Infection, Human Immunodeficiency Virus
Conditions
Keywords
dolutegravir, lamivudine, Bioavailability, fixed dose combinations
Brief summary
Dolutegravir (DTG) and lamivudine (3TC) are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Fixed dose combination (FDC) tablets of existing approved drugs are preferred by many patients and offer the potential for increased patient adherence and consequently a reduced likelihood of virological failure and viral resistance. The purpose of the present study is to evaluate the relative bioavailability of two experimental FDC tablets of DTG and 3TC relative to co-administration of the single entity products in healthy adult subjects. This study will be conducted as a randomized, open label three-way, crossover design with 6 treatment sequences in approximately 30 subjects. Each subject will have a screening visit within 30 days prior to the first dose of study drug, three treatment periods each with a single dose of study drug and a follow-up visit within 7-14 days after the last dose of study drug. There will be at least 7 days washout between dosing periods. The total duration of participation of a subject in this study will be approximately 9 weeks.
Interventions
A white, film-coated, round tablet debossed with SV 572 on one side and 50 on the other side. Single dose of one tablet will be administered with 240 mL of water.
DRUGLamivudine 300 mg tablet
Gray, diamond-shaped tablet, engraved GX EJ7 on one side and plain on the other side. Single dose of one tablet will be administered with 240 mL of water.
DRUGDolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA)
Immediate release oval tablet embossed 'gsk' on one face with white film coat. Single dose of one tablet will be administered with 240 mL of water.
DRUGDolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB)
Immediate release oval tablet embossed 'gsk' on one face with white film coat. Single dose of one tablet will be administered with 240 mL of water.
Sponsors
GlaxoSmithKline
ViiV Healthcare
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 65 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac evaluation (history, electrocardiogram \[ECG\]). * 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 in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body weight \>= 50 kilogram (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 kg/meter square (m\^2) (inclusive) * Male or Female Female subject of non-reproductive potential: is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine 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 (refer to laboratory reference ranges for confirmatory levels). 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. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DTG: Area under the concentration-time curve from time 0 extrapolated to infinity (AUC[0-inf]) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for pharmacokinetic (PK) analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| DTG: maximum concentration observed (Cmax) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| 3TC: AUC(0-inf) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| 3TC: Cmax | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DTG: Time to observed maximal drug concentration (tmax) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| DTG: Apparent oral clearance (CL/F) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| 3TC:AUC(0-t) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| 3TC: C24 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| 3TC:t1/2 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| 3TC: tlag | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| 3TC: tmax | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| DTG: Area under the concentration-time curve from time 0 to the last measurable timepoint (AUC[0-t]) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| Change from baseline in temperature | Baseline and up to 9 weeks | — |
| Change from baseline in systolic and diastolic blood pressure (BP) | Baseline and up to 9 weeks | — |
| Change from baseline in pulse rate | Baseline and up to 9 weeks | — |
| Number of subjects with adverse events | Up to 9 weeks | — |
| Number of subjects with the Toxicity Grade and Change from baseline summary for the Indicated Hematology Parameters | Up to 9 weeks | The hematology parameters included are platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), neutrophils, lymphocytes, monocytes, eosinophils, basophils. |
| Number of subjects with the Toxicity Grade and Change from baseline summary for the Indicated Clinical Chemistry Parameters | Up to 9 weeks | Clinical chemistry parameters included are blood urea nitrogen (BUN), creatinine, glucose, creatine phosphokinase (CPK), potassium, sodium, calcium, AST, ALT, alkaline phosphatase, total and direct bilirubin, total protein, albumin |
| Number of subjects with urinalysis abnormalities | Up to 9 weeks | Urinalysis parameters included are specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal) |
| 3TC: CL/F | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| DTG: Drug concentration at 24 hours post-dose (C24) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| DTG: Half-life (t1/2) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
| DTG: Absorption lag time (tlag) | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose | Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined. |
Countries
United States
Outcome results
None listed