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`
`t • t
`'
`' i
`
`~Pl'II\COTT 'XiiLll·\\I'> <, \\i LI\. I~"
`
`~
`
`WESTON LIBRARY
`JUN O 8 2000
`JS/120 CLINICAL SCIENCE CENTER
`600 HIGHLA\JD AVE t,~6.D1SON WI 53792
`
`Bausch Health Ireland Exhibit 2007, Page 1 of 17
`Mylan v. Bausch Health Ireland - IPR2022-01102
`
`

`

`7711·rnpr1111c Dmi: M,mirorin.~
`22: 0- 3-l5 0 2000 Loppincou Williams
`
`· Wi1J..t1h, Inc~ Philadelphia
`
`Recommendation for Bio quivalence Te ting of Cyclo porine
`G neric Revi it d
`
`we Chri tian
`
`,:, M. Roy
`
`ir t, t and e lie Z. Benet,'''
`
`~'Deparr111e111 nf Biophar111nce111ical Sde11ces, School of Pharmacy, U11i1•1•rsity nf alifnmia, San Fro11cisco, CA ; t U11iversi1 • nf
`Ci11d111w1i Medical Ce111er, Cinci1111ati. OH
`
`ummary: The immunosuppres:ant cyclo. porine i-; generally con idercd a critical(cid:173)
`do e drug. The validity of t, ndard ritcri.1 to e tablish bioequivalcnce betw en cy(cid:173)
`clo purine formulations ha
`recently been hallen0 ed. Re mmendations included
`e. tabli hment of individual bioequivalcnce rather than average biocquivalencc, estab(cid:173)
`lishment of biocquivalence in transplant patient. and in ubgroup · known to be poor
`:ib orber • as well
`long-term efficac_ and safety studies in transplant p ticnts.
`H wever. :II the moment individual bioequivalcnce s a theoretical concept, the prac(cid:173)
`tical benefit of \\hich ha\'e not tatistically ~en pr ven. The proposed patient phar(cid:173)
`macodynamic studies can be expected to require an unreali tically high number of
`subjccLs to achieve ufficicnl statistical power. It i well e tabli hcd that the common
`pm ti c of bl od-concentration-guidcd d
`ing of cy losporine efficiently compensate.
`for interindividoal nnd inLr:1individual variability and Hows for. afoly w,rching cy(cid:173)
`clo p rinc formulation as bioincquiv:ilent as andimmune an
`eor:il. R
`nt
`tu ies
`omparing the gcncri cycl porin
`fo1mulation ang ya with coral, incl u ino in(cid:173)
`dividual bioequivale cc. biocquivalencc in tran plant patients. and I ng-tcrm
`,1fcty
`afters, itching from and immune to ang
`'a, confirmed that it wns valid t conclude
`biocquivalencc of both cyclo porinc fonnulations based on standard a eragc bio(cid:173)
`equi\'alence criteria. Present FD gu idelin s for approving biocquivnlcn e can be
`considered adequnte and uffici nt for generic cyclo porinc formulation . c Word :
`yclo porine- Cyclo ·porine generics-Bioequivalence- lndividual bioequiva-
`lenc Therapeutic drug monitoring.
`
`Mostl y a a result of the i troduction of the undeca(cid:173)
`peptide cyclo porine a
`immun suppressant, graft and
`patient ur ival ha c
`ignific:mtly improved during the
`last two d cade and tran plantation is an e tabli hcd
`standard procedure at mo I large medical center . How(cid:173)
`ever there arc considerable co t for immune uppre sive
`therapy requ iring life-Jong maintenance lo prevent the
`transplant organ from being rejected (l ,2). In the United
`tates and Europe there ar more than 200,000 tran plant
`recipient
`requiring daily immuno uppre
`i e therapy
`for the re t of their li ve
`the majority of whom are re-
`
`Received June 10, 1999; accepted December 30, 1999.
`Addrc. s corrc pondcncc and reprin requc,ts to Lc~lie z. Benet,
`Ph.D., Pmfo. or, Department of Biopharm, cuti al Sci nee~, School
`of Pharmacy. Univcr uy of C:ili fornia, San
`ran i co, 33 Parna~ u
`1•e. Room U-68, San f'ranci co, CA 94 143-()446
`
`eiving immuno uppre
`i e drug regimen based on c~ (cid:173)
`clo ·porine. Worldwide ale of the innovator' cyclo(cid:173)
`sporine formulation Sandimmune and eoral (
`Pharma, Basel, witzerland) were estimated at
`billion in 1997. In the United
`tates, the innovaror s
`patent protection expires after 17- 20 year and orhcr
`companie are then free t manufacture interchange(cid:173)
`able generi product . Novani
`comp sition of mau~r
`patent on cyclo porine expired in th
`nited
`tate
`in
`September 1995. One generic cyclo po1ine formulation.
`SannCya ( angStat
`edical, an Mateo, CA. SA 1.
`recently be n appro ed by the United
`ha
`tat Fo ti
`and Drug Ad ministration (FDA). Others have filed for
`appro al.
`In 1984 th Drun Pri e Competition and Term Re. -
`t ration ct (3) all \ ed the FDA to use a implific<l
`approval procc
`for generic drug products the o-callcd
`
`330
`
`Bausch Health Ireland Exhibit 2007, Page 2 of 17
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`
`

