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`MERMER--101 TABLETS: A PILOT BIOAVAILABILITY STUDY OF A NOVEL ORAL FORMULATION OF ZOLEDRONIC ACID101 TABLETS: A PILOT BIOAVAILABILITY STUDY OF A NOVEL ORAL FORMULATION OF ZOLEDRONIC ACID
`
`Thomas W. Leonard1 , Catherine McHugh2, Bozena Adamczyk2, Angela Walsh2
`
`1 Merrion Pharmaceuticals LLC, Wilmington, North Carolina, United States
`2 Merrion Pharmaceuticals Ireland Ltd, Dublin, Ireland
`
`STUDY OBJECTIVE
`
`RESULTS (contd.)
`
`To compare the absorption from two strengths, 10mg and 20mg MER-101 enteric coated tablets to the
`parenteral reference product, commercially-available zoledronic acid intravenous infusion, (Zometa®
`Injection, Novartis).
`
`TABLE 2
`
`Ratio for Cumulative Excretion Values
`
`STUDY DESIGN
`
`Test Item
`
`Least Square Mean
`Ratio
`
`Ln Transformed Ratio
`
`(90% CI)
`
`0.661
`
`(90% CI)
`
`0.723
`
`MER-101A / Zometa®
`
`(0.42 - 1.02)
`
`(0.48 - 0.91)
`
`MER-101B / Zometa®
`
`(0.76 - 1.36)
`
`(0.69 - 1.31)
`
`1.060
`
`0.949
`
`MER-101B / MER-101A
`
`(1.06 - 1.87)
`
`(1.05 - 1.96)
`
`1.466
`
`1.436
`
`MER-101-01 Results Zoledronic Acid in Urine(mg)
`Arithmetic Means
`
`+/- 31.4%
`
`+/-21.7%
`
`+/- 46.1%
`
`0.700
`
`0.600
`
`0.500
`
`0.400
`
`0.300
`
`0.200
`
`0.100
`
`0.000
`
`MER-101A 10mg n = 12
`
`MER-101B 20mg n = 12
`
`Zometa® 1mg IV n = 11
`
`DISCUSSION
`
`(cid:190) MER-101 20mg tablets gave 44% greater mean 48-hour urinary excretion of zoledronic acid versus
`MER-10110mg tablets, based on the analysis of the Ln transform data.
`(cid:190) Mean zoledronic acid excretion for MER-101 20mg tablets was similar to Zometa® 1mg Injection
`(0.514mg and 0.541mg respectively).
`
`CONCLUSION
`
`(cid:190) A tablet dosage form of zoledronic acid has been successfully developed to enable a
`once weekly treatment regimen.
`(cid:190) The dose administered via a 20mg tablet is equivalent to a 1mg intravenous infusion.
`(cid:190) The MER-101 tablets were well-tolerated and there were no serious adverse events
`associated with administration.
`(cid:190) MER-101 tablets are an improved alternative to bisphosphonate products currently
`marketed.
`(cid:190) They enable a weekly administration of zoledronic acid, which should yield improved
`therapy due to the ability to better target rapidly growing metastatic tissues.
`(cid:190) The key advantages include an altered site of absorption to proximal small intestine via
`enteric coating, to substantially reduce gastrointestinal side effects, improve tolerability,
`patient compliance, and eliminate the requirement to remain upright or standing with
`fasting after dosing.
`(cid:190) There is currently an unmet market need for an oral bisphosphonate in oncology.
`(cid:190) The advantages of oral tablets include:
`(cid:153)Improved quality of life for the patient.
`(cid:153)Flexibility in the dosing regimen.
`(cid:153)Improved compliance.
`
`Introduction
`The purpose of the study was to compare the absorption of two strengths of an investigational oral dosage
`form of MER-101, a tablet form of zoledronic acid, to the parenteral reference product, commercially-available
`zoledronic acid intravenous infusion, (Zometa® Injection, Novartis). MER-101 was developed by Merrion
`Pharmaceuticals using GIPET™ I technology to improve the oral bioavailability of zoledronic acid and thereby
`enable the development of an oral dosage form. GIPET™ I is based on proprietary penetration enhancers
`which improve the absorption of such drugs in the small intestine. There is no chemical modification to the
`active drug. The enhancer system is comprised of food-based material which is on the US GRAS list. These
`are important factors in reducing regulatory requirements and the time to market. GIPET™ technology is
`equally applicable to small molecules, macromolecules and biologics, and is broadly applicable over a wide
`range of marketed and emerging products.
`Zoledronic acid is a bisphosphonate used in the treatment of bone metastases. Bisphosphonates are
`synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. The current marketed
`dosage form of zoledronic acid is a given as an infusion to overcome the limitations of oral dosing of
`bisphosphonates, including low bioavailability, gastric irritation, and gastric reflux.
`Experimental Procedures
`The study was a single-dose, three-way crossover bioequivalence study in 13 postmenopausal female
`subjects with osteoporosis. There was a washout period of at least 7 days between dosing days. Cumulative
`urinary excretion of zoledronic acid over a 48-hour period was used as the basis for the pharmacokinetic
`analysis. Eleven subjects successfully completed all treatment periods of the study and were included in the
`final analysis.
`The treatments administered during the clinical trial were: MER-101 10mg and 20mg Enteric Coated Tablets
`and Zometa® Injection 1mg, administered as a 15-minute infusion in 100mL of normal saline. The treatments
`were well tolerated in all cases.
