317
`ASCO Breast Cancer Symposium
`San Francisco, CA
`October 2009
`
`STUDIES OF BIOAVAILABILITY AND FOOD EFFECTS OF
`MER-101 ZOLEDRONIC ACID TABLETS IN POSTMENOPAUSAL WOMEN
`Thomas W. Leonard, RPh, PHD1, Catherine McHugh, MSC 2, Kieran Madigan, BSc2, Angela Walsh, MSc2, John S. Fox, PhD2
`1Merrion Pharmaceuticals LLC, Wilmington, NC, USA
`2Merrion Pharmaceuticals Ireland Ltd, Dublin, Ireland
`
`CLINICAL MER-101-01
`
`CLINICAL MER-101-02 Contd.
`
`MER-101-02 Zoledronic Acid Ln Least-Squares Means of Serum Levels (n=28)
`
`Test A (15mg tablet fasted)
`Test B (20mg tablet fasted)
`Test C (20mg tablet fed)
`Test D (20mg tablet bedtime)
`Ref. E (1mg IV)
`
`45
`
`23
`
`01
`
`-1
`
`-2
`
`-3
`
`-4
`
`LN Concentration
`
`0
`
`5
`
`10
`
`15
`
`20
`Hours
`
`25
`
`30
`
`35
`
`40
`
`Background
`MER-101 (Orazol) is an alternate administration route for zoledronic acid (ZA) IV infusion (Zometa). The weekly enteric-coated tablet
`delivers systemic ZA doses equivalent to monthly 4mg infusions. MER-101 uses GIPET to achieve oncological doses with excellent GI
`tolerability. The objectives of MER-101-01 and MER-101-02 were to examine the bioavailability and food effects on absorption of different
`strengths and regimens of MER-101 versus ZA 1mg IV infusion.
`Methods
`MER-101-01, a single weekly dose, open label, 3-way crossover study in 13 osteoporotic women examined 10mg and 20mg MER-101
`tablets versus a 1mg IV infusion. Absorption was determined via an LCMS urine assay of aliquots for 48 hours post-dose. Dosing was after
`an overnight fast, which continued 4-hours post-dose.
`MER-101-02, a single-dose, open label, 5-way crossover study in 30 postmenopausal women examined MER-101 15mg and 20mg tablets
`versus the IV infusion. Absorption was determined using LCMS assay of serum collected pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 5, 7, 10, 14,
`24, and 36 hours post-dose.
`Treatment arms:
`(A) MER-101 15mg, overnight fast, breakfast 30 minutes later.
`(B) MER-101 20mg, overnight fast, breakfast 30 minutes later.
`(C) MER-101 20mg, FDA standardized breakfast.
`(D) MER-101 20mg, bedtime, following a 4-hour fast.
`(E) ZA 1mg IV infusion.
`Safety assessments included AE monitoring, PE, hematology, urinalysis, and blood chemistry panels.
`Results
`Bioavailability of MER-101 20mg tablet was equal to a 1mg ZA infusion; the 10mg tablet was approximately half the 1mg ZA infusion.
`Administration of the 20mg tablet with food resulted in a large reduction in bioavailability.
`MER-101 absorption improved with the nighttime dosing regimen and with the morning dose/4-hour fasting regimen. Serum profiles indicate
`retention of enteric tablets in the stomach longer than 30 minutes. The resultant food interaction from the shorter fasting time likely resulted
`in reduced bioavailability.
`Conclusions
`The MER-10120mg tablet dosed weekly for 4 weeks provides a systemic dose equivalent to a 4mg ZA IV infusion.
`MER-101 potentially offers a substantial improvement over IV infusion in bisphosphonate therapy for women with breast cancer.
`
`BACKGROUND
`
`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, decreasing bone resorption by reducing
`osteoclastic activity. Studies have demonstrated that zoledronic acid reduces the incidence of skeletal-related
`events (SREs) in metastatic bone cancer. A reduction in levels of markers of bone metabolism, particularly urinary
`NTX, has been shown to be prognostic of a reduction in SREs.[1] MER-101 has been shown to reduce urinary NTX
`and serum CTX levels to an extent greater than or equal to the reduction achieved with Zometa IV infusion 4mg
`administered every 4 weeks.
