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`WILDINGBIOEQUIVALENCE TESTING FOR GASTROINTESTINAL PRODUCTSDRUG DEVELOPMENT
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`DRUG DEVELOPMENT
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`Bioequivalence Testing for Locally
`Acting Gastrointestinal Products:
`What Role for Gamma Scintigraphy?
`
`Ian Wilding, PhD
`
`Bioequivalence testing for locally acting gastrointestinal
`products is a challenging issue for both the pharmaceutical
`industry and the global regulatory authorities. It is widely ac-
`cepted that for medicinal products not intended to be deliv-
`ered into the systemic circulation, pharmacokinetic
`bioavailability cannot be used. However, it is becoming in-
`creasingly accepted that local availability may be assessed,
`where appropriate, by approaches that qualitatively reflect
`
`the presence of the active substance at the site of action.
`These methods must be specifically chosen for that combina-
`tion of active substance and route of drug delivery. This paper
`argues for the use of gamma scintigraphy as a validated mea-
`sure of local availability and bioequivalence for topically act-
`ing products administered to the gastrointestinal tract by the
`oral and rectal route.
`Journal of Clinical Pharmacology, 2002;42:1200-1210
`©2002 the American College of Clinical Pharmacology
`
`Ulcerative colitis is an inflammatory disease of the
`
`colonic mucosa with unknown etiology, which in
`almost all cases affects the rectum and often extends to
`more proximal regions of the colon. Crohn’s disease is a
`transmural inflammatory disease, which can affect the
`small bowel only (29%), the colon only (30%), or both
`the small bowel and colon simultaneously (33%). In
`8% of individuals, the disease is located in the upper
`intestine or perianal area.1 Collectively, these condi-
`tions are often referred to under the broader name of in-
`flammatory bowel disease (IBD).
`The use of oral anti-inflammatory agents is one of
`the main treatment approaches for IBD, and the princi-
`ple therapeutic moiety is mesalazine.2 While the drug
`is rapidly and completely absorbed from the upper in-
`testine, when administered as an immediate-release
`tablet, it is poorly absorbed from the colon.3 The precise
`mechanism of action of mesalazine is not known,
`partly because of the failure to understand the
`etiopathogenesis of IBD.4 However, it is generally
`agreed that its main effect is exerted topically at the in-
`
`From Pharmaceutical Profiles, Ltd., Nottingham, United Kingdom.
`Submitted for publication October 12, 2000; revised version ac-
`cepted July 22, 2002. Address for reprints: Pharmaceutical Profiles,
`Ltd., Mere Way, Ruddington Fields, Ruddington, Nottingham, United
`Kingdom, NG11 6JS.
`DOI: 10.1177/0091270002238762
`
`1200 • J Clin Pharmacol 2002;42:1200-1210
`
`flammatory lesions.5 As a consequence, high intra-
`luminal drug concentrations are required at the site of
`inflammation, and therefore the mesalazine products
`on the market are either prolonged-release (e.g.,
`Pentasa®) or targeted-release (e.g., Asacol®, Claversal®)
`formulations.
`This review article will concentrate on mesalazine,
`given its extensive use in the treatment of IBD and be-
`cause a wide variety of formulation types exist, includ-
`ing enteric-coated products, prolonged-release pellets,
`enemas, and suppositories. However, comparable ar-
`guments can be readily established for other locally
`acting gastrointestinal (GI) products (e.g., steroids). The
`issue of bioequivalence testing for these locally acting
`oral products is a complex issue for the regulatory
`authorities.
`The textbook definition of bioequivalence for two
`oral products, designed for systemic drug delivery, is
`that they have identical rate and extent of absorption.
`These assessments are predominantly based on the
`area under the curve (AUC) of the plasma profile (con-
`centration plotted vs. time) and maximum plasma con-
`centration (Cmax). The acceptance of bioequivalence
`of two products requires that the 90% confidence in-
`terval for the ratio of test to reference product lies
`within a predetermined bioequivalence interval; for
`AUC, the generally accepted interval is 0.8 to 1.25 for
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`BIOEQUIVALENCE TESTING FOR GASTROINTESTINAL PRODUCTS
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`log-transformed data. A wider interval may be appro-
`priate for Cmax because of its inherently greater vari-
`ability. Once bioequivalence of the two products is es-
`tablished, then it is assumed that they will be
`therapeutically equivalent.
