Drug-drug Interaction Study of GSK1278863 With Pioglitazone, Rosuvastatin and Trimethoprim in Healthy Adult Volunteers

This study will be a two-part with an open-label, single oral dose, two-way crossover study design. Part A and Part B of the study are independent and may be conducted in parallel. The Part A of the study will assess the effect of an oral dose of GSK1278863 on the pharmacokinetics of a CYP2C8 (pioglitazone) and OATP1B1 (rosuvastatin) probe substrate in order to determine the potential for clinically-significant drug interactions with CYP2C8 and OATP1B1 substrates. The Part B of the study will assess the effect of a weak CYP2C8 inhibitor (trimethoprim) on the pharmacokinetics of GSK1278863 and its six predominant metabolites. Part A will be conducted in approximately 30 healthy subjects, having a randomized study design. There will be approximate 7-day washout period between each dosing period. Part B will be conducted in approximately 20 healthy subjects, having single sequence study design. Follow up will be conducted within 7 to 10 days after the last dose in both Part A and B. The total duration of a subject's involvement in the part A of the study will be approximately 8 weeks (Screening to Follow-up) and in part B will be approximately 7 weeks (Screening to Follow-up).


Eligibility Criteria:
Inclusion Criteria:

* Subjects who are between 18 and 65 years of age, inclusive at the time of signing the informed consent form.
* Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and ECG monitoring obtained at the screening visit. The determination of clinical significance will be made by the investigator and the GlaxoSmithKline (GSK) Medical Monitor and will require that the finding is unlikely to introduce additional risk factors or interfere with the study procedures, or the integrity of the study.
* Hemoglobin values at screening greater than the lower limit of the laboratory reference range and less than or equal to 16.0 grams (g)/ deciliter (dL) for males and less than or equal to 14.0 g/dL for females.
* Body weight \>=50 Kilogram (kg) and Body Mass Index (BMI) within the range 19-29.9 kg/meter (m)\^2 (inclusive).
* Female or Male. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine or serum human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies: a) Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation and Documented hysteroscopic tubal occlusion procedure with follow-up, confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy, b) Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 International units (IU)/ liter (L) and estradiol levels consistent with menopause (\<32 picogram (pg)/ milliliter \[mL\]) are confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrolment. c) Reproductive potential and agrees to follow the contraception requirement for Female Subjects from 30 days prior to the first dose of study treatment and until at least five terminal half-lives or until any continuing pharmacologic effect has ended, whichever is longer after the last dose of study treatment and completion of the follow-up visit.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

* Alanine transaminase (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%).
* Corrected QT interval(QTc): QT interval corrected for heart rate according to Bazetts formula (QTcB) \>450 milliseconds (msec), The QTc must be the QT interval corrected for heart rate according to Bazetts formula (QTcB). For purposes of data analysis, QTcB will be used.
* Hypertensive (diastolic Blood pressure (BP) \>90 millimetre of mercury (mmHg) or systolic BP \>140 mmHg at Screening.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* History of deep vein thrombosis, stroke, transient ischemic attack, pulmonary embolism or other thrombosis related condition.
* History of myocardial infarction or acute coronary syndrome.
* Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or hepatic function that could interfere with the absorption, metabolism, and/or excretion of GSK1278863, trimethoprim, pioglitazone or rosuvastatin. Examples of conditions that could interfere with normal gastrointestinal anatomy or motility include gastrointestinal bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, or celiac sprue.
* Evidence of active peptic, duodenal or esophageal ulcer disease at Screening or history of clinically significant Gastrointestine (GI) bleeding.
* Subjects with chronic inflammatory joint disease (example \[e.g.\]., scleroderma, systemic lupus erythematosis, rheumatoid arthritis).
* Subjects with a history of pulmonary artery hypertension.
* Subjects with a history of malignancy within the prior five years, who are receiving treatment for cancer, or who have a strong family history of cancer (e.g., familial cancer disorders); with the exception of squamous cell or basal cell carcinoma of the skin that has been definitively treated prior to screening through Day -1 (Randomization).
* History of proliferative vascular eye disease (e.g., choroidal or retinal disease, such as neovascular age-related macular degeneration, proliferative diabetic retinopathy or macular edema).
* Subjects with heart failure, as defined by the New York Heart Association (NYHA) functional classification system, including known right heart failure
* Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) except occasional usage of acetaminophen, 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 treatment until completion of the follow-up visit, unless in the opinion of the investigator and GSK Medical Monitor the medication will not interfere with the study.
* 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.
* Urinary cotinine levels indicative of smoking or history or regular use of tobacco or nicotine-containing products prior to screening.
* History of drug abuse or dependence within 6 months of the study.
* History of sensitivity to any of the study treatments (e.g., GSK1278863, pioglitazone, rosuvastatin, trimethoprim), or their components thereof, or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Consumption of \>3 servings/day of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, kale, broccoli, green beans, or apples from 7 days prior to the first dose of investigational product until the follow-up visit, unless in the opinion of the investigator and GSK Medical Monitor this will not interfere with the study procedures or compromise subject safety.
* 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 Human Immunodeficiency Virus (HIV) antibody.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* 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 study treatment (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* Unwillingness or inability to follow the procedures outlined in the protocol.