Healthy Volunteers
Conditions
Brief summary
The purpose of this study is to evaluate the safety and pharmacokinetics of redosing EXPAREL via local subcutaneous infiltration in healthy volunteers.
Detailed description
During Dosing Period 1, blood samples for pharmacokinetic (PK) analysis will be obtained predose (15 minutes prior to administration of EXPAREL) through 12 hours postdose (i.e., at 15 and 30 minutes, 1, 2, 4, 8, and 12 hours) for Cohort 4; through 36 hours postdose (i.e., at 15 and 30 minutes, 1, 2, 4, 8, 12, 24, and 36 hours) for Cohort 3; through 60 hours postdose (i.e., at 15 and 30 minutes, 1, 2, 4, 8, 12, 24, 36, 48, and 60 hours) for Cohort 2; and through 72 hours postdose (i.e., at 15 and 30 minutes, 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours) for Cohorts 1 and 5. During Dosing Period 2 (Cohorts 2, 3, and 4 only), blood samples for PK analysis will be obtained predose (15 minutes prior to administration of EXPAREL) through 72 hours postdose (i.e., at 15 and 30 minutes, 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours).
Interventions
DRUGEXPAREL
Sponsors
Pacira Pharmaceuticals, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Males or females ≥18 years of age. * American Society of Anesthesiologists (ASA) physical status 1 or 2. * Female subjects must be surgically sterile, at least 2 years postmenopausal, or using a medically acceptable method of birth control. If of childbearing potential, must have a documented negative pregnancy test within 24 hours before the first study drug administration. * Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments.
Exclusion criteria
* History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics. * History of abnormal bleeding tendencies/clotting disorders. * Regular use of anticoagulants (except for low dose aspirin for cardioprotection). * Received any investigational drug within 30 days prior to study drug administration, and/or has planned administration of another investigational product or procedure during his/her participation in this study. * Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study drug administration. * Subjects with significant medical conditions or laboratory results that, in the opinion of the Investigator, would constitute a contraindication to participation in the study, or cause inability to comply with the study requirements. * Received bupivacaine or other local anesthetic within 7 days of first study drug administration.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Plasma Concentration (Cmax) | Period(P)1 all cohorts (C) 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects |
| Time to Maximum Concentration (Tmax) | Period(P)1 all cohorts 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects |
| Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC(0-last)] | Period(P)1 all cohorts (C) 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects |
| Apparent Terminal Elimination Half-life | Period(P)1 all cohorts 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects |
| The Apparent Terminal Elimination Rate Constant (λz) | Period(P)1 all cohorts 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Cohort 1 received a single dose of EXPAREL 266 mg on Day 1. No additional dose was given.
EXPAREL | 12 |
| Cohort 2 Cohort 2 received a dose of EXPAREL 266 mg on Day 1 and a second dose of EXPAREL 266 mg on Day 4 at 72 hours.
EXPAREL | 12 |
| Cohort 3 Cohort 3 received a dose of EXPAREL 266 mg on Day 1 and a second dose of EXPAREL 266 mg on Day 3 at 48 hours.
EXPAREL | 12 |
| Cohort 4 Cohort 4 received a dose of EXPAREL 266 mg on Day 1 and a second dose of EXPAREL 266 mg on Day 2 at 24 hours.
EXPAREL | 12 |
| Cohort 5 Cohort 5 received a single dose of EXPAREL 266 mg on Day 1 followed immediately by a second dose of EXPAREL 266 mg (total of 532 mg/40 mL).
