A Single Dose Study to Assess the Regional Absorption and Bioavailability of 100mg GSK2190915A
A Single Dose Study to Assess the Regional Absorption and Bioavailability of 100mg GSK2190915A
GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that
 attenuates the production of leukotrienes through the blockage of the first step in the
 leukotriene pathway, 5-lipoxygenase (5-LO) activation. GSK2190915 inhibits the production of
 leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLTs).

 This is an open label, 4-way, 4-treatment period, non-randomised, crossover study with an
 interim analysis. The GSK2190915 formulations used in this study will be: a 100mg and 200mg
 milled tablet, a 100mg enteric-coated tablet, and a [14C] radiolabelled GSK2190915
 intravenous solution.

 This study aims to determine the pharmacokinetics and absolute bioavailability of GSK2190915
 to enable optimisation of suitable formulations to be used in clinical development Fourteen
 subjects will be dosed to ensure data in 10 at the end of the clinical study. Seven of the
 subjects will receive an IV microtracer in addition to the other treatments.
GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that
 attenuates the production of leukotrienes through the blockage of the first step in the
 leukotriene pathway, 5-lipoxygenase (5-LO) activation. Leukotrienes are potent inflammatory
 molecules produced mainly by mast cells, eosinophils, monocytes/macrophage and neutrophils in
 response to allergic or inflammatory stimuli. GSK2190915 inhibits the production of
 leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLTs).

 This is an open label, 4-way, 4 treatment period, non-randomised, single-dose crossover study
 with an interim analysis following the third treatment period. The GSK2190915 formulations
 used are: milled 100mg and 200mg tablets, a 100mg enteric-coated tablet, and a [14C]
 radiolabelled GSK2190915 intravenous solution.

 There will be 4 periods. Period 1 includes two cohorts (of 7 subjects each), both of which
 will be administered the 100mg GSK2190915 milled tablet orally; however, the second cohort
 will in addition be dosed with an intravenous radiolabelled infusion of the drug. In the
 second period, a 100mg dose of milled GSK2190915 tablet (a ground half of a 200mg tablet) is
 administered directly to the proximal small bowel using an Enterion capsule. The same dose is
 repeated in the third period, but is administered directly to the distal small bowel. An
 interim analysis will then follow. The decision to proceed will be made following a review of
 the pharmacokinetic data from the first three treatments. In the fourth and final period, the
 treatment will be a 100mg enteric-coated tablet of GSK2190915 administered orally. There will
 be a minimum washout of 7 days in between each period.

 This study aims to determine the pharmacokinetics and absolute bioavailability of GSK2190915
 to enable optimisation of suitable formulations to be used in clinical development. Periods 1
 to 3 will characterise the absolute bioavailability of GSK2190915 using IV tracer and oral
 formulation, in addition to defining the regional absorption characteristics of the drug when
 released in the proximal and distal parts of the gastro-intestinal tract. The fourth period
 will investigate the oral bioavailability of an enteric coated formulation of GSK2190915.

 Fourteen subjects will be dosed to ensure data in 10 at the end of the clinical study. Seven
 of the subjects (in cohort 2, Period 1) will receive an IV microtracer in addition to the
 other treatments.
Inclusion Criteria:

 -  Healthy females as determined by an experienced study physician, based on a medical
 evaluation including medical history, physical examination, neurological examination,
 laboratory tests and electrocardiogram (ECG). 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;

 -  Females must be either:

 -  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 [in questionable cases a blood sample with simultaneous follicle
 stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is
 confirmatory]. [Females on hormone replacement therapy (HRT) and whose menopausal
 status is in doubt will be required to use one of the contraception methods in Section
 9.4 of the protocol if they wish to continue their HRT during the study. Otherwise,
 they must discontinue HRT to allow confirmation of post-menopausal status prior to
 study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the
 cessation of therapy and the blood draw; this interval depends on the type and dosage
 of HRT. Following confirmation of their post-menopausal status, they can resume use of
 HRT during the study without use of a contraceptive method.]

 -  Of child-bearing potential and agrees to use one of the contraception methods listed
 in Section 9.4 of the protocol for an appropriate period of time (as determined by the
 product label or investigator) prior to the start of dosing to sufficiently minimize
 the risk of pregnancy at that point. Female subjects must agree to use contraception
 until 3 months after the last dose.

