Infection, Human Immunodeficiency Virus
Conditions
Keywords
Dolutegravir, safety, Rilpivirine, fixed dose combination, relative bioavailability
Brief summary
Treatment of human immunodeficiency virus (HIV) infection requires daily oral administration of a combination of antiretroviral drugs to reduce the patient's HIV levels. Dolutegravir (DTG), a HIV-1 integrase inhibitor (INI), and Rilpivirine (RPV), a non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI), are approved for the treatment of HIV infection. This study is aimed to evaluate the relative bioavailability and food effect of single doses of several experimental fixed dose combination (FDC) tablets of Dolutegravir 50 milligrams (mg) and Rilpivirine 25 mg (DTG/RPV 50 mg/25 mg) relative to co-administration of a single dose of the reference single entity products (DTG 50 mg and RPV 25 mg) in healthy adult subjects. This is a 2-part study. Part 1 will be conducted as a randomized, open label, 3-way, crossover design in 24 subjects. Part 1 will evaluate the relative bioavailability of up to 4 test formulations relative to the reference single entity products administered in fed state. Part 2 will be conducted as a randomized, open-label, 3-way crossover design in 3 distinct cohorts each with 12 subjects. Part 2 will evaluate the relative bioavailability of up to 3 most promising FDC formulation selected from Part 1 (DTG/RPV FDC-1, DTG/RPV FDC-2, DTG/RPV FDC-3) administered in fasted and fed state. Subjects will also receive the reference treatment from Part 1 co-administered under fasted conditions. This study will consist of a screening visit, three treatment periods each with a single dose of study drug separated by a washout of at least 9 days and a follow-up visit. The total duration of participation of a subject in this study will be approximately 10 weeks.
Interventions
DRUGDTG 50 mg
Dolutegravir will be supplied as a white, film-coated, round tablet with a unit dose strength of 50 mg to be administered orally
DRUGRPV 25 mg
Rilpivirine will be supplied as a white to off-white, film-coated, round biconvex tablet with a unit dose strength of 25 mg to be administered orally
DRUGDTG/RPV 50 mg/25 mg: Product Code AS
DTG/RPV will be supplied as a pink, film coated, round biconvex tablet with a unit dose strength of 50 mg DTG and 25 mg RPV to be administered orally
DRUGDTG/RPV 50 mg/25 mg: Product Code AM
DTG/RPV will be supplied as a pink, film coated, oval, biconvex tablet with a unit dose strength of 50 mg DTG and 25 mg RPV to be administered orally
DRUGDTG/RPV 50 mg/25 mg: Product Code AQ
DTG/RPV will be supplied as a pink, film coated, round, biconvex tablet with a unit dose strength of 50 mg DTG and 25 mg RPV to be administered orally
DRUGDTG/RPV 50 mg/25 mg: Product Code AK
DTG/RPV will be supplied as pink, film coated, oval, biconvex tablet with a unit dose strength of 50 mg DTG and 25 mg RPV to be administered orally
DRUGDTG/RPV 50 mg/25 mg: Product Code AR
DTG/RPV will be supplied as a pink, film coated, round, biconvex tablet with a unit dose strength of 50 mg DTG and 25 mg RPV to be administered orally
Sponsors
Janssen Pharmaceuticals
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 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 kg/square meter (m\^2) (inclusive). * Male or Female- 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: 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) 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 GlaxoSmithKline (GSK) modified list of highly effective methods for avoiding pregnancy in females of reproductive potential (FRP) requirements from 30 days prior to the first dose of study medication and until at least five terminal half-lives (10 days) after the last dose of study medication and completion of the follow-up visit. GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis. * Intrauterine device that meets the standard operating procedure (SOP) effectiveness criteria including a \<1% rate of failure per year, as stated in the product label. * Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject. * Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository). These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Male: * Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until \[at least five half-lives of study medication OR for a cycle of spermatogenesis following five terminal half-lives\] after the last dose of study medication. 