Pharmacokinetic and Safety Study of HYR-PB21 vs Bupivacaine Hydrochloric Acid in Healthy Participants

Official title

A Phase I, Randomized, Single-blind, Active-controlled, Parallel Study to Evaluate the Safety and Pharmacokinetics of Single-Dose HYR-PB21 Versus Bupivacaine Hydrochloric Acid for Subcutaneous Injection in Healthy Participants

Overview

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

• Drug HYR-PB21， 100 mg
  HYR-PB21， 100 mg, administered as a single subcutaneous injection.
• Drug HYR-PB21， 200 mg
  HYR-PB21 200 mg, administered as a single subcutaneous injection.
• Drug HYR-PB21， 400 mg
  HYR-PB21 400 mg, administered as a single subcutaneous injection.
• Drug Bupivacaine hydrochloride， 100 mg (as base)
  Bupivacaine Hydrochloric acid injection 100 mg (expressed as bupivacaine base), administered as a single subcutaneous injection. Active comparator.

Primary outcome measures

• Maximum observed plasma concentration(Cmax) of bupivacaine [Time frame: 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]
• Maximum observed plasma concentration(Cmax) of pamoic acid [Time frame: 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]
• Area Under the Curve(AUC0-t) of bupivacaine [Time frame: 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]
• Area Under the Curve(AUC0-t) of pamoic acid [Time frame: 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]
• Terminal elimination half-life(t1/2) of bupivacaine [Time frame: 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]
• Terminal elimination half-life(t1/2) of pamoic acid [Time frame: 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]
• Time of maximum observed plasma concentration(Tmax) of bupivacaine [Time frame: 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]
• Time of maximum observed plasma concentration(Tmax) of pamoic acid [Time frame: 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]

Secondary outcome measures (1)

• Number of participants with abnormal laboratory tests results, abnormal vital signs,abnormal ECG readings, abnormal physical examination findings [Time frame: Baseline through Day 28 (or 30 days post-dose)]

Eligibility criteria

Inclusion criteria

• Healthy male or female adult participants
• Age 18 to 50 years old (inclusive)
• Body mass index (BMI) of 18.0 to 32.0 kg/m2 and weight ≥50 kg.
• 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:

• 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 :

• 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.
• Surgically sterile at least 6 months prior to screening with documentation.

<!-- -->

• Bilateral tubal ligation
• Hysterectomy (partial or total)
• Bilateral salpingectomy
• Bilateral oophorectomy
• 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.
• 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.
• 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.)
• 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

• A history of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics;
• 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.
• Participants who were detected to have Glucose-6-phosphate dehydrogenase(G6PD) deficiency during the screening period.

Additional detailed exclusion criteria include:

• Females who are pregnant, lactating, or have plans to become pregnant during the study
• History and/or recent evidence within six months prior to Screening of alcohol or drug/substance abuse disorder
• History of clinically significant allergies, including drug allergies, or allergic bronchial asthma, or related bronchospastic conditions
• Participants who have a history of unexplained syncope or fainting or a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration.
• Participants who have used P-gp and/or Cytochrome P450 hepatic microsomal enzyme-inducing or inhibiting drugs (e.g., propafenone, voriconazole, fluconazole, cimetidine) within 30 days of first dosing, refer to Appendix 15-16 for detailed list
• Participants with a history or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychiatric disease, or active sexually transmitted disease to include:

• Current or history of thrombosis or thromboembolic disorders
• Any history of malignancy, especially breast cancer or other hormone-sensitive cancers
• Undiagnosed abnormal vaginal bleeding unrelated to pregnancy
• Cholestatic jaundice of pregnancy
• Liver tumors, benign or malignant, or active liver disease
• Uncontrolled hypertension
• History or evidence of acute or chronic respiratory disorders, including but not limited to chronic obstructive pulmonary disease (COPD) or asthma
• History or presence of significant cardiovascular abnormalities, including, without limitation, severe bradycardia, sick sinus syndrome, second- or third-degree atrial ventricular block, long QT syndrome, cardiogenic shock, and decompensated heart failure
• Participant family history of sudden cardiac death or long QT syndrome and baseline QT prolongation >450 for males and >470 for females at screening
• Participants with estimated glomerular filtration rate (eGFR - utilizing Chronic Kidney Disease Epidemiology Collaboration formula) < 80 mL/min/1.73 m2; participants with slightly lower values may be included upon agreement between the sponsor medical representative and the Principal Investigator at screening
• Participants meeting any of the following laboratory criteria will be excluded:

• Screening total bilirubin > 1.3 mg/dL; participants with a documented history of Gilbert's syndrome can be enrolled if the direct bilirubin is < 0.4 mg/dL
• Screening alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) > upper limits of normal (ULN)
• Screening platelets < 140,000/microliter
• Screening international normalized ratio > 1.2
• Participants who test positive at screening for human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), or Hepatitis C virus (HCV) antibody
• Participants who test positive at Screening and/or admission (Day 0) for alcohol and/or drugs of abuse
• Participants who donated ≥ 500 mL of blood within 56 days prior to the study period or ≥ 50 mL and ≤ 499 mL of blood within 30 days prior to the study period
• Participants who are unable to refrain from or anticipatethe use of any medication, including prescription and non-prescription drugs or herbal remedies (such as St. John's Wort \[Hypericum perforatum\]) approximately 2 weeks prior to study drug administration.
• Participant who is unable to refrain from excessive alcohol consumption within one week prior to the study start throughout the study, until the final study visit. Moderate alcohol consumption is defined as one standard drink per day for women and two drinks per day for men; whereby one standard drink is equivalent to 12 oz beer (5% alcohol), 5 ounces of wine (12% alcohol), and 1.5 ounces of 80 proof (40% alcohol). Excessive consumption would be considered consistently in excess of twice the moderate recommendation.
• Participant who consumes excessive amounts of caffeine for one month prior to the study drug administration, defined as greater than six servings (one serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day
• Participants who donated plasma (e.g., plasmapheresis) within 14 days prior to the study period; participants will be advised not to donate plasma for 14 days after completing the study
• Participant with tattoos to the abdominal area, which in the opinion of the investigator, could interfere with study drug administration.
• Participant has poor venous access or has a history of difficulty tolerating venipuncture such as vasovagal syncope.
• Participants who have participated in another clinical trial which required blood draws within 30 days prior to the first study drug dosing
• Have any other condition that, in the opinion of the Investigator, would interfere with a participant's ability to adhere to the protocol, interfere with assessment of the investigational product, or compromise the safety of the participant or the quality of the data.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Basic science

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07717086 · HYR-PB21-US-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