Zoledronic acid has two formulations, Reclast and Zometa. Are there any pharmacokinetic differences between the two? Reclast recommends using total body weight for the creatinine clearance calculation. What weight should be used for Zometa creatinine clearance calculation? What weight did initial studies for FDA approval use for in the creatinine clearance calculation of Zometa renal adjustments?

Comment by InpharmD Researcher

Zometa was withdrawn from the market in 2009. Per an official notice published by the FDA, the reason for withdrawal was not attributed to concerns over safety or efficacy; an exact reason has not been specified. In general, limited data exist comparing Zometa with Reclast, though both brands share similar pharmacokinetic properties. Notably, however, their elimination patterns exhibit some differences. For instance, Zometa's plasma concentration declines in a multiphasic manner, while Reclast shows a triphasic decline (see Table 1). A previous Zometa package insert recommends using the Cockcroft-Gault formula to calculate creatinine clearance (CrCl), though a specific weight needed for the calculation is not provided. In clinical trials, Zometa treatment was resumed only when creatinine levels returned to within 10% of baseline and should be reinitiated at the same dose as before the treatment interruption.

Background

According to an official notice published by the Food and Drug Administration in 2009, Zometa was withdrawn for sale in the United States. The reasons were not for safety or efficacy reasons, but an exact reason was not specified. An article from the Genetic Engineering & Biotechnology News dated from 2010 expands upon the reason, citing a phase III study that failed to show benefit when added to post-surgery chemotherapy and hormone therapy in breast cancer. These findings do not affect the current approved indications of zoledronic acid: treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors and treatment of hypercalcemia of malignancy. The FDA Orange Book confirms that all Zometa products are currently unavailable. [1], [2], [3]

Relevant Prescribing Information

2.1 Hypercalcemia of Malignancy [1]
Dose adjustments of Zometa are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 micromol/L or less than 4.5 mg/dL).

2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors [1]
Upon treatment initiation, the recommended Zometa doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 2. These doses are calculated to achieve the same area under the
curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula.

During treatment, serum creatinine should be measured before each Zometa dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows [1]:
For patients with normal baseline creatinine, increase of 0.5 mg/dL
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL

In the clinical studies, Zometa treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zometa should be reinitiated at the same dose as that prior to treatment interruption. [1]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-3 for your response.

Pharmacokinetic Differences Between Zometa and Reclast Based on Available Data
	Distribution	Metabolism	Excretion	Clearance
Zometa[1]	Characterized by a multiphasic plasma disposition with half-lives of 0.2 and 1.4 at end-of-infusion C_max to < 1% of C_max 24 hours post-dose; and 39, and 4526 hours between days 2 and 28 postdose.	Does not appear to undergo metabolism	Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, with an average time 0 to 24 hours postdose (Ae_0-24h) of 38-41%.	Moderate correlation with creatinine clearance.
Reclast[2]	The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process, with half-lives of 0.24 hour (t_1/2α) and 1.87 hours (t1/2β) for the early disposition phases, and a terminal elimination half-life (t_1/2γ) of 146 hours.	Does not appear to undergo metabolism	On average, 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with the balance presumably bound to bone.	Independent of dose but dependent on the patient's creatinine clearance.

References:

[1] Chen T, Berenson J, Vescio R, et al. Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol. 2002;42(11):1228-1236. doi:10.1177/009127002762491316
[2] RECLAST (zoledronic acid injection). Prescribing information. Novartis Pharmaceuticals Corporation; 2022.

Reduced Doses for Patients with Baseline creatinine clearance (CrCl) Less than or Equal to 60 mL/min
Baseline CrCl (mL/min)	Zometa Recommended Dose*
Greater than 60	4 mg
50–60	3.5 mg
40–49	3.3 mg
30–39	3 mg
*Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl= 75 mL/min)

References:

Adapted from:
Zometa® (zoledronic acid injection). Prescribing information. Novartis Pharmaceuticals Corporation; 2014.

