Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid

NCT04719650 | Unknown Phase 4

• 1 other identifier: M2020427
• Study Type: interventional
• Target: 64
• Locations: 0 countries
• Sites: N/A

Brief Summary

The recommended dosing regimen of zoledronic acid in Chinese osteoporosis patients is completely in accordance with the one of 5 mg per year abroad that based on the dosing regimen in Paget's disease. This dosing regimen lacks the actual supportive clinical data of Chinese patients. In addition, the overall incidence of acute phase response, the main adverse event after the first infusion, in Chinese patients is higher than that in Caucasian patients population. Moreover, the results of the similar drug clinical study in the Japanese patients shown that the purpose of effective treatment for osteoporosis could be achieved with half of the dosage in Caucasian population. Thus, it could be inferred from these that the dosing regimen of zoledronic acid might be inappropriate in Chinese osteoporosis patients. Therefore, the main purpose of this clinical trail is to compare the zoledronic acid pharmacokinetic and pharmacodynamic characteristic of different doses in Chinese postmenopausal subjects with low bone mass or osteoporosis and explore the best dosing regimen in Chinese patients.

Conditions

Postmenopausal Osteoporosis

Keywords

zoledronic acid; pharmacokinetic; pharmacodynamic; Chinese osteoporosis

Outcome Measures

Primary Outcomes (20)

• Concentration of Zoledronic acid

  Zoledronic acid concentration in plasma and urine.

  Predose, 30 minutes, 2 hours, 24 hours, day 7, day 29, 3 months, 6 months, 12 months, 24 months, and 36 months post dose

• Maximum concentration of Zoledronic acid

  The observed maximum concentration following administration (Cmax) in plasma after zoledronic acid infusion.

  0-36 months

• Time to reach maximum concentration of Zoledronic acid

  The time to reach the maximum concentration after administration (Tmax) in plasma after zoledronic acid infusion.

  0-36 months

• AUC of Zoledronic acid

  The area under the concentration-time curve (AUC) in plasma after zoledronic acid infusion.

  0-36 months

• terminal half-life of Zoledronic acid

  The terminal half-life (t1/2) of zoledronic acid after administration.

  0-36 months

• apparent clearance of Zoledronic acid

  The apparent clearance (CL/F) of zoledronic acid after administration.

  0-36 months

• apparent volume of distribution of Zoledronic acid

  The apparent volume of distribution of zoledronic acid after administration.

  0-36 months

• Concentration of bone turnover markers

  Concentration-time profile of procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (ALP), osteocalcin (OCN), C-telopeptide (CTx), and tartrate-resistant acid phosphatase 5b (TRACP-5b) with unit of ng/mL.

  0-36 months

• Concentration of 25(OH)D and FGF23

  Concentration determination of 25(OH)D and fibroblast growth factor 23 (FGF23) with unit of ng/mL

  0-36 months

• PTH concentration determination

  Assessment of the profile of parathyroid hormone (PTH)

  0-36 months

• Serum sclerostin concentration determination

  Concentration-time profile of sclerostin (SOST) after zoledronic acid infusion.

  0-36 months

• Pharmacodynamic of zoledronic acid

  Assessment of lipid metabolism markers, such as low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol, and triglycerides.

  0-36 months

• Pharmacodynamic of zoledronic acid

  Assessment of fibroblast growth factor 19 (FGF19).

  0-36 months

• Pharmacodynamic of zoledronic acid

  Assessment of total bile acid.

  0-36 months

• Pharmacodynamic of zoledronic acid

  Assessment of bone mineral density at the lumbar spine, neck of femur, and total hip.

  0-36 months

• Change of immune indicator

  Changes in white blood cells(WBC)

  0-36 months

• Change of immune indicator

  Changes in C reaction protein (CRP)

  0-36 months

• Change of immune indicator

  Changes in interferon-γ (IFN-γ)

  0-36 months

• Change of immune indicator

  Changes in interleukin-6 (IL-6)

  0-36 months

• Change of immune indicator

  Changes in γδT cells activation

  0-36 months

Secondary Outcomes (1)

• Incidence of adverse event

  0-36 months

Study Arms (4)

zoledronic acid 1mg

EXPERIMENTAL

Add 20 mL of Zoledronic acid injection (100mL : 5mg) with 80 mL of normal saline to 100 mL. Infusion 20 minutes with constant speed. Administration only once.

