Effect of Rifabutin on the Pharmacokinetics of Oral Cabotegravir in Healthy Subjects
Condition: Infection, Human Immunodeficiency Virus; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes
Intervention: Cabotegravir; Rifabutin
Intervention description: It will be available as a white aquarius film coated tablet for oral administration. CAB Tablet is composed of GSK1265744B (micronized) lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate; It will be available as an opaque red-brown hard gelatin capsules containing 150 mg of rifabutin for oral administration. These capsules are composed of rifabutin, microcrystalline cellulose, sodium lauryl sulphate, magnesium stearate, and silica gel
Intervention MeSH terms: Rifabutin; Cabotegravir
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This is a 2-period crossover study in healthy adults
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Tuberculosis; Human Immunodeficiency Virus; Rifabutin; Drug-drug interaction; Cabotegravir

Summary:

      This is a Phase I, single-center, open-label, fixed-sequence, 2-period crossover study in
      healthy adults to evaluate the effect of oral rifabutin (RBT) 300 milligram (mg) on the
      pharmacokinetics of oral cabotegravir (CAB) 30 milligram ( mg). This study will evaluate the
      drug-drug interaction (DDI) potential between CAB and RBT to inform dosing strategies for
      tuberculosis in subjects receiving CAB for human immunodeficiency virus (HIV) treatment or
      prevention. In Treatment Period 1 (Treatment A) participants will receive CAB 30 mg once
      daily for 14 days, followed by Treatment Period 2 (Treatment B) where participants will
      receive RBT 300 mg once daily with CAB 30 mg once daily for 14 days. The total study duration
      will be approximately for 10 weeks. Approximately 15 healthy subjects will be enrolled to
      ensure that 12 subjects complete dosing and critical assessments.
    

Eligibility criteria:

        Inclusion Criteria

          -  Males and females between 18 and 65 years of age inclusive, at the time of signing the
             informed consent.

          -  Healthy as determined by the investigator or medically qualified designee based on a
             medical evaluation including medical history, physical examination, laboratory tests
             and cardiac monitoring.

          -  A subject with a clinical abnormality or laboratory parameter(s) which is/are not
             specifically listed in the inclusion or exclusion criteria, outside the reference
             range for the population being studied may be included only if the investigator in
             consultation with the Medical Monitor agree and document that the finding is unlikely
             to introduce additional risk factors and will not interfere with the study procedures.
             Additionally, laboratory assessments that are specifically listed in the inclusion or
             exclusion criteria and are outside of the reference range can be repeated once during
             the screening period.

          -  Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 18.5 - 31.0
             kg/ meter square (kg/m^2) (inclusive).

          -  A female subject is eligible to participate if she is not pregnant (as confirmed by a
             negative serum human chorionic gonadotrophin (hCG) test), not lactating, and if she is
             of:

               -  Non-reproductive potential defined as pre-menopausal with documented tubal
                  ligation, hysteroscopic tubal occlusion procedure with follow-up confirmation of
                  bilateral tubal occlusion, Hysterectomy, Bilateral Oophorectomy, Postmenopausal
                  defined as 12 months of spontaneous amenorrhea [in questionable cases a blood
                  sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels
                  consistent with menopause FSH: >40 milli international unit/mililiter (MIU/mL)
                  and estradiol <40 picogram (pg)/mL (<147 picomoles/L) is confirmatory];

               -  Reproductive potential and agrees to follow one of the options listed in the
                  Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of
                  Reproductive Potential (FRP) from 30 days prior to the first dose of study
                  medication until the completion of the follow-up visit.

        The investigator is responsible for ensuring that subjects understand how to properly use
        these methods of contraception.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

          -  ALT, alkaline phosphatase and bilirubin <=1x upper limit of normal (ULN) (isolated
             bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin
             <35%).

          -  White blood cell count and absolute neutrophil count in the normal range.

        Exclusion Criteria

          -  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 clinically significant cardiovascular disease including

               -  Exclusion criteria for screening ECG (a single repeat is allowed for eligibility
                  determination): male subjects with heart rate <45 and >100 beats per minute (bpm)
                  and female subjects with heart rate <50 and >100 bpm, QRS duration (males and
                  females) >120 millisecond (msec), QTc corrected by Fridericia's formula (QTcF)
                  >450 msec for males and females.

               -  Evidence of previous myocardial infarction (pathologic Q waves, S-T segment
                  changes (except early repolarization).

               -  History/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery
                  bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty
                  (PCTA) or any clinically significant cardiac disease.

               -  Conduction abnormality (including but not specific to left or right complete
                  bundle branch block, AV block [2nd degree (type II) or higher], Wolf Parkinson
                  White [WPW] syndrome) which in the opinion of the principal Investigator and Viiv
                  Medical Monitor, will interfere with the safety for the individual subject.

               -  Sinus pauses >3 seconds.

               -  Any significant arrhythmia which, in the opinion of the principal Investigator
                  and ViiV Medical Monitor, will interfere with the safety for the individual
                  subject.

               -  Non-sustained (>=3 consecutive ventricular ectopic beats) or sustained
                  ventricular tachycardia.

          -  History of inflammatory bowel disease.

          -  History of cholecystectomy or other gastrointestinal surgery (except appendectomy more
             than three months prior to study).

          -  History of peptic ulceration or pancreatitis within the preceding 6 months of
             screening.

          -  Participants determined by the Investigator to have a high risk of seizures, including
             participants with an unstable or poorly controlled seizure disorder. A participant
             with a prior history of seizure may be considered for enrolment if the Investigator
             believes the risk of seizure recurrence is low. All cases of prior seizure history
             should be discussed with the Medical Monitor prior to enrolment.

          -  Current or past history of uveitis.

          -  Any other medical condition which, in the judgment of the investigator and medical
             monitor, could jeopardize the safety of the subject or the integrity of the data
             derived from that subject. This includes but is not limited to any pre-existing
             condition that interferes with normal gastrointestinal anatomy or motility that could
             interfere with the absorption, metabolism, and/or excretion of the study drug.

          -  Unable to refrain from the 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 ViiV Medical Monitor the medication will not interfere with the study
             procedures or compromise subject safety.

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >14 drinks. One drink is equivalent to 12 gram 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.

          -  A history of regular use of tobacco, or nicotine-containing products within 30 days
             prior to screening.

          -  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 Medical
             Monitor, contraindicates their participation.

          -  Presence of Hepatitis B surface antigen (HBsAg) positivity at screening or within 3
             months prior to first dose of study treatment. Positive Hepatitis B core antibody
             (HBcAb) with negative hepatitis B surface antibody should also be excluded.

          -  Positive Hepatitis C antibody test.

          -  A positive pre-study drug/alcohol screen.

          -  A positive test for HIV antibody.

          -  A positive QuantiFERON Gold test or clinical evidence of tuberculosis (TB) infection.

          -  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
             investigational product (whichever is longer).

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day.