1. Vasectomy with documentation of azoospermia. 2. Male condom plus partner use of one of the contraceptive options below: * Contraceptive subdermal implant that meets the SOP effectiveness criteria including a \<1% rate of failure per year, as stated in the product label. * Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a \<1% rate of failure per year, as stated in the product label. * Oral Contraceptive, either combined or progestrogen alone. * Injectable progestrogen. * Contraceptive vaginal ring. * Percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. 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 protocol which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of pharmacokinetic (PK) parameters of a single dose of DTG and RPV administered together in a FDC tablet compared to co-administration of the single-entity DTG and RPV products in fed state (Part 1) | Part 1: Pre-dose and 0.25 hours (h), 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 7 h, 9 h, 12 h, 16 h, 24 h, 48 h, 72 h, 120 h, and 168 hours post-dose in each treatment period. | PK parameters will include area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC \[0-Infinity\]), maximum observed concentration (Cmax) and apparent oral clearance (CL/F) |
| Composite of PK parameters of a single dose of DTG and RPV administered together in a FDC tablet compared to co-administration of the single-entity DTG and RPV products in fasted state (Part 2) | Part 2: Pre-dose and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 7 h, 9 h, 12 h, 16 h, 24 h, 48 h, 72 h, 120 h, and 168 hours post-dose in each treatment period. | PK parameters will include AUC (0-Infinity), Cmax and CL/F |
| Composite of PK parameters of DTG and RPV to evaluate the effect of food on the bioavailability of selected FDC formulation(s) of DTG and RPV (Part 2) | Part 2: Pre-dose and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 7 h, 9 h, 12 h, 16 h, 24 h, 48 h, 72 h, 120 h, and 168 hours post-dose in each treatment period. | PK parameters will include AUC (0-Infinity), Cmax and CL/F |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in vital signs | Part 1 and 2: Baseline (Day 1) and up to Day 35 | Vital signs will include systolic and diastolic blood pressure and pulse rate |
| Composite of PK parameters of a single dose of DTG and RPV administered together in a FDC tablet compared to co-administration of the single-entity DTG and RPV products in fed state (Part 1) | Part 1: Pre-dose and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 7 h, 9 h, 12 h, 16 h, 24 h, 48 h, 72 h, 120 h, and 168 hours post-dose in each treatment period. | PK parameters will include area under the curve from time of dose administration to time of last quantifiable post-dose sample (AUC\[0-t\]), observed concentration at 24 h post-dose (C24), terminal elimination phase half-life (t1/2), lag time for absorption (tlag) and time to maximum observed concentration (tmax). |
| Composite of clinical laboratory assessments | Part 1 and 2: Up to Day 35 | Clinical laboratory tests will include hematology, clinical chemistry, urinalysis parameters |
| Number of subjects with adverse events (AEs) | Part 1 and 2: Up to Day 35 | AEs and serious adverse events (SAEs) will be collected from the start of study treatment until the follow-up contact. |
| Composite of PK parameters of a single dose of DTG and RPV administered together in a FDC tablet compared to co-administration of the single-entity DTG and RPV products in fasted state (Part 2) | Part 2: Pre-dose and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 7 h, 9 h, 12 h, 16 h, 24 h, 48 h, 72 h, 120 h, and 168 hours post-dose in each treatment period. | PK parameters will include AUC (0-t), C24, t1/2, tlag and tmax. |
| Composite of PK parameters of DTG and RPV to evaluate the effect of food on the bioavailability of selected FDC formulation(s) of DTG and RPV (Part 2) | Part 2: Pre-dose and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 7 h, 9 h, 12 h, 16 h, 24 h, 48 h, 72 h, 120 h, and 168 hours post-dose in each treatment period. | PK parameters will include AUC (0-t), C24, t1/2, tlag and tmax. |
Countries
United States
Outcome results
None listed