`The European regulatory authorities in the form of
`the Committee of Proprietary Medical Products
`(CPMP) has stated that for “locally acting products
`[pharmacokinetic] bioequivalence generally is not a
`suitable way to show therapeutic equivalence, since
`plasma levels are not relevant for local efficacy, al-
`though they may play a role with regard to safety.”6
`Therefore, while measurement of drug plasma levels
`could prove useful from a safety perspective, it pro-
`vides little or no information on the in vivo fate of the
`therapeutic moiety at its target site. An alternative as-
`sessment method is therefore required, and the CPMP
`guidance states that “human pharmacodynamic stud-
`ies, local availability studies or where appropriate even
`animal or in vitro studies can be considered, provided
`that all studies used are adequately validated.”6
`In the draft CPMP guidance on bioavailability and
`bioequivalence, published in December 1998, it was
`clarified that “for medicinal products not intended to
`be delivered into the general circulation, the common
`systemic bioavailability approach cannot be applied.”7
`However, the guidance explicitly states that “the (lo-
`cal) availability may be assessed, where necessary, by
`measurements qualitatively reflecting the presence of
`the active substance at the site of action using methods
`specifically chosen for that combination of active sub-
`stance and localisation.”
`The objective of this review article is to discuss the
`use of gamma scintigraphy as a validated measure of lo-
`cal availability and bioequivalence for topically acting
`products administered to the GI tract by the oral and
`rectal route.
`
`GAMMA SCINTIGRAPHY
`AND ITS APPLICATION TO
`BIOAVAILABILITY ASSESSMENT
`
`Gamma scintigraphy was originally developed as a nu-
`clear medicine technique, using gamma ray–emitting
`radionuclides that localize in the specific organs of the
`body and are visualized by a gamma camera coupled to
`a sophisticated data-processing system, providing in-
`formation on the structure and function of various
`body systems. However, drug formulations can also be
`radiolabeled, and therefore gamma scintigraphy has
`been widely applied to assess the delivery of drugs
`given by a variety of routes.8
`
`With the advent of novel oral drug delivery systems,
`the requirement to understand exactly what the formu-
`lation is doing within the GI tract has increased dramat-
`ically. The interaction between drug, dosage form, and
`gut physiology plays a crucial role in determining the
`potential of any product, and scintigraphy allows this
`dynamic process to be visualized in a noninvasive
`manner.
`To follow the fate of a pharmaceutical dosage form, it
`is not usually possible to radiolabel the drug molecule.
`This is because, in general, drug molecules are com-
`pounds of carbon, hydrogen, oxygen, and nitrogen, and
`none of these elements has isotopes suitable for gamma
`camera studies. Instead of labeling the drug molecule, a
`radiolabel is usually incorporated into the dosage form
`and is used to define the in vivo performance of the sys-
`tem. Radiolabeling can be achieved either by the direct
`incorporation of a radiolabeled compound into the
`preparation or by neutron activation of a dosage form
`that contains a nonradioactive tracer. The latter method
`avoids the need to handle radioactive materials during
`lengthy or complex formulation procedures and per-
`mits dosage form manufacture to be conducted under
`normal production conditions. The quantity of mate-
`rial needed to be incorporated into a formulation to
`render it suitable for use in a gamma scintigraphic
`study is very small and does not compromise the per-
`formance characteristics of the delivery system.