`
`Zoledronic acid has a molecular weight of 290.1 with an empirical formula C5H10N2O7P2.H2O. The structural formula
`is:
`
`MER-101-01 Study
`(cid:137) Phase 1, single dose, randomized, open label, 3-way crossover study
`(cid:137) The study population was 13 postmenopausal women with osteoporosis
`Objective
`(cid:137) To compare absorption of 2 investigational oral dosage forms of zoledronic acid to the market product IV
`infusion
`Method
`(cid:137) Three treatment arms:
`A. MER-101 Tablet 10mg
`B. MER-101 Tablet 20mg
`C. Zometa IV Infusion 1mg
`(cid:137) Fasting 10.5 hours prior to dosing until 4 hours post-dose
`(cid:137) 7 Day interval between doses
`(cid:137) Bioavailability was determined from urinary excretion data collected over 48 hours and assayed using
`LC/MS/MS in urine
`Results
`(cid:137) Mean urinary excretion of zoledronic acid over 48 hours for the MER-101 Tablet 20mg is comparable to a
`1mg infusion of Zometa IV
`(cid:137) The 10mg tablet was approximately half the 1mg ZA infusion
`
`MER-101-01 Zoledronic Acid in Urine (mg) Arithmetic Means
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`MER-101-A 10mg
`N=12
`
`MER-101-B 20mg
`N=12
`
`Zometa 1mg IV
`N=11
`
`
`Test Item
`
`Ratio for Cumulative
`Excretion Values
`
`0.358
`
`MER-101-02 Untransformed Data:
`Comparison of AUC of Oral Treatment Groups with IV Infusion
`Ratio of
`Mean
`Ratio of
`Treatment Mean AUC0-t
`Test/Reference
`AUC0-∞*
`Test/Reference
`(%CV)
`90% CI
`(%CV)
`90% CI
`69.0
`0.607
`120.3
`0.975
`15mg Tablet
`(105.7)
`0.254 – 0.960
`(56.6)
`0.490 – 1.46
`Fasted
`85.6
`0.733
`120.9
`0.831
`20mg Tablet
`(90.2)
`0.375 – 1.09
`(57.9)
`0.358 – 1.30
`Fasted
`10.6
`0.108
`39.9
`0.154
`20mg Tablet
`(145.4)
`0.00 – 0.469
`(43.8)
`0.00 – 0.924
`Fed
`210.8
`1.85
`275.6
`2.30
`20mg Tablet
`(83.5)
`1.50 – 2.21
`(71.4)
`1.85 – 2.75
`Bedtime
`1mg IV
`116.2
`121.6
`Infusion
`(15.4)
`(15.4)
`Reference
`*AUC0-∞ excludes all subjects with substantial food effects, as kel could not be
`estimated for these subjects.
`
`
`n/a
`
`n/a
`
`MER-101-02 Geometric Means Transformed Data:
`Comparison of AUC of Oral Treatment Groups with IV Infusion
`Ratio of
`Ratio of
`Ln Means
`Ln Means
`Test/Reference
`Test/Reference
`AUC0-t
`AUC0-∞*
`90% CI
`90% CI
`0.427
`0.810
`0.240 – 0.759
`0.593 – 1.11
`0.319
`0.716
`0.183 – 0.559
`0.528 – 0.972
`0.0417
`0.228
`0.0227 – 0.0766
`0.139 – 0.375
`1.34
`1.75
`0.785 – 2.27
`1.30 – 2.34
`
`Treatment
`
`52.1
`
`39.0
`
`5.1
`
`163.2
`
`122.2
`
`n/a
`
`120.6
`
`n/a
`
`15mg Tablet
`Fasted
`20mg Tablet
`Fasted
`20mg Tablet
`Fed
`20mg Tablet
`Bedtime
`1mg IV
`Infusion
`Reference
`*AUC0-∞ excludes all subjects with substantial food effects, as kel could not be
`estimated for these subjects.
