Pharmacokinetics and Safety of Bupivacaine HCl Spinal Block and EXPAREL Local Infiltration in Total Knee Arthroplasty

Study Overview
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Brief Summary
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This is a Phase 4, multicenter, open-label study designed to characterize the pharmacokinetic (PK) profile of total bupivacaine in approximately 15 adult subjects undergoing primary unilateral total knee arthroplasty (TKA) with bupivacaine hydrochloride (HCl) spinal nerve block (SNB) and EXPAREL local infiltration into the surgical site.

Detailed Description
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On Day 1, following an epinephrine wash of the spinal block syringe, eligible subjects will receive a single 1.6 mL dose of bupivacaine HCl 7.5 mg/mL within 2 hours prior to the surgical procedure as a spinal block. EXPAREL 266 mg in 20 mL (expanded with 70 mL of preservative-free sterile normal saline to a total volume of 90 mL) will be infiltrated into the surgical site at the end of the surgery prior to wound closure. There will be no local co-administration of the two drugs. Blood samples for bupivacaine PK analysis will be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, and 72 hours after the beginning of EXPAREL administration, and on Day 14.

Official Title
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Evaluation of the Pharmacokinetics and Safety of Bupivacaine HCl Spinal Block and EXPAREL Local Infiltration in Subjects Undergoing for Unilateral Total Knee Arthroplasty

Conditions
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Pain

Intervention / Treatment
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* Drug: Bupivacaine SNB
* Drug: EXPAREL Infiltration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ≥18 years of age. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3. Scheduled to undergo spinal block in conjunction with unilateral TKA. Female subjects must be surgically sterile, at least 2 years postmenopausal, or using a medically acceptable method of birth control. Females of childbearing potential must have a documented negative blood or urine pregnancy test result within 24 hours before surgery. Able to provide informed consent, adhere to the study schedule, and complete all study assessments. Exclusion Criteria: History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics or opioids. Contraindication to bupivacaine. Received bupivacaine or any other local anesthetic within 7 days of EXPAREL administration. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after EXPAREL administration. Planned concurrent surgical procedure (e.g., bilateral TKA). Body weight <50 kg (110 pounds) or a body mass index ≥45 kg/m2. Received any investigational drug within 30 days prior to EXPAREL administration, and/or has planned administration of another investigational product or procedure during the subject's participation in this study. Previous participation in an EXPAREL study. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. Current or historical evidence of any clinically significant disease or condition, especially cardiovascular or neurological conditions that, in the opinion of the Investigator, may increase the risk of surgery or complicate the subject's postsurgical course. Clinically significant medical or psychiatric disease 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. In addition, the subject will be ineligible to receive EXPAREL if he or she meets the following criteria during surgery: Any clinically significant event or condition uncovered during the surgery (e.g., excessive bleeding, acute sepsis) that might render the subject medically unstable or complicate the subject's postsurgical course.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bupivacaine SNB + EXPAREL Infiltration<br>Spinal block with bupivacaine HCl 7.5 mg/mL. Local infiltration of EXPAREL 266 mg. | Drug: Bupivacaine SNB<br>* SNB with a single 1.6 mL dose of bupivacaine HCl 7.5 mg/mL within 2 hours prior to the surgical procedure.<br>* Other names: Bupivacaine;Drug: EXPAREL Infiltration<br>* Local infiltration of EXPAREL 266 mg into the surgical site at the end of the surgery just prior to wound closure.<br>* Other names: Bupivacaine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) |  | baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14 | 
| Time to Peak Plasma Concentration (Tmax) |  | baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14 | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Collection Time After Drug Administration (AUC0-last) |  | baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14 | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity After Drug Administration (AUC0-∞) |  | baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14 | 
| The Apparent Terminal Elimination Rate Constant (λz) |  | baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14 | 
| The Apparent Terminal Elimination Half-life (t1/2el) |  | baseline, 15,30 min, 1,2,4,8,12,24,48,72 hours post dose, day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Total knee arthroplasty