`Gamma scintigraphy has been described as an “ele-
`gant technique for phase I investigation of the locality
`of in vivo release”9 and has “become the method of
`choice for investigating the fate of pharmaceutical dos-
`age [forms] in the body.”10 The ability to visualize the
`drug delivery process in a noninvasive manner acts to
`fill a significant void in current understanding. Alter-
`native methods of assessing drug delivery, such as
`pharmacokinetic evaluation for locally acting oral
`products, could be described essentially as “blunt”
`measures, lacking a clear outcome.11 While other ap-
`proaches for assessing local drug bioavailability have
`been proposed (e.g., intestinal perfusion12), these have
`the disadvantage of being highly invasive, thereby po-
`tentially altering the absorption/secretion balance in
`the distal bowel. Gamma scintigraphy is, however, a
`more incisive noninvasive approach, allowing much
`greater information to be imparted on the in vivo per-
`formance of locally acting products without changing
`intestinal characteristics.
`Gamma scintigraphy is widely accepted by the sci-
`entific community as a validated measure of product
`behavior in the intestine. For products containing drug
`designed for local therapy, where systemic levels are a
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`poor predictor of product performance, gamma
`scintigraphy can provide a surrogate measure of local
`bioavailability. Examples will be provided of the vali-
`dation of the scintigraphic approach using mesalazine
`as an example for a range of pharmaceutical products
`intended for topical therapy in the bowel.
`
`VALIDATION OF GAMMA
`SCINTIGRAPHY FOR BIOEQUIVALENCE
`TESTING OF LOCALLY ACTING
`GASTROINTESTINAL PRODUCTS
`
`Example A: Enteric-Coated
`Mesalazine Products
`
`Delayed-release enteric-coated preparations have been
`developed to prevent release of mesalazine until the
`formulation has reached the terminal ileum and colon.
`These include several commercially available
`mesalazine delayed-release systems (e.g., Asacol® and
`Claversal®).13 Both preparations use copolymers of
`methacrylic acid and methyl methacrylate, available
`commercially as the Eudragit® range of polymers, to de-
`liver drug to the colon.
`Claversal® (available in some countries as Mesasal®)
`has been commercially available in Germany for many
`years.14 The tablets contain 250 mg of mesalazine and
`are coated with the enteric-coating polymer,
`methacrylic acid copolymer, type A (Eudragit L). This
`pH-sensitive polymer is resistant to gastric conditions
`but soluble above pH 6.0 in the intestine. A relatively
`thick polymer coating is applied to the tablets to delay
`drug release until the product reaches the terminal il-
`eum and proximal colon.
`Studies have been undertaken to investigate the GI
`transit of the enteric-coated tablets in patients with
`colitic disease to determine the site of mesalazine re-
`lease by gamma scintigraphy.15
`Blood samples were also taken during the studies to
`enable any of the drug absorbed to be related to the
`scintigraphic information and to examine the extent of
`mesalazine absorption. Thirteen patients with quies-
`cent IBD—7 with Crohn’s disease and 6 with ulcerative
`colitis—were studied. The 111In radiolabel was incor-
`porated into the mesalazine granules before compres-
`sion into tablets and subsequent coating with the poly-
`mer. Frequent scintigraphic images and blood samples
`were acquired for each subject.
`Tablet location and the point of tablet dispersion
`were readily determined (Figure 1). The median time
`for gastric emptying of the tablets was 2.9 hours, rang-
`
`1202 • J Clin Pharmacol 2002;42:1200-1210
`
`Table I Transit and Disintegration Times
`of the Claversal® Tablets in Patients with
`Inflammatory Bowel Disease (Example A)
`
`Gastric
`Emptying (h)
`
`Colonic
`Arrival (h)
`
`Disintegration Time
`(h after leaving
`stomach)
`
`Median
`
`2.9
`
`6.8
`
`3.2
`
`ing from 0.8 hours to more than 11 hours (Table I). None
`of the tablets disintegrated in the stomach. On average,
`the tablets disintegrated 3.2 hours after leaving the
`stomach, resulting in drug dispersion in the distal
`small intestine or proximal colon, except in 1 of the
`surgically treated patients with a right hemicolectomy,
`in whom dispersed preparation was first detected in
`the transverse colon.
