Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid

Phase 4UnknownNCT04719650

Peking University Third Hospital64 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Postmenopausal Osteoporosis

Interventions

Eligibility

Sex: FEMALEMin age: 60 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Concentration of Zoledronic acid

Zoledronic acid concentration in plasma and urine.

Time frame: 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.

Time frame: 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.

Time frame: 0-36 months

AUC of Zoledronic acid

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

Time frame: 0-36 months

terminal half-life of Zoledronic acid

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

Time frame: 0-36 months

apparent clearance of Zoledronic acid

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

Time frame: 0-36 months

apparent volume of distribution of Zoledronic acid

The apparent volume of distribution of zoledronic acid after administration.

Time frame: 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.

Time frame: 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

Time frame: 0-36 months

PTH concentration determination

Assessment of the profile of parathyroid hormone (PTH)

Time frame: 0-36 months

Serum sclerostin concentration determination

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

Time frame: 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.

Time frame: 0-36 months

Pharmacodynamic of zoledronic acid

Assessment of fibroblast growth factor 19 (FGF19).

Time frame: 0-36 months

Pharmacodynamic of zoledronic acid

Assessment of total bile acid.

Time frame: 0-36 months

Pharmacodynamic of zoledronic acid

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

Time frame: 0-36 months

Change of immune indicator

Changes in white blood cells(WBC)

Time frame: 0-36 months

Change of immune indicator

Changes in C reaction protein (CRP)

Time frame: 0-36 months

Change of immune indicator

Changes in interferon-γ (IFN-γ)

Time frame: 0-36 months

Change of immune indicator

Changes in interleukin-6 (IL-6)

Time frame: 0-36 months

Change of immune indicator

Changes in γδT cells activation

Time frame: 0-36 months

Secondary Outcomes

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.

Time frame: 0-36 months

Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts