Bioavailability Study of 10 Milligram (mg) and 5 mg Tablets Versus Conventional Tablets of Dolutegravir

NCT03095638 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 205893
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this cross-over study is to compare the relative bioavailability and pharmacokinetic parameters of both 10 mg conventional tablets and 5 mg dispersible tablets of dolutegravir (DTG) with that of 25 mg or 50 mg conventional DTG tablets. The study will be carried out in 2 parts. Part 1 of the study will be open-label, 2 period designs with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 10 mg DTG tablets or one 50 mg DTG tablet in a crossover manner in the fasting state. Part 2 of the study will be a 3 period crossover design with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 5 mg DTG tablets (administered as dispersed with water or directly to mouth) or one 25 mg DTG tablet in a crossover manner in the fasting state. Subjects will have a follow-up visit 7-10 days post last dose of study treatment. Approximately 14 healthy subjects will participate in Part 1 and approximately 24 healthy subjects will participate in Part 2 of the study. The total duration of Part 1 will be approximately 7 to 8 weeks and that of part 2 will be approximately 8 to 9 weeks. TIVICAY® is a trademark of the GlaxoSmithKline group of companies.

Conditions

HIV Infections

Keywords

Dispersible tablets; Bioavailability; Dolutegravir; Healthy; Conventional tablets

Outcome Measures

Primary Outcomes (4)

• Area Under the Plasma Concentration-time Curve From Time of Dose Extrapolated to Infinite Time (AUC[0-infinity]) of DTG for Part 1

  Blood samples were collected at the indicated time points after administration of study treatment to investigate the pharmacokinetic (PK) profile of DTG tablets in fasted state. PK parameters were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 6.4 or higher based on actual sampling times. The PK Population was defined as participants in the All Subjects Population for whom a PK sample was obtained and that had evaluable PK assay results.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1

• Area Under the Plasma Concentration-time Curve From Time of Dose to Last Measurable Concentration AUC [0-t] of DTG for Part 1

  Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of DTG tablets in fasted state. PK parameters were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 6.4 or higher based on actual sampling times..

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1

• Maximum Observed Concentration (Cmax) of DTG for Part 1

  Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of DTG tablets in fasted state. PK parameters were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 6.4 or higher based on actual sampling times.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1

• AUC (0-infinity) of DTG for Part 2

  Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of DTG tablets in fasted state. PK parameters were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 6.4 or higher based on actual sampling times..

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2

Secondary Outcomes (52)

• AUC (0-t) of DTG for Part 2

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2

• Cmax of DTG for Part 2

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2

• Plasma DTG Lag Time Before Observation of Drug Concentrations (Tlag) for Part 1

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1

• Time to First Occurrence of Cmax (Tmax) of DTG for Part 1

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1

• Terminal Phase Half-life (t1/2) of DTG for Part 1

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1

Study Arms (8)

Treatment sequence A/B: Part 1

EXPERIMENTAL

Eligible subjects will be randomized in sequence A/B in Part 1 and will receive A: conventional 10 mg DTG tablet (5 tablets) in Period 1 and B: conventional 50 mg DTG tablet in Period 2, administered directly to mouth.

Drug: Conventional dolutegravir 10 mg tablet; Drug: Conventional dolutegravir 50 mg tablet

Treatment sequence B/A: Part 1

EXPERIMENTAL

Eligible subjects will be randomized in sequence B/A in Part 1 and will receive B: conventional 50 mg DTG tablet in Period 1 and A: conventional 10 mg DTG tablet (5 tablets) in Period 2, administered directly to mouth.

Drug: Conventional dolutegravir 10 mg tablet; Drug: Conventional dolutegravir 50 mg tablet

Treatment sequence C/D/E: Part 2

EXPERIMENTAL

Eligible subjects will be randomized in sequence C/D/E in Part 2 and will receive C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 1, D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 2 and E: conventional 25 mg DTG tablet administered as direct to mouth in Period 3.

Drug: Dispersible dolutegravir 5 mg tablet; Drug: Conventional dolutegravir 25 mg tablet

Treatment sequence D/E/C: Part 2

EXPERIMENTAL

Eligible subjects will be randomized in sequence D/E/C in Part 2 and will receive D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 1, E: conventional 25 mg DTG tablet administered as direct to mouth in Period 2 and C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 3.