`There was a close correlation between the detection
`of tablet disintegration and the onset of drug absorp-
`tion (r = 0.988, p < 0.001) (Figure 2). The patients’ indi-
`vidual plasma mesalazine and principal metabolite
`Ac-5-ASA concentrations correlated with the
`scintigraphic data throughout the 24 hours. The
`plasma concentrations of Patient 7, for example, are
`shown in Figure 1, with the corresponding
`scintigraphic images. The observation of tablet disinte-
`gration at 5.0 hours after dosing corresponds well with
`the first detection of the drug and its metabolite in
`plasma. Plasma mesalazine concentrations then in-
`creased to a maximum of 0.54 µg/ml at 6.0 hours. The
`scintigraphic images show that the dispersed
`radiotracer then moved mainly from the small intestine
`into the cecum and ascending colon by 7.0 hours, and
`this coincided with a rapid fall in plasma mesalazine
`levels. Drug absorption was relatively low in all pa-
`tients once the preparation had entered the colon.
`In conclusion, gamma scintigraphy has been dem-
`onstrated to be a very effective and validated approach
`for visualizing the location of in vivo drug release from
`enteric-coated mesalazine products.
`
`Example B: Oral Modified-Release
`(MR) Mesalazine Products
`
`While enteric-coated targeted-release preparations
`have been shown to release mesalazine in the terminal
`ileum/cecum, the product known as Pentasa® has been
`designed as a preparation consisting of a large number
`of MR ethylcellulose-coated mesalazine microgranules
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`BIOEQUIVALENCE TESTING FOR GASTROINTESTINAL PRODUCTS
`
`Figure 1. Gastrointestinal transit
`tablet in a patient
`of the Claversal
`with ulcerative colitis (Patient 7),
`showing tablet dispersion in the ter-
`minal ileum and plasma mesalazine
`) and Ac-5-ASA levels
`levels (
`) (concentrations in µg/ml) (Ex-
`(
`ample A).
`
`intended for delivery of the drug throughout the GI
`tract.16
`A combined scintigraphic and pharmacokinetic
`(pharmacoscintigraphic) study in healthy volunteers
`has evaluated the location of mesalazine release from
`Pentasa® tablets in the GI tract under fasted and fed
`
`conditions.17 Disintegration of the tablet preparation
`occurred in the stomach within 20 minutes, and
`Ac-5-ASA was detectable in the plasma less than 60
`minutes after ingestion. The microgranules were in the
`colon by 8 hours after dosing, and in all subjects, the
`preparation became dispersed fully in the large bowel.
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`However, higher dosages of mesalazine are now be-
`ing used to treat IBD since clinical trials have demon-
`strated greater efficacy at higher dosages in both ulcer-
`ative colitis (2-4 g/day) and Crohn’s disease (2-4
`g/day).19,20
`The 250 mg Pentasa® preparation has been available
`since 1986 and the 500 mg tablet since 1990 in many
`European countries. As a consequence of the increase
`in the recommended daily dose of mesalazine (up to 4
`g), a sachet formulation, designed to release drug in the
`same manner as the Pentasa® tablets, has been devel-
`oped to improve patient compliance.21 The sachet for-
`mulation consists of an aluminum foil wrapping in
`which the microparticles are loosely contained. The
`contents of the sachet are emptied into a glass of water
`prior to dosing.
`A scintigraphic study in healthy volunteers was un-
`dertaken to evaluate the disposition, dispersion, and
`movement of the Pentasa® microgranules in the GI tract
`following dosing either as tablets (2 × 500 mg) or 1 g sa-
`chet (unit-dose) with a view to demonstrating
`bioequivalence for the new sachet product versus the
`marketed tablet preparation.22 All formulations were
`radiolabeled by the use of neutron activation and in-
`volved 153Sm labeled preparation.
`Pentasa® preparations were radiolabeled via neu-
`tron activation. Dissolution testing at pH 7.5 showed
`comparable in vitro release properties for the tablet and
`sachet preparations; t1/2 for the tablets and sachet was
`100 and 110 minutes, respectively. Eight healthy vol-
`unteers provided written informed consent to partici-
`pate in the two-way randomized, crossover, single-
`dose study. Subjects were randomized to (1) two
`Pentasa® 500 mg tablets, each labeled with 0.5 MBq of
`153Sm, or (2) one Pentasa® 1 g sachet of microgranules
`labeled with 1 MBq of 153Sm. Scintigraphic images
`were acquired at frequent intervals for up to 12 hours
`using a gamma camera.
