An Open-label, Randomized, Single Period, Parallel-Cohort Study To Evaluate Serum and Pulmonary Pharmacokinetics Following Single and Multiple Dose Administration of Intravenous GSK2251052 in Healthy Adult Subjects

This study has been completed.
Sponsor:
Information provided by:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01267968
First received: December 16, 2010
Last updated: March 1, 2012
Last verified: February 2012
  Purpose

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.


Condition Intervention Phase
Community-acquired Infection
Drug: GSK2251052
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: An Open-label, Randomized, Single Period, Parallel-Cohort Study To Evaluate Serum and Pulmonary Pharmacokinetics Following Single and Multiple Dose Administration of Intravenous GSK2251052 in Healthy Adult Subjects

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Epithelial lining fluid (ELF)/ plasma ratios for GSK2251052 at early, mid, and late dosing interval timepoints following intravenous administration of 1500 mg q12h. [ Time Frame: up to 3 days ] [ Designated as safety issue: No ]
  • Alveolar macrophage (AM)/ plasma ratios for GSK2251052 at early, mid, and late dosing interval timepoints following intravenous administration of 1500 mg q12h. [ Time Frame: up to 3 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Plasma AUC (0-t), Cmax, CL, Vss, and t½, following intravenous administration of GSK2251052, as permitted by the data. [ Time Frame: up to 3 days ] [ Designated as safety issue: No ]
  • GSK2251052 concentrations in urine following single and repeat dose administration [ Time Frame: up to 3 days ] [ Designated as safety issue: No ]
  • Safety and tolerability parameters, including adverse event, concurrent medication, clinical laboratory, cardiac monitoring, and vital signs assessments. [ Time Frame: up to 14 days ] [ Designated as safety issue: Yes ]

Enrollment: 25
Study Start Date: January 2011
Study Completion Date: March 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
GSK2251052 1500 mg Single dose (i.v., 60 min)
Drug: GSK2251052
1500 mg (dosing detailed in Arm description)
Experimental: Cohort 2
GSK2251052 1500 mg IV q12h x 5 doses infused over 60 minutes
Drug: GSK2251052
1500 mg (dosing detailed in Arm description)

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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 exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
  • A subject will not be eligible for inclusion in this study if any of the following criteria apply:
  • Contraindications to bronchoalveolar lavage including hypercapnia >50 mm Hg, 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.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines.
  • A positive test for HIV antibody.
  • History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • History of sensitivity to pre- and post-procedure medications related to the BAL procedure such as codeine, atropine, lidocaine, midazolam, and fentanyl.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • Pregnant females as determined by positive urine hCG test at screening or prior to dosing.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  • Consumption of red wine, seville oranges, grapefruit or grapefruit juice [and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices] from 7 days prior to the first dose of study medication.
  • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate < 45 and > 100 bpm (males), < 50 and > 100 bpm (females); PR interval <120 and > 220 msec; QTcB interval >450 msec
  • Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization).
  • Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], Wolf Parkinson White [WPW] syndrome), sinus pauses> 3 seconds, non-sustained or sustained ventricular tachycardia (≥3 consecutive ventricular ectopic beats) or any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety of the individual subject.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01267968

Locations
United States, Minnesota
GSK Investigational Site
Minneapolis, Minnesota, United States, 55404
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT01267968     History of Changes
Other Study ID Numbers: 114926
Study First Received: December 16, 2010
Last Updated: March 1, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by GlaxoSmithKline:
pharmacokinetics
bronchoalveolar lavage
GSK2251052
pulmonary
healthy volunteer
antimicrobial

Additional relevant MeSH terms:
Community-Acquired Infections
Infection

ClinicalTrials.gov processed this record on September 30, 2014