New Drug Update 2009-2010 - LAFP

ZOLEDRONIC ACID INJECTION in Paget Disease and Osteoporosis – Reclast (Novartis)
INDICATIONS: Zoledronic acid has been approved for the treatment of hypercalcemia of malignancy,
osteolytic lesions of multiple myeloma, and osteolytic bone metastases associated with solid tumors.
Another new drug application (NDA) has been submitted requesting approval for use in the treatment of
Paget disease and the treatment of osteoporosis in postmenopausal women. The Food and Drug
Administration (FDA)-approved indications for the intravenous (IV) bisphosphonates are summarized in
Table 1. As of June 2008 the following inications was added: In patients at high risk of fracture, defined as
a recent low-trauma hip fracture, Reclast reduces the incidence of new clinical fractures. In Dec 2008
treatment to increase bone mass in men with osteoporosis and in March 2009 treatment and prevention
of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12
months. As of June 1, 2009 the FDA has approved Reclast in a single dose every two years to treat
ostopenia, or low bone mass, which can lead to osteoporosis.
Table 1. FDA-Approved Indications for IV Ibandronate, Pamidronate, and Zoledronic Acid
Indication Ibandronate Pamidronate Zoledronic
Acid
Treatment of osteoporosis in postmenopausal women X X
Treatment of osteopenia
X
Treatment of Paget disease of bone X X
Treatment/prevention of steroid induced osteoporosis
X
Treatment of hypercalcemia of malignancy X X
Treatment of osteolytic lesions of multiple myeloma X X
Treatment of osteolytic bone metastases from solid
X
tumors
Treatment of osteolytic bone metastases of breast cancer
X
CLINICAL PHARMACOLOGY: Zoledronic acid is a bisphosphonic acid. Like other bisphosphonates, it
inhibits osteoclast formation, osteoblast proliferation, and DNA synthesis. Zoledronic acid is a more
potent inhibitor of bone resorption than risedronate, alendronate, pamidronate, or etidronate. Zoledronic
acid is 100 to 850 times more potent than pamidronate. It has minimal effects on skeletal mineralization.
In long-term animal osteoporosis models, zoledronic acid prevented time- and dose-dependent bone loss
in the total body, lumbar spine, and femur, and was associated with increases in bone mass at those
sites. Trabecular deterioration was also prevented. When administered IV as single equipotent doses in
mice, the magnitude of effect and duration of action were comparable with alendronate, risedronate,
ibandronate, and zoledronic acid.
Zoledronic acid has also been demonstrated to decrease type II collagen degradation, suggesting it may
have chondroprotective effects. It also has the ability to preserve cortical bone integrity in inflammatory
arthritis and enhanced bone strength.
PHARMACOKINETICS: Changes in zoledronic acid plasma concentrations are dose proportional.
Although within 24 hours after the infusion plasma concentrations fall to less than 1% of the concentration
obtained at the end of the infusion, zoledronic acid remains detectable up to day 29 after IV
administration. Elimination is triphasic, with an alpha half-life of 0.23 hours, a beta half-life of 1.75 hours,
and a terminal elimination half-life of 167 hours observed in cancer patients with bone metastases.
Zoledronic acid is quickly taken up into the bone, then slowly released. The mean terminal elimination
half-life is 146 hours. It is only approximately 22% plasma protein bound.
Zoledronic acid does not undergo biotransformation in vivo; it is primarily eliminated intact via the kidney.
Clearance correlates with renal function in patients with healthy to moderately impaired renal function.
Clearance does not appear to be influenced by body weight, body mass index, gender, age, or race
(white, black, or Asian), and is independent of the dose. Pharmacokinetics have not been evaluated in
patients with hepatic impairment or severe renal function impairment.
Table 2 compares the pharmacokinetics of injectable ibandronate, pamidronate, and zoledronic acid.
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