 -  Aged 18-65 years;

 -  Body Mass Index (BMI) of 18-35 kilogram per sqare metre (km/m2);

 -  Subjects must demonstrate their ability to swallow an empty size 000 capsule;

 -  Must be willing and able to participate in the whole study and must provide written
 informed consent;

 -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase
 and bilirubin ≤ 1.5xUpper Limit of Normal (ULN) (isolated bilirubin >1.5xULN is
 acceptable if bilirubin is fractionated and direct bilirubin <35%);

 -  QTcB or QTcF < 450 msec

 -  Subjects of child-bearing potential must agree to use one of the contraception methods
 listed in Section 9.4 from the time of the first dose of study medication until 3
 months following the last dose.

 -  Exclusion Criteria:

 -  Participation in a clinical research study involving investigational drugs or dosage
 forms within the previous 3 months or 4 months if new chemical entity (NCE);

 -  Subjects who have previously been enrolled in this study;

 -  Subjects who have ever sought advice from or been referred to a General Practitioner
 or counsellor for abuse or misuse of alcohol, non medical drugs, medicinal drugs or
 other substance abuse e.g. solvents;

 -  Subjects who admit to any current or previous use of Class A drugs such as opiates,
 cocaine, ecstasy, lysergic acid diethylamide (LSD) and intravenous amphetamines
 (Subjects who admit to occasional past use of cannabis will not be excluded as long as
 they have a negative drugs of abuse test and have been abstinent for at least 12
 months;)

 -  Positive drugs of abuse test result;

 -  Regular alcohol consumption >14 units per week (1 Unit = ½ pint beer, a 25 milliLitre
 (mL) shot of 40% spirit or a 125 mL glass of wine);

 -  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 Medical
 Monitor the medication will not interfere with the study procedures or compromise
 subject safety.

 -  Current smokers and those who have smoked within the last 12 months. A breath carbon
 monoxide reading of greater than 10 ppm at screening;

 -  Radiation exposure from clinical trials, including that from the present study,
 excluding background radiation but including diagnostic X-rays and other medical
 exposures, exceeding 5 milliSieverts (mSv) in the last twelve months or 10 mSv in the
 last five years. No occupationally exposed worker, as defined in the Ionising
 Radiation Regulations 1999, shall participate in the study;

 -  Subjects must not have had any 14C exposure within the last 12 months.

 -  Clinically significant abnormal biochemistry, haematology or urinalysis as judged by
 the Principal Investigator (PI);

 -  History of gastrointestinal surgery (with the exception of appendectomy unless it was
 performed within the previous 12 months);

 -  History of clinically significant cardiovascular, renal, hepatic, respiratory and
 particularly gastrointestinal disease, especially peptic ulceration, gastrointestinal
 bleeding, ulcerative colitis, Crohn's Disease or Irritable Bowel Syndrome;

 -  History of adverse reaction or allergy to study drug or its excipients, e.g. lactose
 or rescue medication (if specified by the Sponsor);

 -  If subject suffers from hayfever they must not have or be expecting to have symptoms
 during the study period;

 -  Acute diarrhoea or constipation in the 7 days before the predicted first study day. If
 screening occurs >7 days before the first study day, this criterion will be determined
 on first study day. Diarrhoea will be defined as the passage of liquid faeces and/or a
 stool frequency of greater than three times per day. Constipation will be defined as a
 failure to open the bowels more frequently than every other day;

 -  Donation, or significant loss as judged by the investigator, of blood within the
 previous three months;

 -  Presence of non-removable metal objects such as metal plates, screws, etc, in the
 abdominal region of the body (with the exception of sterilisation clips);

 -  Subjects will be excluded from the study if they are considered by the PI to be at
 risk of transmitting, through blood or other body fluids, the agents responsible for
 acquired immunodeficiency syndrome (AIDS) or other sexually transmitted disease or
 hepatitis;

 -  Positive Hepatitis B Virus, Hepatitis C Virus or Human Immunodeficiency Virus
 (HIV)results;

 -  Unwillingness or inability to follow the procedures outlined in the protocol;

 -  Subject is mentally or legally incapacitated;

 -  Failure to satisfy the PI of fitness to participate for any other reason.