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To Evaluate Plasma and Pulmonary Pharmacokinetics of GSK2140944

12. mai 2017 oppdatert av: GlaxoSmithKline

An Open-label Study To Evaluate Plasma and Pulmonary Pharmacokinetics Following Intravenous Administration of GSK2140944 in Healthy Adult Subjects (BTZ116666)

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.

Studieoversikt

Studietype

Intervensjonell

Registrering (Faktiske)

22

Fase

  • Fase 1

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

    • Maryland
      • Baltimore, Maryland, Forente stater, 21225
        • GSK Investigational Site

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år til 55 år (Voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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.
  • 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 grams (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 participant has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication.
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, or use of St. John's Wort within 14 days prior to the first dose of study medication. By exception, the volunteer may take paracetamol or acetaminophen (<=2 grams/day) up to 48 hours prior to the first dose of study medication. However, the Investigator and GSK study team can review medication on a case by case basis to determine if its use would compromise participant safety or interfere with the study procedures or data interpretation.
  • History of sensitivity to any of the study medications, including GSK2140944 and those that may be used in association with the BAL procedure, 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.
  • Donation of blood in excess of 500 mL within 12 weeks prior to dosing.
  • History of tendon rupture.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
  • Consumption of red wine, pomegranate, seville oranges, grapefruit or grapefruit juice, pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices containing such products 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, Males <40 and >100 Beat Per Minute (bpm), females <50 and >100 bpm; PR interval <120 and >220 msec; QRS duration <70 and >100 msec; A QT interval corrected for heart rate using the Bazett's formula (QTcB) or Single QT duration corrected for heart rate by Fridericia's formula (QTcF) interval >450 msec. Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization). A participant has Bundle Branch Block. 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 participant.

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Ikke-randomisert
  • Intervensjonsmodell: Enkeltgruppeoppdrag
  • Masking: Ingen (Open Label)

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: 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
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.
Eksperimentell: Part A (Cohort2)
In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 4 hours x 1 dose
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.
Eksperimentell: Part A (Cohort3)
In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 8 hours x 1 dose
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.
Eksperimentell: Part A (Cohort4)
In Part A, participants will receive GSK2140944 1000 mg intravenous (IV) infusion over 12 hours x 1 dose
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.
Eksperimentell: 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.
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.
Eksperimentell: 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.
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.
Eksperimentell: 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.
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).
Eksperimentell: 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.
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).
Eksperimentell: 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.
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).
Eksperimentell: 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.
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).
Eksperimentell: 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.
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).
Eksperimentell: 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.
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).

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Pulmonary pharmacokinetics of GSK2140944 following intravenous single-dose administration.
Tidsramme: 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.
Day 1, Day 2, Day 3
Plasma pharmacokinetics of GSK2140944 following intravenous single-dose administration.
Tidsramme: 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).
Day 1, Day 2, Day 3
Pulmonary pharmacokinetics of GSK2140944 following repeat daily multiple intravenous dose administration.
Tidsramme: 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.
Day1, Day 2, Day 3, Day 4, Day 5
Plasma pharmacokinetics of GSK2140944 following repeat daily multiple intravenous dose administration.
Tidsramme: 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).
Day1, Day 2, Day 3, Day 4, Day 5

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Characterisation of the safety profile of GSK2140944 with adverse events (AEs) following intravenous single-dose administration
Tidsramme: Up to study day 15
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
Characterisation of the safety profile of GSK2140944 with chemistry and haematology laboratory values following intravenous single-dose administration
Tidsramme: Up to study day 15
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
Tidsramme: Up to study day 15
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
Tidsramme: Up to study day 15
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
Tidsramme: Up to study day 18
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
Tidsramme: Up to study day 18
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
Tidsramme: Up to study day 18
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
Tidsramme: Up to study day 18
Vital sign measurements will include systolic and diastolic blood pressure, body temperature, pulse rate.
Up to study day 18

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Publikasjoner og nyttige lenker

Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Faktiske)

25. september 2013

Primær fullføring (Faktiske)

21. desember 2013

Studiet fullført (Faktiske)

21. desember 2013

Datoer for studieregistrering

Først innsendt

29. august 2013

Først innsendt som oppfylte QC-kriteriene

29. august 2013

Først lagt ut (Anslag)

4. september 2013

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

15. mai 2017

Siste oppdatering sendt inn som oppfylte QC-kriteriene

12. mai 2017

Sist bekreftet

1. mai 2017

Mer informasjon

Begreper knyttet til denne studien

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

Ja

IPD-planbeskrivelse

Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Studiedata/dokumenter

  1. Annotert saksrapportskjema
    Informasjonsidentifikator: 116666
    Informasjonskommentarer: For additional information about this study please refer to the GSK Clinical Study Register
  2. Datasett for individuell deltaker
    Informasjonsidentifikator: 116666
    Informasjonskommentarer: For additional information about this study please refer to the GSK Clinical Study Register
  3. Klinisk studierapport
    Informasjonsidentifikator: 116666
    Informasjonskommentarer: For additional information about this study please refer to the GSK Clinical Study Register
  4. Skjema for informert samtykke
    Informasjonsidentifikator: 116666
    Informasjonskommentarer: For additional information about this study please refer to the GSK Clinical Study Register
  5. Datasettspesifikasjon
    Informasjonsidentifikator: 116666
    Informasjonskommentarer: For additional information about this study please refer to the GSK Clinical Study Register
  6. Statistisk analyseplan
    Informasjonsidentifikator: 116666
    Informasjonskommentarer: For additional information about this study please refer to the GSK Clinical Study Register
  7. Studieprotokoll
    Informasjonsidentifikator: 116666
    Informasjonskommentarer: For additional information about this study please refer to the GSK Clinical Study Register

Denne informasjonen ble hentet direkte fra nettstedet clinicaltrials.gov uten noen endringer. Hvis du har noen forespørsler om å endre, fjerne eller oppdatere studiedetaljene dine, vennligst kontakt register@clinicaltrials.gov. Så snart en endring er implementert på clinicaltrials.gov, vil denne også bli oppdatert automatisk på nettstedet vårt. .

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