EXPAREL | 12 |
| Total | 60 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 5 | Cohort 4 | Cohort 3 | Cohort 2 |
|---|---|---|---|---|---|---|
| Age, Continuous | 45.6 years STANDARD_DEVIATION 11.9 | 41.2 years STANDARD_DEVIATION 12.39 | 44.1 years STANDARD_DEVIATION 14.56 | 41.6 years STANDARD_DEVIATION 12.38 | 36.9 years STANDARD_DEVIATION 10.83 | 37.8 years STANDARD_DEVIATION 11.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 60 Participants | 12 Participants | 12 Participants | 12 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 42 Participants | 8 Participants | 9 Participants | 9 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 18 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants |
| Region of Enrollment United States | 12 participants | 60 participants | 12 participants | 12 participants | 12 participants | 12 participants |
| Sex: Female, Male Female | 7 Participants | 23 Participants | 6 Participants | 8 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 37 Participants | 6 Participants | 4 Participants | 10 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 12 | 2 / 12 | 7 / 12 | 2 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Apparent Terminal Elimination Half-life
Time frame: Period(P)1 all cohorts 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects
Population: Where n per group \<12, values were either not calculated or not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Apparent Terminal Elimination Half-life | 80.24 hours | Standard Deviation 22.64 |
| Cohort 2 | Apparent Terminal Elimination Half-life | 44.88 hours | Standard Deviation 25.64 |
| Cohort 3 | Apparent Terminal Elimination Half-life | 51.70 hours | Standard Deviation 26.99 |
| Cohort 4 | Apparent Terminal Elimination Half-life | 33.22 hours | Standard Deviation 3.8 |
| Cohort 5 | Apparent Terminal Elimination Half-life | 59.13 hours | Standard Deviation 25.03 |
Primary
Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC(0-last)]
Time frame: Period(P)1 all cohorts (C) 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC(0-last)] | 5917 H*ng/mL | Standard Deviation 1738 |
| Cohort 2 | Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC(0-last)] | 10976 H*ng/mL | Standard Deviation 2879 |
| Cohort 3 | Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC(0-last)] | 10201 H*ng/mL | Standard Deviation 3721 |
| Cohort 4 | Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC(0-last)] | 15227 H*ng/mL | Standard Deviation 7463 |
| Cohort 5 | Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC(0-last)] | 11567 H*ng/mL | Standard Deviation 3737 |
Primary
Maximum Plasma Concentration (Cmax)
Time frame: Period(P)1 all cohorts (C) 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Maximum Plasma Concentration (Cmax) | 129 ng/mL | Standard Deviation 47 |
| Cohort 2 | Maximum Plasma Concentration (Cmax) | 207 ng/mL | Standard Deviation 57 |
| Cohort 3 | Maximum Plasma Concentration (Cmax) | 202 ng/mL | Standard Deviation 74 |
| Cohort 4 | Maximum Plasma Concentration (Cmax) | 290 ng/mL | Standard Deviation 119 |
| Cohort 5 | Maximum Plasma Concentration (Cmax) | 246 ng/mL | Standard Deviation 78 |
Primary
The Apparent Terminal Elimination Rate Constant (λz)
Time frame: Period(P)1 all cohorts 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects
Population: Where n per group \<12, values were either not calculated or not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | The Apparent Terminal Elimination Rate Constant (λz) | 0.009 1/hours | Standard Deviation 0.003 |
| Cohort 2 | The Apparent Terminal Elimination Rate Constant (λz) | 0.019 1/hours | Standard Deviation 0.007 |
| Cohort 3 | The Apparent Terminal Elimination Rate Constant (λz) | 0.016 1/hours | Standard Deviation 0.007 |
| Cohort 4 | The Apparent Terminal Elimination Rate Constant (λz) | 0.021 1/hours | Standard Deviation 0.002 |
| Cohort 5 | The Apparent Terminal Elimination Rate Constant (λz) | 0.014 1/hours | Standard Deviation 0.006 |
Primary
Time to Maximum Concentration (Tmax)
Time frame: Period(P)1 all cohorts 15 m in pre, 15,30m, 1,2,34,8,12h postdose. C3: +24, 36 h postdose. C2: C3+48,60h postdose; C1 and C5: C2+72h postdose; P2: C2,3,4 only: 15m pre, 1,2,4,8,12,24,36,48,60,72h postdose. Final at D14- all subjects
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Maximum Concentration (Tmax) | 24 hours |
| Cohort 2 | Time to Maximum Concentration (Tmax) | 48 hours |
| Cohort 3 | Time to Maximum Concentration (Tmax) | 48 hours |
| Cohort 4 | Time to Maximum Concentration (Tmax) | 36 hours |
| Cohort 5 | Time to Maximum Concentration (Tmax) | 24 hours |