Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Bone Metastases

The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa®), a new‐generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three...

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Published in:Journal of clinical pharmacology 2002-11, Vol.42 (11), p.1228-1236
Main Authors: Chen, Tianling, Berenson, James, Vescio, Robert, Swift, Regina, Gilchick, Alicia, Goodin, Susan, LoRusso, Patricia, Ma, Peiming, Ravera, Christina, Deckert, Fabienne, Schran, Horst, Seaman, John, Skerjanec, Andrej
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Area Under Curve
Biological and medical sciences
Bone Neoplasms - drug therapy
Bone Neoplasms - metabolism
Bone Neoplasms - secondary
Bones, joints and connective tissue. Antiinflammatory agents
Diphosphonates - adverse effects
Diphosphonates - pharmacokinetics
Diphosphonates - pharmacology
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Imidazoles - adverse effects
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Infusions, Intravenous
Male
Medical sciences
Middle Aged
Models, Biological
Pharmacology. Drug treatments
Time Factors
Zoledronic Acid
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Summary:The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa®), a new‐generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5), 4 mg/15 min (n = 7), 8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half‐lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end‐of‐infusion Cmax to < 1% of Cmax at 24 hours postdose and half‐lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0‐24h and Cmax were dose proportional and showed little accumulation (AUC0_24h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered Cmax by 34%, with no effect on AUC0‐24h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0‐24h of 38% ± 13%, 41% ± 14%, and 37% ± 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24‐hour urines. Renal clearance (Ae0‐24h)/(AUC0‐24h) was on average 69 ± 28, 81 ± 40, and 54 ± 34 ml/min after 4, 8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 ± 23, 82 ± 25, and 80 ± 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine‐corrected urine C‐telopeptide (by 74%), N‐telopeptide (69%), pyridinium cross‐links (19–33%), and calcium (62%), with an increasing trend (by 12%) in bone alkaline phosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0‐24j, AUC0‐24h, or Cmax. The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.
ISSN:0091-2700
1552-4604
DOI:10.1177/009127002762491316