An Open-label Study To Evaluate Plasma and Pulmonary Pharmacokinetics Following Intravenous Administration of GSK2140944 in Healthy Adult Subjects (BTZ116666)
Overview
- Phase
- Phase 1
- Intervention
- GSK2140944 (Single dose)
- Conditions
- Infections, Bacterial
- Sponsor
- GlaxoSmithKline
- Enrollment
- 22
- Locations
- 1
- Primary Endpoint
- Pulmonary pharmacokinetics of GSK2140944 following intravenous single-dose administration.
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5x Upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
- •Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, vital signs, electrocardiograms (ECGs), physical examination, and laboratory tests. A participant with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included if in the Investigator's judgement 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 participant 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. To confirm post-menopausal status, a blood sample for simultaneous follicle stimulating hormone (FSH) \> 40 milli-international units per milliliter (MlU/ml) and estradiol \< 40 picrograms (pg)/ml (\<147 picromoles/Liter \[pmol/L\]) is confirmatory. Male participant with female partners of child-bearing potential must agree to use one of the contraception methods listed as per protocol. This criterion must be followed from the time of the first dose of study medication until the final follow-up visit.
- •Body weight \>= 50 kg and Body mass index (BMI) within the range 19 - 31Kilograms/meter\^2(kg/m\^2) (inclusive).
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Exclusion Criteria
- •Contraindications to bronchoalveolar lavage including hypercapnia \>50 millimeters of mercury (mm Hg), known or suspected intolerability to medications necessary for bronchoscopy, refractory hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial infarction in the last 6 months, heart failure, and severe hemostatic alterations.
- •A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or positive Human Immunodeficiency Virus (HIV) antibody.
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions that, in the opinion of the investigator may place the participant at an unacceptable risk as a participant in this trial or may interfere with the absorption, distribution, metabolism or excretion of drugs.
- •A positive urine test for drugs of abuse or alcohol (or alcohol breath test) at screening.
- •A screening urinalysis positive for protein or glucose (greater than "trace" findings of protein or glucose).
- •A serum creatinine value that is out of the normal range, or an increase of 0.2 milligrams/decilitre (mg/dL) (or 15.25 micromoles/Liters \[µmol/L\]) in serum creatinine value between screening and Day -1 visit.
- •History of photosensitivity to quinolones.
- •Unwillingness to commit to avoid excessive exposure to sunlight (or exposure whilst on a tanning bed) which would cause a sunburn reaction from first dose up to and including the follow-up visit.
- •History of drug abuse within 6 months of the study or a history of smoking or use of nicotine containing products within 3 months of screening, or a positive urine cotinine indicative of smoking at screening.
Arms & Interventions
Part A(Cohort1)
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
Intervention: GSK2140944 (Single dose)
Part A (Cohort2)
In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 4 hours x 1 dose
Intervention: GSK2140944 (Single dose)
Part A (Cohort3)
In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 8 hours x 1 dose
Intervention: GSK2140944 (Single dose)
Part A (Cohort4)
In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 12 hours x 1 dose
Intervention: GSK2140944 (Single dose)
Part A (Cohort5)
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.
Intervention: GSK2140944 (Single dose)
Part A (Cohort6)
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.
Intervention: GSK2140944 (Single dose)
Part B (Cohort1)
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.
Intervention: GSK2140944 (Multiple dose)
Part B (Cohort2)
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.
Intervention: GSK2140944 (Multiple dose)
Part B (Cohort3)
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.
Intervention: GSK2140944 (Multiple dose)
Part B (Cohort4)
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.
Intervention: GSK2140944 (Multiple dose)
Part B (Cohort5)
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.
Intervention: GSK2140944 (Multiple dose)
Part B (Cohort6)
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.
Intervention: GSK2140944 (Multiple dose)
Outcomes
Primary Outcomes
Pulmonary pharmacokinetics of GSK2140944 following intravenous single-dose administration.
Time Frame: Day 1, Day 2, Day 3
Blood samples will be collected assessment of PK parameters including Epithelial Lining Fluid (ELF) and Alveolar Macrophages (AM) (AUC\[0- τ\]), 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.
Plasma pharmacokinetics of GSK2140944 following intravenous single-dose administration.
Time Frame: Day 1, Day 2, Day 3
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).
Pulmonary pharmacokinetics of GSK2140944 following repeat daily multiple intravenous dose administration.
Time Frame: Day1, Day 2, Day 3, Day 4, Day 5
Blood samples will be collected assessment of PK parameters including ELF and AM AUC(0- τ)), 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.
Plasma pharmacokinetics of GSK2140944 following repeat daily multiple intravenous dose administration.
Time Frame: Day1, Day 2, Day 3, Day 4, Day 5
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).
Secondary Outcomes
- Characterisation of the safety profile of GSK2140944 with chemistry and haematology laboratory values following intravenous single-dose administration(Up to study day 15)
- Characterisation of the safety profile of GSK2140944 with vital signs following repeat daily multiple intravenous dose administration(Up to study day 18)
- Characterisation of the safety profile of GSK2140944 with adverse events (AEs) following intravenous single-dose administration(Up to study day 15)
- Characterisation of the safety profile of GSK140944 electrocardiograms (ECG) following intravenous single-dose administration(Up to study day 15)
- Characterisation of the safety profile of GSK2140944 with adverse events (AEs) following repeat daily multiple intravenous dose administration(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(Up to study day 18)
- Characterisation of the safety profile of GSK140944 electrocardiograms (ECG) following repeat daily multiple intravenous dose administration(Up to study day 18)
- Characterisation of the safety profile of GSK2140944 with vital signs following intravenous single-dose administration(Up to study day 15)