Drug: Dispersible dolutegravir 5 mg tablet; Drug: Conventional dolutegravir 25 mg tablet

Treatment sequence E/C/D: Part 2

EXPERIMENTAL

Eligible subjects will be randomized in sequence E/C/D in Part 2 and will receive E: conventional 25 mg DTG tablet administered as direct to mouth in Period 1, C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 2 and D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 3.

Drug: Dispersible dolutegravir 5 mg tablet; Drug: Conventional dolutegravir 25 mg tablet

Treatment sequence C/E/D: Part 2

EXPERIMENTAL

Eligible subjects will be randomized in sequence C/E/D in Part 2 and will receive C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 1, E: conventional 25 mg DTG tablet administered as direct to mouth in Period 2 and D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 3.

Drug: Dispersible dolutegravir 5 mg tablet; Drug: Conventional dolutegravir 25 mg tablet

Treatment sequence D/C/E: Part 2

EXPERIMENTAL

Eligible subjects will be randomized in sequence D/C/E in Part 2 and will receive D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 1, C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 2 and E: conventional 25 mg DTG tablet administered as direct to mouth in Period 3.

Drug: Dispersible dolutegravir 5 mg tablet; Drug: Conventional dolutegravir 25 mg tablet

Treatment sequence E/D/C: Part 2

EXPERIMENTAL

Eligible subjects will be randomized in sequence E/D/C in Part 2 and will receive E: conventional 25 mg DTG tablet administered as direct to mouth in Period 1, D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 2 and C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 3.

Drug: Dispersible dolutegravir 5 mg tablet; Drug: Conventional dolutegravir 25 mg tablet

Interventions

Conventional dolutegravir 10 mg tablet DRUG

Single dose of five 10 mg DTG tablets will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence A/B: Part 1; Treatment sequence B/A: Part 1

Conventional dolutegravir 50 mg tablet DRUG

Single dose of one 50 mg tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence A/B: Part 1; Treatment sequence B/A: Part 1

Dispersible dolutegravir 5 mg tablet DRUG

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence C/D/E: Part 2; Treatment sequence C/E/D: Part 2; Treatment sequence D/C/E: Part 2; Treatment sequence D/E/C: Part 2; Treatment sequence E/C/D: Part 2; Treatment sequence E/D/C: Part 2

Conventional dolutegravir 25 mg tablet DRUG

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence C/D/E: Part 2; Treatment sequence C/E/D: Part 2; Treatment sequence D/C/E: Part 2; Treatment sequence D/E/C: Part 2; Treatment sequence E/C/D: Part 2; Treatment sequence E/D/C: Part 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:

• Between 18 and 65 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• Body weight \>= 50 kilogram (kg) for males and \>= 45 kg for females and body mass index (BMI) within the range 18.5 - 31.0 kg per meter square (kg/m\^2) (inclusive).
• Male or female. Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause\]. 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 post-menopausal status prior to study enrolment. 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 and until 2 weeks after dosing with study medication and completion of the follow-up visit.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions.
• Alanine amino transferase (ALT) and bilirubin \>1.5x Upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QT correction using Fridericia Formula (QTcF) \>450 Milliseconds (msec).
• Unable to refrain from the use of prescription \[that is (i.e. 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 for males or \>7 drinks for females. One drink is equivalent to 12 gram (g) of alcohol: 12 ounces (360 milliliters \[mL\]) 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 within 1 month 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.
• Creatinine clearance (CrCL) \<90 mL/minute.
• A positive hepatitis B surface antigen (HBsAg) or a positive hepatitis B core antibody with a negative hepatitis B surface antibody, positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
• A positive pre-study drug/alcohol screen.
• A positive test for Human Immuno-deficiency Virus (HIV) antibody.
• Where participation in the study would result in donation of blood or blood product in excess of 500 mL within 56 days.

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Austin, Texas, 78744, United States

Location

Related Publications (1)

• Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.

  PMID: 34817414 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Tablets

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: March 23, 2017
• First Posted: March 29, 2017
• Study Start: May 3, 2017
• Primary Completion: June 23, 2017
• Study Completion: June 23, 2017
• Last Updated: July 23, 2019
• Results First Posted: December 21, 2018

Record last verified: 2019-07

Locations

US (1)