`
`
`97.7
`
`86.3
`
`27.5
`
`210.4
`
`(cid:137) The statistical analysis for the Least Squares Means dataset indicates that the 20mg tablet has a greater bioavailability
`than the 15mg tablet. The Ln transformed analysis indicates the opposite
`(cid:137) This is facilitated in part by the food effect given by the meal 30 minutes post dosing, and is demonstrated in the following
`table:
`
`Protocol /
`Treatment
`
`Food Effect: # of Subjects with No Absorption
`Pre-Dose Fast /
`# of Subjects
`Post-Dose Fast
`
`# with no
`absorption /
`# with poor
`absorption*
`
`
`
`MER-101-01
`0 / 0
`12
`10.5h / 4h
`10mg Fasted
`0 / 0
`12
`10.5h / 4h
`20mg Fasted
`MER-101-02
`
`
`
`7 / 11
`28
`10.5h / 0.5h
`15mg Fasted
`3 / 7
`27
`10.5h / 0.5h
`20mg Fasted
`7 / 21
`26
`0h / 4h
`20mg Fed
`*Absorption was very poor, and insufficient data are available to calculate the kel.
`
`
`(cid:137) With an enteric coated tablet, time of absorption is dictated by the pH environment of the tablet, therefore, there is some
`diversity in the time of the peak serum level based on GI transit
`(cid:137) A plot of AUC versus Tmax indicates that a decrease in bioavailability is seen proportional to the Tmax when food is
`consumed with or shortly after the dose. Therefore, with longer tablet GI transit times, more food contact occurs during
`absorption, and the bioavailability is lower
`
`MER-101-02: 15mg and 20mg Tablets Morning Dosing (Trts A, B, & C) AUC 0-t vs. Tmax
`Subjects with AUC = 0 Excluded
`
`AUC = (-15.566 x Tmax) + 99.402
`R2 = 0.1739
`
`200
`
`175
`
`150
`
`125
`
`100
`
`75
`
`50
`
`25
`
`Area Under the Curve 0-t
`
`0
`
`0
`
`0.5
`
`1
`
`1.5
`
`2
`
`2.5
`
`3
`
`4
`3.5
`Time of Peak (hours)
`
`4.5
`
`5
`
`5.5
`
`6
`
`6.5
`
`7
`
`7.5
`
`Subjects with Tmax <2h Transformed Data:
`Comparison of AUC of Oral Treatment Groups with IV Infusion
`Ratio
`Treatment
`AUC-MFE0-∞ *
`90% CI
`0.769
`0.556 – 1.07
`0.848
`105.2
`20mg Tablet Fasted
`0.595 – 1.21
`*MFE – Minimal Food Effect: subjects with Tmax less than 2 hours.
`
`
`15mg Tablet Fasted
`
`92.6
`
`All bisphosphonates, including zoledronic acid, have poor oral bioavailability. This has limited their use in
`oncological therapies to intravenous infusion to achieve the doses required for efficacy. The local gastric irritation
`that occurs with existing oral bisphosphonates is also an important consideration in oncological indications, as it can
`result in esophageal erosions and ulceration.