`The individual transit profiles have been charac-
`terized by the half-life (t1/2), and the relevant parame-
`
`Figure 2. Relationship between tablet dispersion and drug absorp-
`tion (r = 0.988, p <0.001) (Example A).
`
`The pharmacoscintigraphic study confirmed that
`mesalazine release from Pentasa® occurred throughout
`the GI tract.
`A further scintigraphic study was undertaken on the
`Pentasa® 250 mg tablets to evaluate mesalazine release
`sites in patients with Crohn’s disease. This revealed
`very similar findings to the investigation in healthy
`volunteers.18 Disintegration of the tablets was found to
`occur in the stomach, and the temporal association be-
`tween location of the microgranules and mesalazine
`plasma levels was comparable in the patient popula-
`tion to those reported previously in normal subjects.
`
`Table II Gastrointestinal Transit (t1/2) (min) for Pentasa® Microgranules
`Dosed in Either Tablet (2 × 500 mg) or Sachet (1 g) Form (Example B)
`
`Gastric Emptying
`
`Tablets
`
`Sachet
`
`Small Intestinal Transit
`
`Tablets
`
`Sachet
`
`Mean
`Standard deviation
`Median
`Number
`
`17
`5
`19
`8
`
`22
`10
`20
`8
`
`213
`45
`230
`8
`
`185
`83
`195
`8
`
`Colon Arrival
`
`Tablets
`
`Sachet
`
`230
`49
`247
`8
`
`206
`86
`227
`8
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`BIOEQUIVALENCE TESTING FOR GASTROINTESTINAL PRODUCTS
`
`Figure 3. Mean gastric emptying and colon arrival profiles for microgranules dosed as tablet or sachet (Example B).
`
`ters for gastric emptying, small bowel transit, and co-
`lon arrival are provided in Table II. Mean gastric
`emptying and colon arrival profiles are provided in
`Figure 3.
`This in vivo trial showed that the disposition of the
`Pentasa® microgranules, administered either as tablets
`(2 × 500 mg) or a 1 gsachet (single unit), were compara -
`ble. There were no differences in transit parameters
`throughout the GI tract; gastric emptying, small intesti-
`nal transit, and colon arrival were similar for both for-
`mulations. Pentasa® 1 g sachet microgranules therefore
`have comparable in vitro dissolution and in vivo tran-
`sit characteristics to the currently marketed Pentasa®
`tablet when given in equal doses; therapeutic equiva-
`lence is therefore a logical corollary of this observation,
`and this indeed has been established in a subsequent
`clinical trial in active ulcerative colitis patients.23
`
`Example C: Rectal
`Mesalazine Products
`
`Rectal treatment with enemas, foams, and supposito-
`ries is the most efficient method of delivering an ade-
`
`quate quantity of locally active anti-inflammatory drug
`to the distal colon for the treatment of ulcerative colitis.
`Several drug formulations available for this purpose
`contain mesalazine. Rectal administration is also bene-
`ficial because a large amount of drug can be delivered
`to the target site with low systemic absorption and
`therefore a low incidence of side effects. Enemas and
`suppositories have thus become widely accepted in the
`treatment of patients with distal ulcerative colitis and
`proctitis, respectively.24,25
`The spread of rectally administered formulations
`within the distal colon is dependent on both the type
`and volume of preparation administered. This can be
`readily assessed by gamma scintigraphy.26
`Previous scintigraphic studies have shown that the
`spread of both suspension enemas and rectal foams is
`more extensive than that observed for suppository formu-
`lations.27,28 The spread of suppositories has been shown
`to be largely confined to the rectum, while suspension en-
`emas and rectal foams, depending on volume, spread as
`far as the transverse colon in colitic patients.28,29
`Smaller volume suspension enemas and rectal
`foams are targeted to reach the rectum and sigmoid co-
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`lon, whereas larger volume preparations are targeted to
`more proximal areas of the colon.30
`Previous rectal scintigraphic studies have shown
`comparable colonic spread data for rectal foam prod-
`ucts between healthy volunteers and patients with qui-
`escent ulcerative colitis.29 A scintigraphic study has
`been recently undertaken to compare the colonic
`spread of a 100 ml enema (1 g mesalazine), a rectal foam
`(1 g mesalazine in 5 ml concentrate expanding to ≈ 40
`ml on actuation), and a suppository (1 g mesalazine) in a
`group of 8 healthy male volunteers.31 The preparations
`had been developed to target drug delivery to the distal
`colon, sigmoid colon, and rectum, respectively, for the
`treatment of colitic disease. The two enema formula-
`tions were radiolabeled with 99mTc and the suppository
`by neutron activation of 152Sm to produce 153Sm.