Drug: Zoledronic Acid Injection

zoledronic acid 2.5mg

EXPERIMENTAL

Add 50 mL of Zoledronic acid injection (100mL : 5mg) with 50 mL of normal saline to 100 mL. Infusion 20 minutes with constant speed. Administration only once.

Drug: Zoledronic Acid Injection

zoledronic acid 5mg

EXPERIMENTAL

Infusion 100 mL of Zoledronic acid injection (100mL : 5mg) with constant speed in 20 minutes. Administration only once.

Drug: Zoledronic Acid Injection

placebo

PLACEBO COMPARATOR

Infusion 100 mL of normal saline with constant speed in 20 minutes. Administration only once.

Drug: Placebo

Interventions

Zoledronic Acid Injection DRUG

Infusion 1mg zoledronic acid once.

Also known as: Yigu

zoledronic acid 1mg

Placebo DRUG

Infusion normal saline once.

Also known as: Yigu Placebo

placebo

Eligibility Criteria

• Age: 60 Years - 70 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Chinese postmenopausal women
• Aged between 60 and 70.
• Bone mineral density (BMD) values of less than 1 standard deviations (SD) below the normal adult mean.
• Willing to participate in this study.

You may not qualify if:

• Hypersensitivity to zoledronic acid or other bisphosphonate or zoledronic acid formulation (excipients).
• Secondary osteoporosis.
• Receiving the following drugs that affect bone metabolism prior to randomization:
• (1) intravenous biphosphonates or denosumab. (2) oral biphosphonates, parathyroid hormone or its analogues, strontium, or fluoride within 12 months.
• (3) glucocorticoid, steroids, immunosuppressive agents, calcitonin, calcitriol or its analogues, thiazides diuretics, long-acting estrogen/progesterone, or statins within 3 months.
• \. Combine other diseases affect bone metabolism: osteogenesis imperfecta, hyperthyroidism, malignant tumors, Paget's disease, rheumatoid arthritis, osteomalacia, osteopetrosis, ankylosing spondylitis, liver failure, or renal failure.
• \. Hyperthyroidism or hypothyroidism during screening.
• \. Treatment with any investigational drug within the past 3 months.
• \. Creatinine clearance \< 35 mL/min.
• \. 25(OH)D level\< 20 ng/mL.
• \. Serum calcium level \< 2.0 mmol/L (8 mg/dL), or \>2.8 mmol/L (11.0 mg/dL).
• \. Fever, severe infections, severe injuries, or major surgical operation within 30 days.
• \. ECG corrected QT interval (QTc) \> 480 ms.
• \. Pending invasive dental procedure or in progress.
• \. History of smoking within 6 months.

Sponsors & Collaborators

• Peking University Third Hospital: lead

Related Publications (3)

• Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R; National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359-81. doi: 10.1007/s00198-014-2794-2. Epub 2014 Aug 15.

  PMID: 25182228 BACKGROUND

• Shiraki M, Fukunaga M, Kushida K, Kishimoto H, Taketani Y, Minaguchi H, Inoue T, Morita R, Morii H, Yamamoto K, Ohashi Y, Orimo H. A double-blind dose-ranging study of risedronate in Japanese patients with osteoporosis (a study by the Risedronate Late Phase II Research Group). Osteoporos Int. 2003 May;14(3):225-34. doi: 10.1007/s00198-002-1369-9. Epub 2003 Apr 10.

  PMID: 12730746 BACKGROUND

• Ding Y, Zeng JC, Yin F, Zhang CL, Zhang Y, Li SX, Liu X, Zhang C, Xue QY, Lin H, Pei FX. Multicenter Study on Observation of Acute-phase Responses After Infusion of Zoledronic Acid 5 mg in Chinese Women with Postmenopausal Osteoporosis. Orthop Surg. 2017 Aug;9(3):284-289. doi: 10.1111/os.12338.

  PMID: 28960821 BACKGROUND

MeSH Terms

Conditions

Osteoporosis, Postmenopausal

Interventions

Zoledronic Acid

Condition Hierarchy (Ancestors)

Osteoporosis; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Chunli Song, M.D.; Ph. D.

  Peking University Third Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Qi Liu, Ph. D.

CONTACT

+8615501060136; liuqicpu@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 7, 2021
• First Posted: January 22, 2021
• Study Start: October 1, 2021
• Primary Completion: October 1, 2024
• Study Completion: November 1, 2024
• Last Updated: June 23, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share