Infection, Human Immunodeficiency Virus
Conditions
Keywords
GSK1349572, granule, pediatric, CONTREX mineral water, free-acid, chelating, cations, divalent, dolutegravir, dispersible tablet, relative bioavailability
Brief summary
Dolutegravir (DTG) is an HIV-1 integrase inhibitor approved in the United States, Canada, Australia and EU. A dispersible tablet has been developed for pediatric use as an alternative to the granule formulation, already in development, and the approved film-coated tablet. This is a single-center, randomized, open-label, 5-way crossover study in healthy adult subjects. The study will evaluate the relative bioavailability of five dosing regimens: 20 mg DTG pediatric granules (Treatment A) and of DTG 20 mg dispersible tablets (DTG 20 mg DT) after dispersed in: low mineral content(LMC) water (Treatment B); dispersed in CONTREX™ mineral water (Treatment C); dispersed in low mineral content water and consumed after standing for 30 minutes (Treatment D) and dispersed in CONTREX mineral water and consumed after standing for 30 minutes (Treatment E). Safety evaluations and serial PK samples will be collected during each treatment period. A follow-up visit will occur 7-14 days after the last dose of study drug. CONTREX is a trademark of Nestlé Waters Corporation.
Interventions
DRUGDolutegravir Pediatric Granules
Dolutegravir pediatric granules are supplied as 40 grams bulk bottles containing 0.4% weight by weight of dolutegravir to be reconstituted with 73 mL of purified water to yield a dolutegravir concentration of 1.6 milligram / millilitre. 12.5 mL of reconstituted granules contain 20 mg DTG
Dolutegravir is available as 5mg dispersible tablets and can be administered as 4 tablets dispersed in 12.5 mL LMC water and consumed immediately or 4 tablets dispersed in 12.5 mL CONTREX mineral water and consumed immediately or 4 tablets dispersed in 12.5 mL LMC water, allow to stand at room temperature for 30 mins, re-suspend mixture and consumed or 4 tablets dispersed in 12.5 mL CONTREX mineral water, allow to stand at room temperature for 30 mins, re-suspend mixture and consumed
Sponsors
GlaxoSmithKline
ViiV Healthcare
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Males or 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 agree and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body weight +/- 50 kilogram (kg) for males and +/- 45 kg for females and body mass index (BMI) within the range 18.5 - 31.0 kilogram/square meter (kg/m\^2) (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, bilateral salpingectomy, bilateral oophorectomy 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 per milliliter (pg/ml) (\<147 picomole/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 and 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 have 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 transaminase (ALT), alkaline phosphatase and bilirubin \<= 1.5x upper limit of the normal range (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). A single repeat from screening to period 1, day -1 is allowed for eligibility determination. * QT duration corrected for heart rate (QTc) \< 450 millisecond (msec), using Bazett Correction Formula, QT correction using Bazett Formula (QTcB). A single repeat from screening to period 1, day -1 is allowed for eligibility determination.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of pharmacokinetic (PK) parameters following single dose administration of DTG 20 mg DT dispersed in LMC water | Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours post dose), Day 2 (24 hours) and Day 3 (48 hours) | PK parameters include area under the concentration-time curve from time zero extrapolated to infinite time (AUC \[0-infinity\]) Maximum observed concentration (Cmax) and apparent oral clearance (CL/F) |
| Composite of PK parameters following single dose administration of DTG 20 mg DT dispersed in CONTREX mineral water | Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours post dose), Day 2 (24 hours) and Day 3 (48 hours) | PK parameters include AUC (0-infinity), Cmax and CL/F |
| Composite of PK parameters following single dose administration of DTG 20 mg DT dispersed in LMC water with 30-minute holding | Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours post dose), Day 2 (24 hours) and Day 3 (48 hours) | PK parameters include AUC (0-infinity), Cmax and CL/F |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite of PK parameters following single dose administration of DTG 20 mg DT in CONTREX mineral water with 30-minute holding | Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours post dose), Day 2 (24 hours) and Day 3 (48 hours) | PK parameters include AUC (0-infinity), Cmax, CL/F, AUC(0-t); C24; t½; tlag; and tmax |
| Composite of PK parameters following single dose administration of DTG 20 mg DT dispersed in LMC water | Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours post dose), Day 2 (24 hours) and Day 3 (48 hours) | PK parameters include area under the plasma concentration-time curve from time of dose administration to time of last quantifiable post-dose sample \[AUC(0-t)\]; observed concentration at 24h post-dose (C24); terminal elimination phase half-life (t½); lag time for absorption (tlag); and time to maximum observed concentration (tmax) |
| Safety as assessed by number of subjects with adverse events, change from baseline in vital signs and as toxicity grading of clinical laboratory tests | Up to 14 weeks | An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Vital signs include blood pressure and heart rate. Clinical laboratory parameters will include hematology and clinical chemistry |
| Palatability of DTG 20 mg DT | Day 1 (Period 1 only) | Palatability questionnaire containing 11 questions will be administered to each subject within 10 minutes following the dose of DTG (Period 1 only) |
| Composite of PK parameters following single dose administration of DTG 20 mg DT dispersed in CONTREX mineral water | Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours post dose), Day 2 (24 hours) and Day 3 (48 hours) | PK parameters include AUC(0-t), C24; t½; tlag; and tmax will be evaluated for DTG 20 mg DT |
| Composite of PK parameters following single dose administration of DTG 20 mg DT dispersed in LMC water with 30-minute holding | Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours post dose), Day 2 (24 hours) and Day 3 (48 hours) | PK parameters include AUC(0-t), C24; t½; tlag; and tmax |
Countries
United States
Outcome results
None listed