Infection, Human Immunodeficiency Virus
Conditions
Keywords
rifampin, drug interaction, pharmacokinetics, cabotegravir
Brief summary
CAB is an integrase inhibitor that is currently in Phase 2 clinical trials for the treatment and prevention of human immunodeficiency virus-1 (HIV-1) infection. RIF, a rifamycin used for treatment of tuberculosis (common co-infection in HIV-infected subjects), is a known inducer of uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) and Cytochrome P450 3A4 (CYP3A4). CAB is primarily metabolized via UGT1A1 and UGT1A9, thus a drug interaction between CAB and RIF is possible. This study will be a phase I, single-center, open label, fixed-sequence cross-over study to compare the single dose PK of CAB oral 30 milligrams (mg) when co-administered with RIF 600 mg once daily at steady-state to those of CAB oral 30 mg administered alone. Fifteen subjects are planned to be enrolled to obtain 12 evaluable subjects for this study.
Interventions
Sponsors
GlaxoSmithKline
ViiV Healthcare
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Males and females 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. * Body weight \>=50 kilogram (kg) and body mass index (BMI) within the range 18.5 - 31.0 kg/meter square (m\^2) (inclusive). * Male or female - A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies: a) Non-reproductive potential defined as: Pre-menopausal females with one of the following \[for this definition, documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy; b) 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 \>40 milli-international units per mililiter (MIU/mL) and estradiol \<40 picogram/milliliter (pg/mL) (\<147 picomoles/liter \[pmol/L\]) is confirmatory\]; c) Reproductive potential and agrees to follow one of the options listed 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 after the last dose of study medication and completion of the follow-up visit. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol. * Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
Exclusion criteria
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * History of clinically significant cardiovascular disease including: a)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma CAB maximum observed concentration after single dose administration (Cmax) | Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28 | Plasma PK samples collected at the following time points: Period 1 pre-dose (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours post dose. Period 3 pre-dose Day 21 (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours (Day 8) post dose. |
| Plasma CAB area under the concentration versus time from time zero to infinity after single dose administration (AUC(0-∞)) | Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28 | Plasma PK samples collected at the following time points: Period 1 pre-dose (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours post dose. Period 3 pre-dose Day 21 (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours (Day 8) post dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma CAB time of occurrence of Cmax (tmax) and terminal phase half-life (t1/2) | Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28 | Plasma PK samples collected at the following time points: Period 1 pre-dose (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours post dose. Period 3 pre-dose Day 21 (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours (Day 8) post dose. |
| Plasma CAB apparent clearance following oral dosing (CL/F) | Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28 | Plasma PK samples collected at the following time points: Period 1 pre-dose (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours post dose. Period 3 pre-dose Day 21 (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours (Day 8) post dose. |
| Number of subjects with adverse events (AEs) as a measure of safety and tolerability | Up to 42 days | AEs will be collected from the start of study treatment until the follow-up contact |
| Plasma CAB concentration at 24 hours post dose (C24) | Days 2 and 22 | Plasma PK samples collected at Period 1 24 hours post dose and at Period 3 24 hours post dose will be used to measure plasma CAB C24. |
| Clinical laboratory screens as a measure of safety and tolerability | Day -1, 8, 13, 20, 23, 25, 28, and follow-up (up to Day 42) | Haematology, clinical chemistry, urinalysis and additional parameters will be tested. |
| Electrocardiogram (ECG) as a measure of safety and tolerability | Day 1, 20, 21, and 23 | — |
| Vital signs assessments as a measure of safety and tolerability | Day 1, 8, 20, 21, 25, 26, 28, and follow-up (up to Day 42) | — |
| Concurrent medication as a measure of safety and tolerability | Up to 42 days | Concurrent medication will be reviewed from the start of study treatment until the follow-up contact. |
| Plasma CAB AUC from time zero to last time point with measurable concentration after single dose administration (AUC (0-t)) | Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28 | Plasma PK samples collected at the following time points: Period 1 pre-dose (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours post dose. Period 3 pre-dose Day 21 (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours (Day 8) post dose. |
Countries
United States
Outcome results
None listed