Zoledronic Acid Preserves Bone Mineral Density in Premenopausal Women Who Develop Ovarian Failure Due to Adjuvant Chemotherapy: Final Results from CALGB Trial 79809
Design	Phase 3 randomized controlled trial (CALGB 79809) N= 439
Objective	To assess whether zoledronic acid (ZA; Zometa®) prevents bone loss in premenopausal women who develop chemotherapy-induced ovarian failure (CIOF)
Study Groups	ZA within 1-3 months after randomization (Group A) ZA 1 year after randomization (Group B)
Inclusion Criteria	Premenopausal, non-pregnant women aged 40 years or older with localized (stages I-III) invasive breast cancer; actively menstruating or last menstrual period within 6 months prior to randomization
Exclusion Criteria	Prior treatment with bisphosphonates; women receiving cardiac glycosides; impaired renal function or hypocalcemia concerns
Methods	Patients were randomized to receive either an intravenous (IV) infusion of ZA 4 mg over 15 minutes every 3 months (total of 8 treatments), starting either within 1–3 months after beginning adjuvant chemotherapy (Group A) or 12–14 months after randomization (Group B). Within 4 weeks prior to randomization, all participants underwent baseline dual-energy x-ray absorptiometry (DEXA) scan, estradiol (E2), follicle-stimulating hormone (FSH), and non-pregnant β-human chorionic gonadotropin (β-HCG) tests. These tests were repeated at 1 and 3 years after randomization. Every 3 months, participants had assessments including medical history, vital signs, ECOG performance status, physical exam, toxicity assessment (for Group B, starting 1 year after randomization), serum calcium and magnesium levels, and the date of the last menstrual period. Serum creatinine was measured before each ZA dose. Participants were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D daily, with compliance assessed by self-report every 3 months, and actual doses recorded on follow-up forms. Dose reductions of ZA were not permitted. For patients with a baseline serum creatinine ≤ 1.4 mg/dL, a rise of 0.5 mg/dL or more required delaying the ZA dose until creatinine was ≤ 10% above baseline. For those with a baseline creatinine > 1.4 mg/dL, a rise of 1.0 mg/dL or more required a delay until creatinine was ≤ 10% above baseline. If a dose was delayed, the frequency of creatinine monitoring was left to the treating physician's discretion.
Duration	Interventions: 2 years Follow-up: Up to 3 years
Outcome Measures	Primary: Percentage change in lumbar spine BMD at 12 months in women with CIOF Secondary: BMD in lumbar spine at 3 years in all randomized women
Baseline Characteristics		Group A (n= 70)*	Group B (n= 80)*
	Age, years (range)	45 (40 to 57)	48 (40 to 59)
	Race White Black Asian Other	69 (99%) 0% 0% 1 (1%)	73 (91%) 3 (4%) 1 (1%) 3 (4%)
	ECOG PS 0 1	69 (93%) 5 (7%)	71 (91%) 7 (8%)
	Nodal Status Negative Positive Unknown	29 (41%) 34 (49%) 7 (10%)	27 (34%) 45 (56%) 8 (10%)
	Stage I/II III Unknown	55 (79%) 13 (18%) 2 (3%)	65 (82%) 10 (12%) 5 (6%)
	Tamoxifen use	51 (73%)	56 (70%)
	Abbreviations: ECOG= Abbreviations: Eastern Cooperative Oncology Group; PS= performance status *Number of patients in each study group is derived from 177/439 randomized women who had their BMD measured at baseline and 36 months; the initial number of patients randomized into each study group was not provided.
Results		Group A	Group B	p-Value
	Total women with CIOF at 1 year (n= 150) 1-year BMD change (IQR)	1.2% (−0.5 to 2.8)	-6.7 %(-2.9 to -9.7)	<0.001
	Total women at 3 years mos (n= 177) 3-year BMD change (IQR)	1.0 (−1.6 to +5.20)	-0.5 (-3.7 to 3.2)	0.019
	150 (56%) patients met the definition of CIOF at 1 year. 30% of randomized patients either did not undergo a DEXA scan at 1 year or had their scan outside the protocol-specified window of 12 to 14 months.
Adverse Events	Grade 3 toxicities: fatigue (1%), arthralgias (1%), pain (4%). No serious renal toxicity or osteonecrosis observed.
Study Author Conclusions	ZA every 3 months is well tolerated and prevents rapid bone loss in premenopausal women that develop CIOF. Giving ZA with rather than one year after the start adjuvant chemotherapy is the preferred sequence to prevent bone loss.
InpharmD Researcher Critique	The study's strengths include a large sample size, a clear definition of CIOF, and the evaluation of optimal ZA timing. However, its limitations include poor compliance with DEXA scans, the lack of fracture data, and the use of the Zometa brand of zoledronic acid, which has since been discontinued, limiting the generalizability of the findings.

References:

Shapiro CL, Halabi S, Hars V, et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. Eur J Cancer. 2011;47(5):683-689. doi:10.1016/j.ejca.2010.11.024