Infection, Human Immunodeficiency Virus
Conditions
Keywords
Dolutegravir, drug interaction, metformin, pharmacokinetics, healthy volunteers
Brief summary
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.
Interventions
DRUGMetformin 500 mg q12h
Metformin will be supplied as 500 mg tablet to be administered orally.
DRUGDolutegravir 50 mg q24h
Dolutegravir will be supplied as 50 mg tablet to be administered orally. To be taken once a day in the morning in Period 2 (Total daily dose 50 mg per day for Cohort 1 only)
DRUGDolutegravir 50 mg q12h
Dolutegravir will be supplied as 50 mg tablet to be administered orally. To be taken 50 mg tablets every 12 hours in Period 2 (Total daily dose 100 mg per day for Cohort 2 only).
Sponsors
GlaxoSmithKline
ViiV Healthcare
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady state plasma metformin pharmacokinetics (PK) parameters | Day 5 to Day 22 | PK parameters will include: maximum concentration (Cmax), area under the time-concentration curve over the dosing interval \[AUC(0-tau)\] |
| Steady state plasma DTG PK parameters | Day 12 and Day 13 | PK parameters will include: Area under the time-concentration curve over the dosing interval \[AUC(0-tau)\], apparent clearance following oral dosing (CL/F), concentration at time zero (C0) and maximum concentration (Cmax) |
| Steady-state plasma metformin PK parameters in Period 2 as compared to those in Period 1 | Day 5 to Day 12 | PK parameters will include: Terminal phase half-life (t1/2) and Apparent clearance following oral dosing (CL/F) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in vital signs | Upto Day 22 | Vital signs will include systolic and diastolic blood pressure and pulse rate. |
| Number of subjects with adverse events (AEs) | Upto Day 22 | AEs will be assessed throughout the study. |
| Toxicity grading of clinical laboratory tests | Upto Day 22 | Laboratory assessments will include haematology, clinical chemistry and urinalysis parameters. |
| Steady-state plasma metformin PK parameters in Period 3 for each cohort | Upto Day 22 | PK parameters will include: Cmax, concentration curve over the dosing interval \[AUC(0-tau)\], Terminal phase half-life (t1/2) and apparent clearance following oral dosing (CL/F) |
| Changes in serum creatinine upon dosing and discontinuation of DTG | Upto Day 22 | Serum creatinine change will be calculated from baseline over time in each period |
Countries
United States
Outcome results
None listed