| Indication |
For the treatment of hypercalcemia of malignancy. Also for the
treatment of patients with multiple myeloma and patients with documented
bone metastases from solid tumors, in conjunction with standard
antineoplastic therapy. In May of 2007, the drug was approved for
treatment of Paget’s Disease. |
| Pharmacodynamics |
Zoledronate is a bisphosphonic acid which is an inhibitor of
osteoclastic bone resorption. Zoledronate is used to prevent
osteoporosis and skeletal fractures, particularly in patients with
cancers such as multiple myeloma and prostate cancer. It can also be
used to treat hypercalcemia, particularly hypercalcemia of malignancy.
It can also be helpful for treating pain from bone metastases. |
| Mechanism of action |
The action of zoledronate on bone tissue is based partly on its
affinity for hydroxyapatite, which is part of the mineral matrix of
bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase.
Nitrogen-containing bisphosphonates such as zoledronate appear to act as
analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP
synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme
in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and
GGPP) that are essential for the post-translational farnesylation and
geranylgeranylation of small GTPase signalling proteins. This activity
inhibits osteoclast activity and reduces bone resorption and turnover.
In postmenopausal women, it reduces the elevated rate of bone turnover,
leading to, on average, a net gain in bone mass. |
| Absorption |
Poorly absorbed (oral absorption is about 1% of what intravenous absorption is). |
| Volume of distribution |
Not Available |
| Protein binding |
Approximately 22% bound in human plasma, independent of the
concentration. However, Canadian product information states binding to
human plasma protein is approximately 56%. |
| Metabolism |
Zoledronate does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo. |
| Route of elimination |
In 64 patients with cancer and bone metastases, on average (±
s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in
the urine within 24 hours, with only trace amounts of drug found in
urine post-Day 2. |
| Half life |
146 hours |
| Clearance |
|
| Toxicity |
There is no experience of acute overdose. Two patients received
zoledronate (32 mg) over 5 minutes in clinical trials. Neither patient
experienced any clinical or laboratory toxicity. Overdosage may cause
clinically significant hypocalcemia, hypophosphatemia, and
hypomagnesemia. |