`Following administration, all subjects remained ly-
`ing on their left side for 2 hours to aid retention of the
`formulation and then remained sitting between imag-
`ing for the remainder of the study. Dispersion of each
`formulation was monitored at frequent intervals over a
`4-hour period using a gamma camera.
`The data were analyzed to determine the percentage
`of enema and foam present in the rectum, sigmoid co-
`lon, descending colon, and transverse colon. The
`spread of the suppository formulations was confined to
`
`the rectum, and so analysis focused on the extent of the
`local tracer spread.26
`Following dosing with 100 ml solution enemas, dis-
`persion was highly variable, ranging from total reten-
`tion in the rectum and sigmoid colon to complete cov-
`erage of the whole of the large bowel. Only
`occasionally, however, do such preparations spread
`into the ascending colon. The results for the spread of
`the suspension enema (Figure 4) were very similar to
`other published data.30
`Foams offer greater convenience to the patient and
`have been shown to spread more uniformly than sus-
`pension enemas.29 As with solutions, the extent of
`spread of rectal foams is considered to be dependent on
`the quantity administered. The variable dispersion
`profile of the foam compared to the suspension enema
`is a consequence of the comparatively low expanded
`volume for the product (Table III). In some subjects, this
`provides for delivery of drug to the descending colon,
`while in others, material is retained in the sigmoid co-
`lon. However, rectal foams, for use in the treatment of
`proctosigmoiditis, only require dispersion as far as the
`sigmoid colon; therefore, despite the variable spread of
`the foam, the data from the study strongly support the
`use of foam products in this clinical indication. Overall
`spread was comparable to other low-volume foams.
`
`Figure 4. Mean dispersion profile for 100 ml suspension enema in a group of 8 healthy volunteers (Example C).
`
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`Table III Maximal Extent of Spread of a 100 ml Enema and Foam for Each Volunteer (Example C)
`
`% of Dose
`
`Time (h)
`
`Anatomical Location
`
`% of Dose
`
`Time (h)
`
`Anatomical Location
`
`Enema Spread
`
`Foam Spread
`
`9
`25
`70
`27
`5
`32
`22
`2
`
`2.48
`3.57
`4.00
`4.00
`1.03
`3.50
`0.77
`3.00
`
`Transverse colon
`Descending colon
`Sigmoid colon
`Descending colon
`Transverse colon
`Descending colon
`Transverse colon
`Transverse colon
`
`33
`66
`7
`15
`40
`100
`52
`100
`
`2.50
`3.87
`4.03
`3.52
`3.00
`0.02
`3.98
`0.02
`
`Sigmoid colon
`Descending colon
`Descending colon
`Descending colon
`Descending colon
`Rectum and sigmoid colon
`Sigmoid colon
`Rectum and sigmoid colon
`
`Figure 5. Mean dispersion profile for the suppository formulation in a group of 8 healthy volunteers (Example C).
`
`The spread behavior of 111In-labeled suppositories
`has been examined using gamma scintigraphy on pre-
`vious occasions;32 the spread of the mesalazine suppos-
`itory formulation was comparable with findings ob-
`served previously (Figure 5). For the suppository
`formulation, spread was localized in the rectum in all
`
`subjects for the entire duration of the imaging period (4
`hours).
