Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid

The Pharmacokinetics and Pharmacodynamics Study of Intravenous Zoledronic Acid in Chinese Subjects With Low Bone Mass or Osteoporosis: a Randomized Placebo-controlled Trail

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Postmenopausal Osteoporosis
• Intervention / Treatment: Drug: Zoledronic Acid Injection; Drug: Zoledronic Acid Injection; Drug: Zoledronic Acid Injection; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 64
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Qi Liu, Ph. D.; Phone Number: +8615501060136; Email: liuqicpu@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Hypersensitivity to zoledronic acid or other bisphosphonate or zoledronic acid formulation (excipients).
2. Secondary osteoporosis.
3. 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.

4. 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.

5. Hyperthyroidism or hypothyroidism during screening.

6. Treatment with any investigational drug within the past 3 months.

7. Creatinine clearance < 35 mL/min.

8. 25(OH)D level< 20 ng/mL.

9. Serum calcium level < 2.0 mmol/L (8 mg/dL), or >2.8 mmol/L (11.0 mg/dL).

10. Fever, severe infections, severe injuries, or major surgical operation within 30 days.

11. ECG corrected QT interval (QTc) > 480 ms.

12. Pending invasive dental procedure or in progress.

13. History of smoking within 6 months.

14. Diabetes with fasting blood glucose ≥ 7.0 mmol/L, or glycated hemoglobin (HbA1c) >6.3%.

15. History of drug or alcohol abuse.

16. History of stroke, cerebral ischemic stroke, or cerebral hemorrhage.

17. Any physiological or medical condition which, in the opinion of the investigator, would preclude the participant from this trail.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: zoledronic acid 1mg; 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; Infusion 1mg zoledronic acid once.; Other Names: Yigu; Drug: Zoledronic Acid Injection; Infusion 2.5mg zoledronic acid once.; Other Names: Yigu; Drug: Zoledronic Acid Injection; Infusion 5mg zoledronic acid once.; Other Names: Yigu
Experimental: zoledronic acid 2.5mg; 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; Infusion 1mg zoledronic acid once.; Other Names: Yigu; Drug: Zoledronic Acid Injection; Infusion 2.5mg zoledronic acid once.; Other Names: Yigu; Drug: Zoledronic Acid Injection; Infusion 5mg zoledronic acid once.; Other Names: Yigu
Experimental: zoledronic acid 5mg; Infusion 100 mL of Zoledronic acid injection (100mL : 5mg) with constant speed in 20 minutes. Administration only once.	Drug: Zoledronic Acid Injection; Infusion 1mg zoledronic acid once.; Other Names: Yigu; Drug: Zoledronic Acid Injection; Infusion 2.5mg zoledronic acid once.; Other Names: Yigu; Drug: Zoledronic Acid Injection; Infusion 5mg zoledronic acid once.; Other Names: Yigu
Placebo Comparator: placebo; Infusion 100 mL of normal saline with constant speed in 20 minutes. Administration only once.	Drug: Placebo; Infusion normal saline once.; Other Names: Yigu Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse event	The occurrence time and severity of fracture. The occurrence time and severity of acute phase response. The occurrence time and severity of other adverse event.	0-36 months

Collaborators and Investigators

• Sponsor: Peking University Third Hospital

Publications and helpful links

General Publications

• 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. Erratum In: Osteoporos Int. 2015 Jul;26(7):2045-7.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): November 1, 2024

Study Registration Dates

• First Submitted: January 7, 2021
• First Submitted That Met QC Criteria: January 19, 2021
• First Posted (Actual): January 22, 2021

Study Record Updates

• Last Update Posted (Actual): June 23, 2021
• Last Update Submitted That Met QC Criteria: June 21, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: pharmacokinetic; pharmacodynamic; zoledronic acid; Chinese osteoporosis
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Osteoporosis, Postmenopausal; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: M2020427

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No