Effect of Dolutegravir on Metformin Pharmacokinetics in Healthy Adult Subjects

NCT02064374 | Completed Phase 1

• 1 other identifier: 201167
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

Dolutegravir; drug interaction; metformin; pharmacokinetics; healthy volunteers

Outcome Measures

Primary Outcomes (3)

• Steady state plasma metformin pharmacokinetics (PK) parameters

  PK parameters will include: maximum concentration (Cmax), area under the time-concentration curve over the dosing interval \[AUC(0-tau)\]

  Day 5 to Day 22

• Steady state plasma DTG PK parameters

  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)

  Day 12 and Day 13

• Steady-state plasma metformin PK parameters in Period 2 as compared to those in Period 1

  PK parameters will include: Terminal phase half-life (t1/2) and Apparent clearance following oral dosing (CL/F)

  Day 5 to Day 12

Secondary Outcomes (5)

• Change from baseline in vital signs

  Upto Day 22

• Number of subjects with adverse events (AEs)

  Upto Day 22

• Toxicity grading of clinical laboratory tests

  Upto Day 22

• Steady-state plasma metformin PK parameters in Period 3 for each cohort

  Upto Day 22

• Changes in serum creatinine upon dosing and discontinuation of DTG

  Upto Day 22

Study Arms (2)

Cohort 1

EXPERIMENTAL

All subjects will be assigned to a single-sequence of three treatment periods without washout. Subjects will receive Metformin immediate release (IR) 500 mg q12h following a moderate fat meal for 5 days (Period 1), followed by Metformin IR 500 mg q12h plus DTG 50 mg q24h following a moderate fat meal for 7 days (Days 1-7 of Period 2), followed by Metformin IR 500 mg q12h following a moderate fat meal (Days 1-10 of period 3).

Drug: Metformin 500 mg q12h; Drug: Dolutegravir 50 mg q24h

Cohort 2

EXPERIMENTAL

All subjects will be assigned to a single-sequence of three treatment periods without washout. Subjects will receive Metformin IR 500 mg q12h following a moderate fat meal (Day 1-5 of Period 1), followed by Metformin IR 500 mg q12h plus DTG 50 mg q12h following a moderate fat meal for 7 days (Days 1-7 of Period 2), followed by Metformin IR 500 mg q12h following a moderate fat meal (Days 1-10 of period 3).

Drug: Metformin 500 mg q12h; Drug: Dolutegravir 50 mg q12h

Interventions

Metformin 500 mg q12h DRUG

Metformin will be supplied as 500 mg tablet to be administered orally.

Cohort 1; Cohort 2

Dolutegravir 50 mg q24h DRUG

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)

Cohort 1

Dolutegravir 50 mg q12h DRUG

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).

Cohort 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Song IH, Zong J, Borland J, Jerva F, Wynne B, Zamek-Gliszczynski MJ, Humphreys JE, Bowers GD, Choukour M. The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects. J Acquir Immune Defic Syndr. 2016 Aug 1;72(4):400-7. doi: 10.1097/QAI.0000000000000983.

  PMID: 26974526 DERIVED

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome

Interventions

Metformin; dolutegravir

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2014
• First Posted: February 17, 2014
• Study Start: February 1, 2014
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: May 26, 2014

Record last verified: 2014-05

Locations

US (1)