`In conclusion, gamma scintigraphy can be clearly
`used to visualize the spread/retention of rectal prod-
`ucts and therefore the bioavailability of locally acting
`drugs following rectal dosing.
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`POSSIBLE DATA PACKAGES FOR
`MEASURING BIOEQUIVALENCE
`FOR LOCALLY ACTING
`GASTROINTESTINAL PRODUCTS
`USING GAMMA SCINTIGRAPHY
`
`To establish the in vivo performance of gastrointestinal
`products and thereby local bioequivalence, appropri-
`ate radiolabeling procedures need to be selected. A
`range of approaches has been developed, adopted, and
`validated for locally acting GI products, and these are
`outlined in Table IV. All the techniques have been sub-
`jected to wide scrutiny by the scientific community in
`peer-reviewed journals.
`The choice of a specific study design and data pack-
`age for demonstrating bioequivalence for locally acting
`oral products is a subject for discussion between an in-
`dividual sponsor and the relevant regulatory authority.
`In addition, the data package is clearly influenced by
`the nature of the formulations being compared. How-
`ever, some outline concepts are provided below.
`
`Enteric-Coated Tablets
`
`An extensive in vitro program of dissolution studies at
`multiple pH values (e.g., pH 1.2, 5, 5.5, 6, 6.5, 7, 7.5)
`would need to be undertaken comparing test and refer-
`ence preparations.
`Such investigations should give confidence that the
`two products will have comparable in vivo delivery
`characteristics. However, it is well recognized that the
`environment within the gastrointestinal tract is highly
`
`variable and heterogeneous,33 which precludes an in
`vitro–only basis for bioequivalence.
`To demonstrate that two products have “essentially
`similar” local bioavailability, a pharmacoscintigraphic
`study in 24 healthy volunteers is recommended com-
`paring test and reference products.
`This involves the simultaneous assessment of tran-
`sit and disintegration via scintigraphy and systemic
`drug exposure using a conventional pharmacokinetic
`evaluation. The combined approach has the advantage
`of establishing both safety and efficacy parameters. It is
`well known that if enteric-coated tablets disintegrate in
`the mid to distal small bowel, mesalazine is rapidly ab-
`sorbed, leading to pronounced Cmax values that have
`potential safety implications.5 In addition, while it is
`accepted that pharmacokinetic data alone cannot be
`used for equivalence testing for enteric-coated locally
`acting products, comparable AUC and Cmax values for
`the two products would be beneficial supportive data.
`The pivotal data will be the anatomical site of initial
`and complete tablet disintegration in the gastrointesti-
`nal tract as assessed by scintigraphy. Therefore, the
`true test of equivalence will be essential similarity in
`the locality of the in vivo drug delivery for the two
`products. This can be readily illustrated graphically
`(Figure 6). Confidence intervals can be subsequently
`calculated and traditional bioequivalence arguments
`developed.
`Therefore, in summary, if two enteric-coated tablets
`have comparable in vitro release at various pH levels
`and essentially similar locality of in vivo release with
`comparable systemic drug exposure, then it should be
`
`Table IV Radiolabeling Strategies for Locally Acting Gastrointestinal Products
`
`Enteric-coated tablets
`
`Oral modified-release
`pellets
`
`Rectal solution
`or suspensions
`
`Test Product
`
`Reference Product
`Drill-and-fill approacha (drill microhole 5 × 1.2 mm
`Neutron activation (152Sm to 153Sm)
`Hot manufacture (111In)
`to facilitate labeling with 111In resin or 153Sm, then
`Drill-and-fill approach (111In or 153Sm)
`seal with bone cement or cyanoacrylate adhesive)
`Add small quantity of 111In-labeled placebo pellets of Neutron activation (152Sm to 153Sm)
`Hot manufacture (111In)
`same size, same density, and same polymeric
`coating
`Direct incorporation of 99mTc-DTPA via syringe
`inserted through the applicator. Hole is
`subsequently sealed with cyanoacrylate adhesive.
