Postoperative Analgesia
Conditions
Brief summary
This is a Phase I, randomized, single-blind, active-controlled, single-dose, parallel-group study to evaluate the safety and pharmacokinetic (PK) profile of HYR-PB21, a pamoate-formulated bupivacaine injectable, in healthy adult participants. Participants are randomized to receive a single subcutaneous dose of HYR-PB21 at one of three dose levels (100 mg, 200 mg, or 400 mg) or a single 100 mg dose of Bupivacaine hydrochloride injection (as base) as active control. The primary objectives are to characterize the PK profile of HYR-PB21 at the three dose levels compared with Bupivacaine hydrochloride, and to determine the Pharmacokinetics characteristics of the pamoic acid moiety following HYR-PB21 administration. Secondary objectives are to extend cumulative safety and tolerability observations of single subcutaneous doses of HYR-PB21 in healthy adults.
Detailed description
Background and Rationale HYR-PB21 for Injectable Suspension (HYR-PB21) is a novel long-acting formulation under investigation for local analgesia. Preclinical and clinical data supporting this investigational new drug include four previous Phase 1 or 2 studies conducted in Chinese participants and one Phase 1 study in Australian participants. These prior studies evaluated the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of HYR-PB21. The current study is designed to serve as a bridging study to extrapolate the existing ex-US PK and safety data to a North American population. Upon successful completion, the data from this study will be utilized to define the proposed Phase 3 efficacy dose or dose range for North American patients. Study Design and Objectives This is a Phase I, randomized, single-blind, active-controlled, single-dose, parallel-group study designed to evaluate the safety and pharmacokinetic profile of HYR-PB21 compared to Bupivacaine HCl Injection in healthy adult participants. The primary objectives are: To characterize and compare the plasma PK profile of three dose levels of HYR-PB21 (100 mg, 200 mg, and 400 mg) versus a single dose of 100 mg Bupivacaine hydrochloride Injection (calculated as base). To determine the pharmacokinetic characteristics of the pamoic acid component following administration of HYR-PB21 at the aforementioned dose levels. The secondary objective is to further evaluate the cumulative safety and tolerability of single subcutaneous doses of HYR-PB21 in healthy participants. Participants and Interventions A total of 28 healthy adult participants will be randomized in a 1:1:1:1 ratio into four parallel treatment arms (N=7 per arm).All treatments will be administered via subcutaneous injection. Extensive blood sampling will be conducted to characterize the plasma concentration-time profiles. Sampling time points are: pre-dose (within 2 hours prior to dosing), 15 (±2) min, 30 (±2) min, 1 (±2) h, 2 (±3) h, 4 (±3) h, 8 (±5) h, 12 (±5) h, 18 (±5) h, 24 (±5) h, 30 (±5) h, 36 (±5) h, 48 (±5) h, 60 (±5) h, 72 (±5) h, 96 (±5) h, 120 (±5) h, and 144 (±5) h post-dose. Safety and tolerability will be monitored throughout the study duration. Assessments include: Treatment-emergent adverse events (TEAEs), including monitoring for Local Anesthetic Systemic Toxicity (LAST) and local injection site reactions, etc.
Interventions
DRUGHYR-PB21， 100 mg
HYR-PB21， 100 mg, administered as a single subcutaneous injection.
DRUGHYR-PB21， 200 mg
HYR-PB21 200 mg, administered as a single subcutaneous injection.
DRUGHYR-PB21， 400 mg
HYR-PB21 400 mg, administered as a single subcutaneous injection.
DRUGBupivacaine hydrochloride， 100 mg (as base)
Bupivacaine Hydrochloric acid injection 100 mg (expressed as bupivacaine base), administered as a single subcutaneous injection. Active comparator.
Sponsors
Fruithy Holdings Limited
Frontage Clinical Services
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female adult participants 2. Age 18 to 50 years old (inclusive) 3. Body mass index (BMI) of 18.0 to 32.0 kg/m2 and weight ≥50 kg. 4. Participant is generally healthy, as determined by the Investigator based on medical history, physical examination, clinical laboratory test results, vital signs, and 12-lead electrocardiogram (ECG) at screening. Additional Detailed Inclusion Criteria Include: 5. Female participants who engage in heterosexual intercourse must be non-pregnant or non-lactating. Female participants of childbearing potential must agree to use 2 acceptable methods of contraception with their male partner from screening until 6 months after the last dose of the study drug and refrain from donating ovum for this same period. (Refer to contraception section).Females of non-childbearing potential must either be : 1. Post menopausal as defined by at least 12 months of consecutive Amenorrhea and Follicle-Stimulating Hormone(FSH) and estradiol confirming Post menopausal status at screening. See Appendix Section 13 for additional details. 2. Surgically sterile at least 6 months prior to screening with documentation. <!-- --> 1. Bilateral tubal ligation 2. Hysterectomy (partial or total) 3. Bilateral salpingectomy 4. Bilateral oophorectomy 6. Male participants, if sexually active with a female partner of child-bearing potential, must be vasectomized or agree to take appropriate precautions to prevent conception, including practicing an effective method of contraception, and must not donate sperm from screening through 12 weeks following administration of the last dose of study medication. 7. Only non-smokers are eligible. For a period of at least six months prior to Screening, all participants must have been free from excessive alcohol intake or regular use of illegal recreational drugs. Participants with any past or current history of marijuana use are not eligible for the study. 8. Ability to understand and willingness to sign a written informed consent form (The consent form must be signed by the participant prior to any study-specific procedures.) 9. Willingness and able to comply with catheter placement and blood draws throughout the course of study and comply with study procedures and follow-up examination.
