame: Cohorts A, B, C, D, E on Day 1
GSK1322322 PK parameters after single IV dose AUC(0-t)
Time frame: Cohorts A, B, C, D, E on Day 1
GSK1322322 PK parameters after single IV dose AUC(0-∞).
Time frame: Cohorts A, B, C, D, E on Day 1
GSK1322322 PK parameters after single IV dose Cmax
Time frame: Cohorts A, B, C, D, E on Day 1
GSK1322322 PK parameters after single IV dose mean residence time intravenous (MRTiv)
Time frame: Cohort A, B, C, D, E on Day 1
GSK1322322 PK parameters after single IV dose t1/2
Time frame: Cohort A, B, C, D, E on Day 1
Absolute bioavailability will be determined by comparing oral AUC(0-∞) to IV AUC(0-∞)
Time frame: Cohort B and C on Day -2 and Day 1
MAT of oral tablet will be determined (=MRTpo-MRTiv)
Time frame: Cohort B and C on Day -2 and Day 1
After repeated IV doses, pharmacokinetic parameters including Area under the concentration-time curve over the dosing interval (AUC(0-τ))
Time frame: Cohorts A, B, C on Days 3 - 6
After repeated IV doses, pharmacokinetic parameters including Cmax
Time frame: Cohorts A, B, C on Days 3 - 6
After repeated IV doses, pharmacokinetic parameters including CL
Time frame: Cohorts A, B, C on Days 3 - 6
GSK1322322 concentrations in BAL obtained in epithelial lining fluid (ELF) and alveolar macrophages (AM) as compared to that in plasma
Time frame: Cohort C Day 6
GSK1322322 urine PK parameters: amount excreted (Ae) of unchanged GSK1322322, fraction of the dose excreted in the urine (fe) and renal clearance (CLr) following single dose IV administration from Period 2 and Period 3.
Time frame: cohort B and C on Day 1 and 2
Day 6 GSK1322322 AUC(0-τ) compared to AUC(0-12) on Day 1 to evaluate the accumulation ratio following repeat IV administration of GSK1322322.
Time frame: Cohorts A, B, C Day 6 and Day 1
Day 6 GSK1322322 AUC(0-τ) compared to AUC(0-∞) on Day 1 to evaluate time invariance following repeat IV administration of GSK1322322.
Time frame: Cohorts A, B, C Day 6 and Day 1
GSK1322322 PK parameters: AUC(0-∞) on Day 1 and AUC(0-τ) on Day 6 following IV administration at different doses for the assessment of dose proportionality.
Time frame: Cohorts A, B, C Day1 and 6
Microbiome analysis of stool prior to and after exposure to GSK1322322
Time frame: Cohort A, B,C, D, E single sample predose and single sample post dose
GSK1322322J safety parameters including the number of subjects with adverse events (AEs)
Time frame: Cohort D and E up to 11 days, Cohort F up to 14 days
GSK1322322J safety parameters including absolute values and changes over time of clinical safety laboratory assessments
Time frame: Cohort D and E up to 11 days; Cohort F up to 14 days
GSK1322322J safety parameters including the change from baseline in vital signs (blood pressure (BP) and heart rate)
Time frame: Cohort D and E up to 11 days; Cohort F up to 14 days
GSK1322322J safety parameters including change from baseline in electrocardiogram (ECG) parameters
Time frame: Cohort D and E up to 11 days: Cohort F up to 14 days
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