`Drill-and-fill approacha (111In or 152Sm)
`
`Suppositories
`
`Neutron activation (152Sm to 153Sm)
`Hot manufacture (111In)
`Drill-and-fill approach (111In or 153Sm)
`a. Extensive in vitro validation testing is routinely undertaken to ensure that the pre- and postlabeled products have equivalent pharmaceutical properties.
`
`1208 • J Clin Pharmacol 2002;42:1200-1210
`
`Cosmo Ex 2002-p. 9
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`BIOEQUIVALENCE TESTING FOR GASTROINTESTINAL PRODUCTS
`
`Figure 6. Equivalence test for essential similarity in the locality of in vivo drug delivery for the two products. PSB, proximal small bowel; DSB,
`distal small bowel; ICJ, ileo cecal junction; AC, ascending colon; HF, hepatic flexure; TC, transverse colon; SF, splenic flexure; DC&R, descend-
`ing colon and rectum.
`
`acceptable, in a regulatory context, to assume thera-
`peutic equivalence.
`
`Oral MR Pellets
`
`The drug delivery characteristics of oral MR products
`are significantly different than those from the delayed-
`release enteric-coated preparations, and therefore sub-
`tly different equivalence arguments are required. Once
`again, comparable in vitro drug release would need to
`be demonstrated (e.g., dissolution tests at pH values of
`1.2 and 7.4); the extremes of intestinal pH should be ad-
`equate to establish in vitro comparability for MR
`products.
`For MR locally acting products (e.g., mesalazine),
`the systemic exposure values are more valuable than
`for the enteric-coated preparations. It is well estab-
`lished that drug released in the upper bowel is rapidly
`absorbed significantly, contributing to the plasma ex-
`posure.5 On average, it takes 4 to 5 hours after dosing for
`the product to arrive in the colon; therefore, for a signif-
`icant period of the release process, the product is in an
`environment of relatively good absorption. As a conse-
`quence, the AUC and Cmax comparison for this type of
`formulation is a more accurate assessment of
`bioequivalence than for the enteric-coated formula-
`tion. This could allow a wider equivalence metric
`(e.g., 0.7-1.43) to be accepted for AUC and Cmax in a test/
`reference comparison, as long as the transit time of the
`
`pellets was essentially similar following simultaneous
`scintigraphic investigation (i.e., the systemic exposure
`data originate from pellets with comparable transit and
`in vitro release rates).
`Therefore, in summary, a conventional pharma-
`cokinetic study coupled with a simultaneous scinti-
`graphic transit study in 24 healthy volunteers for two
`products that have comparable in vitro release proper-
`ties should be an acceptable mechanism to establish
`surrogate “therapeutic equivalence.”
`
`Rectal Formulations
`
`It is readily possible to quantify the extent of spreading
`for the test and reference products, which is the key de-
`terminant of local availability (i.e., it is a measurement
`qualitatively reflecting the presence of the active sub-
`stance at the site of action). As a consequence, a prod-
`uct distribution study in a group of 24 volunteers show-
`ing an essentially similar spread of the test and
`reference should be an acceptable surrogate for thera-
`peutic equivalence.
`
`CONCLUSIONS
`
`Bioequivalence testing for locally acting oral products
`is a challenging issue for both the pharmaceutical in-
`dustry and the global regulatory authorities. Gamma
`
`DRUG DEVELOPMENT
`
`1209
`
`Cosmo Ex 2002-p. 10
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`WILDING
`
`scintigraphy, applied as part of a wider package of eval-
`uations, can play an important role in establishing es-
`sential similarity for two locally acting products and,
`used in a validated context, should be accepted as sur-
`rogate for therapeutic equivalence.
`
`REFERENCES
`
`1. Munkholm P: Crohn’s disease—occurrence, course and prognosis:
`an epidemiologic cohort-study. Thesis, Herlev Hospital, Copenha-
`gen, Denmark, 1997.
`2. Azad Khan AK, Piris J, Truelove S: An experiment to determine the
`active therapeutic moiety of sulphasalazine. Lancet 1977;2:892-895.
`3. Schröder H, Campbell DES: Absorption, metabolis