Exclusion criteria
Participants will be excluded if they have 1. A history of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics; 2. Have a personal or family history of clotting disorder or hematologic abnormality, such as excessive bleeding, joint hematoma, thrombovascular disease, thrombocytopenia, or any chronic condition requiring treatment with transfusions; have a history of recurrent bleeding episodes (eg, epistaxis, bruising or gingival bleeding) within 1 month prior to Screening, or a longstanding history of such bleeding. 3. Participants who were detected to have Glucose-6-phosphate dehydrogenase(G6PD) deficiency during the screening period. Additional detailed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed plasma concentration(Cmax) of bupivacaine | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | The maximum observed plasma concentrations of bupivacaine was directly obtained from the observed concentration-time curves. Units: ng/mL. The PK parameters will be analyzed using the non-partial model. For ease of statistical comparison, the Cmax values will be log-transformed. |
| Maximum observed plasma concentration(Cmax) of pamoic acid | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | The maximum observed plasma concentrations of pamoic acid was directly obtained from the observed concentration-time curves. Units: ng/mL. The PK parameters will be analyzed using the non-partial model. For ease of statistical comparison, the Cmax values will be log-transformed. |
| Area Under the Curve(AUC0-t) of bupivacaine | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | During the period from time zero (the administration time) to Tlast (the last time point when the concentration reaches or exceeds the quantitative lower limit), the area under the plasma concentration-time curve of bupivacaine was calculated according to the mixed logarithmic linear trapezoidal rule. Unit: ng·hour/mL. |
| Area Under the Curve(AUC0-t) of pamoic acid | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | During the period from time zero (the administration time) to Tlast (the last time point when the concentration reaches or exceeds the quantitative lower limit), the area under the plasma concentration-time curve of pamoic acid was calculated according to the mixed logarithmic linear trapezoidal rule. Unit: ng·hour/mL. |
| Terminal elimination half-life(t1/2) of bupivacaine | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | The apparent terminal half-life of bupivacaine was calculated using the formula ln(2)/λz, where λz is the terminal elimination rate constant determined through linear regression of the logarithm of the final stage concentration (at least 3 data points, along with the R² value). The unit is hour. |
| Terminal elimination half-life(t1/2) of pamoic acid | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | The apparent terminal half-life of pamoic acid was calculated using the formula ln(2)/λz, where λz is the terminal elimination rate constant determined through linear regression of the logarithm of the final stage concentration (at least 3 data points, along with the R² value). The unit is hour. |
| Time of maximum observed plasma concentration(Tmax) of bupivacaine | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | The time at which bupivacaine reach their maximum plasma concentrations is recorded based on the actual sampling time corresponding to the Cmax value (if there are multiple identical Cmax values, the time of the first occurrence is taken as the reference). Unit: hour |
| Time of maximum observed plasma concentration(Tmax) of pamoic acid | Predose; 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168 hours and Day 14 post-dose | The time at which pamoic acid reach their maximum plasma concentrations is recorded based on the actual sampling time corresponding to the Cmax value (if there are multiple identical Cmax values, the time of the first occurrence is taken as the reference). Unit: hour |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with abnormal laboratory tests results, abnormal vital signs,abnormal ECG readings, abnormal physical examination findings | Baseline through Day 28 (or 30 days post-dose) | Laboratory tests include hematology (e.g., hemoglobin, white blood cell count, platelet count), blood chemistry (e.g., Alanine Aminotransferase, Aspartate Aminotransferase, total bilirubin, creatinine, glucose), urinalysis, and coagulation (e.g., Prothrombin Time, Activated Partial Thromboplastin Time). Vital signs include sitting systolic/diastolic blood pressure, pulse rate, respiratory rate, and body temperature. Abnormal is defined as a value outside the institutional reference range. Clinically significant abnormal values will also be summarized separately, defined as CTCAE Grade ≥1 . Values are summarized as number (%) of participants. |
Contacts
CONTACTLisa Mulligan, Bachelor
STUDY_DIRECTORshanchun zhang, Doctor
Fruithy Holdings Limited
Outcome results
None listed