`
`MER-101 (Orazol)
`(cid:137) Enhances bioavailability substantially to enable an effective oral oncological dose
`(cid:137) A tablet weekly instead of a regimen of IV infusions every 3 or 4 weeks
`(cid:137) Provides an improvement in administration profile:
`Lower systemic dose taken more frequently
`(cid:131)
`o Less potential for renal damage due to the lower Cmax
`o Ability to titrate frequency and dose
`o More frequent exposure of metastatic cells to plasma levels of drug
`Enteric coating eliminates potential for stomach and esophageal complications associated with other
`bisphosphonates
`Enhanced absorption decreases overall GI drug load
`
`(cid:131)
`
`(cid:131)
`
`Gastrointestinal Permeation Enhancement Technology (GIPET I)
`(cid:137) Oral platform technology for poorly absorbed compounds based on salts of medium chain fatty acids
`(cid:137) Physical mixture of enhancer system and drug in a tablet form
`(cid:137) Facilitates safe absorption - very little effect on the GIT, primary mechanism of mixed micelles to improve
`transcellular absorption
`(cid:137) Classified as food substance:
`(cid:131) Reviewed by EU Scientific Committee for Food and determined ‘safe in use’, and the FAO/WHO Joint
`Expert Committee of Food Additives, with no limit on intake
`Listed in the US CFR as a direct food additive with no limit on intake
`(cid:131)
`(cid:137) Successfully applied to poorly absorbed compounds across several physical/chemical categories
`
`Cumulative Urinary Excretion 0-48 Hours (mg)
`Least-Squares Means
`Dose
`Ln Transformed Means
`(%CV)
`0.398
`(46.1)
`0.583
`(53.9)
`0.557
`(21.7)
`
`10mg
`
`20mg
`
`1mg
`
`Least-Squares Means
`Ratio
`90% CI
`0.723
`0.423 – 1.023
`1.060
`0.760 – 1.360
`
`Ln Transformed Ratio
`90% CI
`0.661
`0.479 – 0.913
`0.949
`0.687 – 1.310
`
`MER-101A / Zometa
`
`MER-101B / Zometa
`
`
`
`0.514
`
`0.541
`
`MER-101A
`
`MER-101B
`
`Zometa
`
`
`
`CLINICAL MER-101-02
`
`MER-101-02 Study
`(cid:137) Single dose, randomized, 5-way crossover study, fasted and fed conditions
`(cid:137) The study enrolled 30 postmenopausal women
`28 subjects had evaluable data
`(cid:131)
`23 subjects completed all treatment arms
`(cid:131)
`Objective
`(cid:137) To determine the effect of food on absorption of zoledronic acid
`(cid:137) To evaluate a nighttime dosing regimen
`Method
`Five treatment arms:
`A. MER-101 Tablets 15mg orally after an overnight fast, FDA standardized breakfast 30 minutes post-
`dosing
`B. MER-101 Tablets 20mg orally after an overnight fast, FDA standardized breakfast 30 minutes post-
`dosing
`C. MER-101 Tablets 20mg orally immediately following FDA standardized breakfast
`D. MER-101 Tablets 20mg orally at bedtime after a 4-hour fast following supper. Breakfast 10.5 hours
`post dosing
`E. Zometa IV infused intravenously (1mg in 100mL sterile 0.9% Sodium Chloride, USP) over 15 minutes
`after an overnight fast, FDA standardized breakfast 30 minutes post-dosing
`(cid:137) 7 Day washout interval between treatment arms
`(cid:137) Bioavailability was assessed by the appearance of unchanged drug in serum collected at intervals over a
`36-hour period after administration of drug
`Results
`(cid:137) The study demonstrated a substantial food effect that precludes co-administration with food
`(cid:137) Post-dose fasting time impacts bioavailability. A half-hour fast is not sufficient in all patients
`(cid:137) The study data from subjects who did not exhibit a food effect with the morning fasted dose confirmed that
`the zoledronic acid serum AUC from the MER-101 (Orazol) Tablet 20mg is the same as the AUC from the
`1mg zoledronic acid infusion
`(cid:137) The oral tablet is very well tolerated (4 treatment arms were oral)
`
`OVERALL CONCLUSIONS
`(cid:137) Bioavailability of the MER-101 20mg tablet is equal to a 1mg zoledronic acid infusion
`(cid:137) Administration of the 20mg tablet with food results in a large reduction in bioavailability
`(cid:137) MER-101 absorption improves with the nighttime dosing regimen
`(cid:137) Serum profiles indicate retention of enteric tablets in the stomach longer than 30 minutes in some
`subjects in MER-101-02. The resultant food interaction from the shorter fasting time results in
`reduced bioavailability
`(cid:137) The MER-101 20mg tablet dosed weekly for 4 weeks provides a systemic dose equivalent to a
`4mg ZA IV infusion
`(cid:137) MER-101 potentially offers a substantial improvement over IV infusion in bisphosphonate therapy
`for oncology patients with bone metastases
`
`[1] Robert E. Coleman et al. Predictive Value of Bone Resorption and Formation Markers in Cancer
`Patients with Bone Metastases Receiving the Bisphosphonate Zoledronic Acid. J Clin Oncol
`23:4925-4935 © 2005 ASCO.
`
`Grun. Exh. 1040
`PGR for U.S. Patent No. 9,539,268
`
`