Pharmacokinetics, Safety and Tolerability Study of Abacavir/ Dolutegravir/ Lamivudine Fixed-dose Combination Tablets in Healthy Japanese Subjects

NCT02539576 | Completed Phase 1

• 1 other identifier: 204662
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

The abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) 600 milligrams (mg)/50 mg/300 mg fixed-dose combination (FDC) tablet is currently approved in the United States (US) and Europe. Although the pharmacokinetics (PK), safety and tolerability of ABC/DTG/3TC FDC tablets have been extensively studied in subjects not of Japanese heritage, these parameters have not been exclusively assessed in Japanese subjects. To support the marketing application in Japan, this single-dose, open-label study will characterize the PK, safety and tolerability of ABC/DTG/3TC FDC tablet in adult Japanese healthy subjects. A maximum of 12 subjects will be enrolled such that approximately 10 evaluable subjects complete the study. The study will consist of a screening, treatment phase (single oral dose under the fasted state) and follow-up visit (within 7-14 days of the last PK sample collected). The total duration of the study for each subject will be approximately up to 48 days.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

pharmacokinetics; Healthy subjects; Abacavir/dolutegravir/lamivudine; Japanese; Fixed-dose combination; safety

Outcome Measures

Primary Outcomes (9)

• Area under the concentration-time curve from time zero (pre-dose) to time of last quantifiable concentration (AUC[0-t]) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinity]) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Maximum observed plasma concentration (Cmax) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Time of occurrence of Cmax (tmax) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Concentration at 24 h after dose administration (C24) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Terminal phase half-time (t1/2) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Apparent clearance following oral dosing (CL/F) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Percentage of AUC(0-infinity) obtained by extrapolation (%AUCex) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

• Terminal phase rate constant (Lambda-z) following a single oral dose administration of ABC/DTG/3TC 600 mg/ 50 mg/ 300 mg FDC tablet in healthy, adult Japanese subjects

  Blood samples for PK analyses will be collected at pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post- dose.

  Day 1: Pre-dose and at 30 minutes, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h and 72 h post dose.

Secondary Outcomes (9)

• Safety as assessed by the number of subjects with adverse events (AE) and serious adverse events (SAE)

  From Day-1 up to follow-up (approx. Day 18)

• Absolute values for composite of clinical chemistry parameters as a safety measure

  Day-1 and follow-up (approx. Day 18)

• Change from baseline values for composite of clinical chemistry parameters as a safety measure

  Day-1 and follow-up (approx. Day 18)

• Urinalysis assessments

  Day-1 and follow-up (approx. Day 18)

• Safety as assessed by systolic and diastolic blood pressure measurements

  Day-1, pre-dose and at 4 h, 24 h, 48 h post-dose, and follow-up (approx. Day 18)

Study Arms (1)

ABC/DTG/3TC FDC

EXPERIMENTAL

Each subject will receive treatment with a single oral dose of ABC 600 mg/DTG 50 mg/3TC 300 mg FDC tablet administered under the fasted state

Drug: ABC/DTG/3TC FDC tablet

Interventions

ABC/DTG/3TC FDC tablet DRUG

ABC/DTG/3TC FDC will be supplied as purple, biconvex, oval tablets debossed with "572 Trı" on one side and plain on the other side. A single dose, with a unit dose strength of 600 mg/50 mg/300 mg will be administered orally.

ABC/DTG/3TC FDC

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
• Japanese subjects who were born in Japan with 4 ethnic Japanese grand parents and must not have lived outside Japan for more than 10 years with being a Japanese passport holder (current or expired).
• Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, and laboratory tests.

You may not qualify if:

• Body weight \>=50 kilograms (kg) (110 pounds \[lbs\]) for men and \>=45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kilogram per meter square (kg/m\^2) (inclusive).
• Male or female
• Females- A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine \[according to the sites standard of practice\] human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:
• 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 below 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.
• The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
• Capable of giving signed informed consent as described in the protocol which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.
• Documentation that the subject is negative for the human leukocyte antigen (HLA) B\*5701 allele.
• Alanine aminotransferase (ALT) \>1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QTcF \>450 millisecond (msec)
• NOTES:
• The QT duration corrected for heart rate (QTc) is the QTcF machine-read or manually over-read.
• The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.
• For purposes of data analysis, QT interval corrected for heart rate using Bazett's formula (QTcB), QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the reporting and analysis plan (RAP).

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Glendale, California, 91206, United States

Location

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome

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

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: August 20, 2015
• First Posted: September 3, 2015
• Study Start: October 1, 2015
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: December 21, 2015

Record last verified: 2015-12

Locations

US (1)