`Data Summary
`The MER-101 20mg tablet had a mean 48-hour urinary excretion of zoledronic acid approximately 44%
`greater than the MER-101 10mg tablet. The MER-101 20mg tablet had a mean zoledronic acid excretion that
`was similar to the Zometa® 1mg Injection (0.514mg and 0.541mg respectively).
`Conclusions
`A tablet dosage form of zoledronic acid has been successfully developed which will allow once weekly
`treatment of patients. The dose administered via a 20mg tablet equals that of a 1mg intravenous infusion.
`MER-101 was well tolerated and there were no serious adverse events associated with its administration.
`
`(cid:190) Single-dose, three-way crossover bioavailability.
`(cid:190) 7 day washout between each of the three periods.
`(cid:190) 12 postmenopausal women with osteoporosis (13 enrolled).
`(cid:190) Mean age 60.4 years, range 49 to 69.
`(cid:190) Mean height 63.9 inches.
`(cid:190) Mean weight 182.1 pounds.
`Treatments were administered:
`(cid:190) After an overnight fast.
`(cid:190) With a full glass of water.
`(cid:190) Patients remained fasted and upright for 4 hours post-dose.
`Treatment arms:
`(cid:190) MER-101A enteric coated tablet (10mg zoledronic acid).
`(cid:190) MER-101B enteric coated tablet (20mg zoledronic acid).
`(cid:190) Zometa® Injection 1mg 15 minute infusion in 100mL normal saline.
`Pharmacokinetic samples:
`(cid:190) Cumulative urinary excretion of zoledronic acid.
`(cid:190) Urine collections pre-dose and 0-12, 12-24, 24-36, and 36-48 hours post-dose.
`(cid:190) All urine output from each patient was collected and measured.
`(cid:190) Urine assay HPLC with tandem mass spectrometry (LOQ of zoledronic acid urinary assay 4.99ng/mL;
`assay range 4.99-4989.60ng/mL).
`
`BACKGROUND
`
`RESULTS
`
`Zoledronic acid is a bisphosphonate which is a potent inhibitor of osteoclastic bone resorption. It is sold in the
`US as a concentrated solution for intravenous infusion under the tradename Zometa® (Novartis). It is
`indicated for the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases of solid
`tumors.
`Zoledronic acid has a molecular weight of 290.1 with an empirical formula C5H10N2O7P2.H2O. The structural
`formula is:
`
`(cid:190) A total of 12 subjects completed all dosing arms of the study.
`(cid:190) All pharmacokinetic calculations were performed using SAS (PC version 6.12).
`(cid:190) Subject 1 inadvertently did not receive the dose in the IV infusion and was excluded from all statistical
`evaluations.
`
`Cumulative Zoledronic Acid (mg) excretion in 48 hours
`
`1
`
`4
`
`2
`3
`Zometa® 1mg injection
`10mg MER-101A
`20mg MER-101B
`
`5
`
`7
`6
`Patient number
`
`8
`
`9
`
`11
`
`12
`
`13
`
`TABLE 1
`
`Cumulative Urinary Excretion 0-48 Hours
`(mg)
`
`Test Item Dose Least Square Means
`
`Ln Transformed
`Means
`
`MER-101A 10mg
`
`MER-101B 20mg
`
`Zometa®
`
`1mg
`
`0.397
`
`0.583
`
`0.550
`
`0.358
`
`0.514
`
`0.541
`
`1.40
`
`1.20
`
`1.00
`
`0.80
`
`0.60
`
`0.40
`
`0.20
`
`0.00
`
`mg Zoledronic Acid excreted in 48 hours
`
`All bisphosphonates, including zoledronic acid, have poor oral bioavailability. Studies carried out by Merrion
`in beagle dogs indicate an oral bioavailability of approximately 3.5%.
`The current marketed dosage form of zoledronic acid is given as an intravenous infusion to overcome the
`issues with oral dosing of bisphosphonates, including:
`(cid:190)Low bioavailability.
`(cid:190)Gastric irritation.
`(cid:190)Gastric reflux.
`The gastric reflux induced by bisphosphonates can result in esophageal erosions. This effect is minimized by
`dosing requirements imposed on all marketed oral bisphosphonates that patients remain upright for 30 to 60
`minutes after dosing. This could prove to be a difficult task for the metastatic cancer population for whom
`Zometa® is indicated.
`MER-101 was developed by Merrion Pharmaceuticals using their GIPET™ technology to improve the oral
`bioavailability of zoledronic acid to enable the development of an oral dosage form. GIPET™ technology has
`demonstrated improved oral absorption of a number of compounds, and bisphosphonates in particular.
`
`GIPETGIPET™™
`
`(cid:190) Is based on GRAS-listed proprietary penetration enhancers.
`(cid:190) No chemical or physical alteration of the drug molecule is involved.
`(cid:190) Preclinical dog studies have demonstrated enhanced absorption of zoledronic acid of approximately 7-
`10%.
`(cid:190) Enteric coating eliminates esophageal reflux issues.
`The MER-101 development program is based on weekly administration of zoledronic acid, which should
`yield improved therapy due to the ability to better target rapidly growing metastatic tissues. The oral doses
`were chosen to result in comparable absorption to the standard parenteral dose of 4mg/month. Since the
`dosing target is a once-a-week, each tablet should deliver 1mg.
`
`