Effect of Dolutegravir on Metformin Pharmacokinetics in Healthy Adult Subjects



Status:Completed
Conditions:HIV / AIDS, HIV / AIDS, HIV / AIDS
Therapuetic Areas:Immunology / Infectious Diseases
Healthy:No
Age Range:18 - 65
Updated:5/3/2014
Start Date:February 2014
End Date:May 2014
Contact:US GSK Clinical Trials Call Center
Email:GSKClinicalSupportHD@gsk.com
Phone:877-379-3718

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A Phase I, Open Label, Parallel Group, Three Period, Fixed Sequence Crossover Study to Evaluate the Effect of Dolutegravir on Metformin Pharmacokinetics in Healthy Adult Subjects

This study will be a phase 1, open label, parallel group, three period crossover study to
evaluate the effect of dolutegravir (DTG) on the steady state pharmacokinetics of metformin
and on the safety and tolerability of dolutegravir and metformin. Subjects will have a
screening visit within 30 days prior to the first dose of study drug, three treatment
periods, and a follow up visit 7-14 days after the last dose of study drug. Eligible
subjects will be assigned to one of the two treatment cohorts. Subjects will receive
metformin 500 milligram (mg) after every 12 hours (q12h) for 5 days in Period 1; metformin
500 mg q12h plus dolutegravir 50 mg after every 24 hours (q24h) (Cohort 1) or 50 mg q12h
(Cohort 2) for 7 days in Period 2; and metformin 500 mg q12h for 10 days in Period 3.
There will be no washout periods between treatments. All doses of study drug will be taken
following a meal. Safety evaluations will be collected during each period. Serial
pharmacokinetic (PK) samples will be collected for metformin on the last day of each period
and for dolutegravir on the last day of Period 2.


Inclusion Criteria:

- Male/females aged between 18 and 65 years of age inclusive, at the time of signing
the informed consent.

- Healthy as determined by a responsible and experienced physician, 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 agrees and documents that the finding is unlikely to introduce
additional risk factors and will not interfere with the study procedures.

- Body weight >=50 kilograms (Kg) for males and >=45 Kg for females and body mass index
(BMI) within the range 18.5 - 31.0 Kg/m^2 (square meters) (inclusive).

- 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
[for this definition, "documented" refers to the outcome of the
investigator's/designee's review of the subject's medical history for study
eligibility, as obtained via a verbal interview with the subject or from the
subject's medical records]; or postmenopausal defined as 12 months of spontaneous
amenorrhea [in questionable cases a blood sample with simultaneous follicle
stimulating hormone (FSH) >40 milli international units per milliliter (MIU/mL) and
estradiol <40 picograms (pg)/mL (<147 picomole per liter (pmol/L) is confirmatory];
Child-bearing potential with negative pregnancy test as determined by [serum or
urine] human chorionic gonadotropin (hCG) test at screening or prior to dosing AND
Agrees to use one of the contraception methods 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 5 days post-last dose. OR has only same-sex partners, when
this is her preferred and usual lifestyle.

- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form

- Alanine aminotransferase, 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%). A single repeat is allowed for eligibility determination.

Exclusion Criteria:

- A positive pre-study drug/alcohol screen.

- A positive test for human immunodeficiency virus (HIV) antibody.

- Pregnant females as determined by positive [serum or urine] hCG test at screening or
prior to dosing.

- 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.

- 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
GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation. Subjects
will allergy to tricyclic antidepressants should not be enrolled.

- 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).

- Lactating females.

- 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).

- Regular use of tobacco- or nicotine-containing products within 6 months prior to
screening.

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

- The subject's systolic blood pressure is outside the range of 90-140 millimeters of
mercury (mmHg), or diastolic pressure is outside the range of 45-90 mmHg, or heart
rate is outside the range of 50-100 beats per minute (bpm) for female subjects or
45-100 bpm for male subjects. A single repeat is allowed for eligibility
determination.

- Exclusion criteria for screening electrocardiogram (ECG) (a single repeat is allowed
for eligibility determination): Heart rate for males <45 and >110 bpm and females <50
and >100 bpm; PR interval <120 and >220 msec, QRS duration <70 and >120 msec, QTc
interval (Bazett) >450 msec. Evidence of previous myocardial infarction (Does not
include ST segment changes associated with repolarization); any clinically
significant arrhythmia which, in the opinion of the investigator and GSK Medical
Monitor, will interfere with the safety for the individual subject; any conduction
abnormality (including but not specific to left or right incomplete bundle branch
block, atrioventricular block [2nd degree or higher], Wolf Parkinson White [WPW]
syndrome), sinus pauses>3 seconds, and non-sustained or sustained ventricular
tachycardia (>=3 consecutive ventricular ectopic beats).
We found this trial at
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Overland Park, Kansas 66210
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Overland Park, KS
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