Participants With Treatment-Emergent Adverse Events (TEAEs)
TEAE=any untoward medical occurrence that develops or worsens in severity after dispensation of the study drug and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= a marked limitation in activity. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent one of the outcomes listed in this definition. A serious AE (SAE) is defined as any AE occurring at any dose that results in any of the following outcomes: death; lifethreatening AE; hospitalization or prolongation of existing hospitalization; a persistent or significant disability/incapacit
Buprenorphine PK: % Fluctuation
% Fluctuation was defined as the degree of fluctuation of buprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cavg*100, expressed as a percentage. Cmax=maximum plasma concentration Cmin=minimum plasma concentration Cavg = average plasma concentration
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6)
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Buprenorphine PK: Area Under Plasma Concentration Time Curves (AUC)
AUC calculated using the linear trapezoidal rule and requiring a minimum of 5 data points for each time range.
Results are reported across four timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Buprenorphine PK: Average Plasma Concentration (Cavg)
Cavg was defined as the AUC (timeframe)/timeframe. For example, the sublingual steady-state Cavg reading on Day -1 = AUC0-24/ 24 hours
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6)
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Buprenorphine PK: Maximum Observed Plasma Concentration (Cmax)
Maximum observed plasma concentration, determined directly from individual concentration time data.
Results are reported across four timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Buprenorphine PK: Minimum Observed Plasma Concentration (Cmin)
Minimum observed plasma concentration, determined directly from individual concentration time data.
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Buprenorphine PK: Swing of Plasma Concentrations
The swing of buprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cmin within the dosing interval.
Cmax=maximum plasma concentration Cmin=minimum plasma concentration
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6)
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Buprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax)
Results are reported across four timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Buprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC))
Accumulation index in terms of AUC calculated as ratio of AUCtau Injection 4/ AUCtau Injection 1. AUCtau = area under plasma concentration time curve over the dosing interval tau (for SC RBP-6000, tau=28 days).
Buprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax))
Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1.
Buprenorphine PK: Apparent Clearance at Steady-State (CLss/F) Following Injections 4 and 6
Apparent clearance at steady-state (CLss/F) = Dose / AUCtau (tau was 28 days).
Buprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 (AUC0-∞)
Area under plasma concentration time curve from time zero of Injection 4 extrapolated to infinity; calculated for Injection 4 (last injection) in subjects not participating in PET imaging sub-study only as:
(AUC0-∞ was reported if the coefficient of determination R2 was at least 0.8 and the extrapolated area is less than 25%). A minimum of 5 data points was required. AUC up to the last measurable concentration (AUClast) was calculated by using the linear trapezoidal rule.
Buprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4
The terminal phase half life calculated for Injection 4 in subjects not participating in PET imaging sub-study. The t1/2 was reported only if the coefficient of determination R2 was at least 0.8.
Norbuprenorphine PK: % Fluctuation
% Fluctuation was defined as the degree of fluctuation of norbuprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cavg*100, expressed as a percentage. Cmax=maximum plasma concentration Cmin=minimum plasma concentration Cavg = average plasma concentration
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6)
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Norbuprenorphine PK: Area Under Plasma Concentration Time Curves (AUC)
AUC calculated using the linear trapezoidal rule and requiring a minimum of 5 data points for each time range.
Results are reported across four timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Norbuprenorphine PK: Average Plasma Concentration (Cavg)
Cavg was defined as the AUC (timeframe)/timeframe. For example, the sublingual steady-state Cavg reading on Day -1 = AUC0-24/ 24 hours
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6)
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Norbuprenorphine PK: Maximum Observed Plasma Concentration (Cmax)
Maximum observed plasma concentration, determined directly from individual concentration time data.
Results are reported across four timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Norbuprenorphine PK: Minimum Observed Plasma Concentration (Cmin)
Minimum observed plasma concentration, determined directly from individual concentration time data.
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Norbuprenorphine PK: Swing of Plasma Concentrations
The swing of norbuprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cmin within the dosing interval.
Cmax=maximum plasma concentration Cmin=minimum plasma concentration
Results are reported across three timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading.
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6)
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6)
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Norbuprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax)
Results are reported across four timeframes:
Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24.
Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48
Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672
Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672
The PK sampling schedule was
hour 0 (predose) on days -7 to -1,
hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4
hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6
Norbuprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC))
Accumulation index in terms of AUC calculated as ratio of AUCtau Injection 4/ AUCtau Injection 1. AUCtau = area under plasma concentration time curve over the dosing interval tau (for SC RBP-6000, tau=28 days).
Norbuprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax))
Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1.
Norbuprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 and 6 (AUC0-∞)
Area under plasma concentration time curve from time zero of Injection 4 extrapolated to infinity; calculated for Injection 4 and 6 (last injection) in subjects not participating in PET imaging sub-study only as:
(AUC0-∞ was reported if the coefficient of determination R2 was at least 0.8 and the extrapolated area is less than 25%). A minimum of 5 data points was required. AUC up to the last measurable concentration (AUClast) was calculated by using the linear trapezoidal rule.
Norbuprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4
The terminal phase half life calculated for Injection 4 in subjects not participating in PET imaging sub-study. The t1/2 was reported only if the coefficient of determination R2 was at least 0.8.