This will be a randomized single sequence open label study. This study is designed to determine if chronic dosing with efavirenz (EFZ) will have an effect on the pharmacokinetics (PK) of intravenously-administered retosiban in healthy volunteers. The study consists of screening (28 days), treatment (1 dosing session) and follow-up (7 to 14 days) period, and the total duration of study participation for each subject will be approximately 8 weeks. During the treatment period, subjects will be admitted to the clinical research unit the day before dosing (Day 1) and will remain until completion of the last assessment on Day 20. All subjects will receive on Day 1, a 6 milligrams (mg) bolus of retosiban for 5 minutes (min), followed by a 6 mg/hour (hr) infusion for 12 hrs. On Day 2, a washout day will occur. On Days 3-17, subjects will receive EFZ 600 mg once daily in the evening. On Day 18, subjects will receive a 6 mg bolus of retosiban for 5 mins, followed by a 6 mg/hr infusion for 12 hrs plus a 600 mg dose of EFZ.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Retosiban will be supplied as clear colorless solution for infusion (300 mg in 20 mL via). Subject will receive loading dose of 6 mg over 5 min infusion followed by 6 mg/hour infusion for 12 hrs on Day 1 and Day 18.
EZF 600 mg will be supplied as a yellow, capsular-shaped, film-coated tablet. Subjects will receive EFZ 600mg OD in the evening from Day 3 till Day 18.
GSK Investigational Site
Baltimore, Maryland, United States
Plasma GSK221149 (parent) and GSK2847065 (metabolite) PK parameters of AUC, Cmax and CL.
The following PK parameters will be determined after administration of GSK221149 with and without EFZ 600 mg: Area under the plasma concentration-time curve (AUC)- from time zero to time t \[AUC(0-t)\] and from time zero extrapolated to infinite time \[AUC(0-infinity)\], maximum observed plasma concentration (Cmax) and clearance (CL). CL will be calculated for parent only.
Time frame: 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours (hrs) after the start of the infusion on Day 1 and Day 18.
Safety and tolerability of administration of GSK221149 with and without EFZ 600 mg as assessed by adverse event, concurrent medication review, clinical laboratory tests, ECG, and vital signs measurements.
Clinical laboratory tests will include hematology, clinical chemistry and urinalysis parameters. Triplicate 12-lead ECGs will be obtained at the screening visit. Single 12-lead ECGs will be obtained at other time points during the study. Vital sign measurements will include systolic and diastolic blood pressure and pulse rate.
Time frame: Up to 8 Weeks
Plasma GSK221149 and GSK2847065 PK parameters of tmax, tlag and t1/2.
The following PK parameters will be determined after administration of GSK221149 with and without EFZ 600 mg: time to Cmax (tmax), lag time (tlag), and terminal phase half-life (t1/2). The terminal half-life (t1/2) is defined as the time required for the plasma concentration of drug to reach half of its original concentration.
Time frame: 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours (hrs) after the start of the infusion on Day 1 and Day 18.
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