`

`CYCLOSPORINE BIOEQUJVALENCE
`
`331
`
`abbreviated new drug applicatio n (ANDA) (4). The
`FDA ' s approval p roce s of generic drugs evaluates
`chemistry, manufacturing and controls, in vivo bio(cid:173)
`cquivalen e, labe ling, in vitro dissolution if applicab le,
`;.llld include inspection and auditing of all faci lities (5),
`Be ause the efficacy and safety of an innovator's drug
`has a lready been e tablished , the FDA regu lations are
`promulgated based on the belief that there i no reason to
`repeat the same studies with the generic ver ion of the
`drug that contains exactly th.e same m le ular entity as
`the in novator's product. Because of the lower co
`' of
`development and competi tion in the market generic
`drugs usually sell fo r significantly less than the price of
`the innovator' s product before the avai labi lity of gener(cid:173)
`ics. It is generally agreed that the prescribing and use of
`generic drugs lead to con siderably redu ced cost. Generic
`drugs also have the potential to im prove the quali ty of
`care. Lower-cost alternatives may improve adherence to
`therapies for patients who cannot afford innovator drugs,
`and these alternatives provide an increased duration of
`therapy for patients with capped medical benefits. Dur(cid:173)
`ing the last 27 years, the FDA has approved more than
`5,000 generic drugs for marketing in the United States
`5 . T o da te. the FDA is not aware of any vali dated study
`of an FDA-de ignated equivalent generic product that
`met FDA pecifications but that was not equiva lent to the
`conesponding innovator' product (6,7 . In addition, the
`FD A's investigation of single cases of decreased efficacy
`or increased toxicity never revealed problems attributed
`to substitution of one approved product for another thera(cid:173)
`peutically equivalent product (7). In spite of this excel(cid:173)
`lent safety record, there is a great reluctance by many
`clinicians to use generic equivalen t fo r so-called "criti(cid:173)
`caJ-dosc drugs." Although ther is no offic ial definition
`for "critical-dose" or "nanow-therapeutic-index•- drags.
`and no general consensus as to which drugs fall within
`
`this category (8), bioequivalence-related issues of criti(cid:173)
`cal-dose drugs have been discussed intensively. Benet
`and Goyan (9) defined narrow-therapeutic-index drugs
`as "those for which small changes in pharmacokinetic
`response lead to marked changes in pharmacodynamic
`response." Accordingly, cyclosporine is generally re(cid:173)
`g arded as a typical critical-dose drug (10-15) . Bio(cid:173)
`equivalence testing procedures, especially in the case of
`critical-dose drugs, have been criticized in the past for
`many reasons, most of which potentially apply to cyclo(cid:173)
`sporin (9,10,12,13). A fundamental problem is the defi(cid:173)
`nition of bioequivalence, which is based on the assump(cid:173)
`tion that bioavailability (rate and extent) is a valid sur(cid:173)
`rogate for efficacy and safety (16, 17). This requires a
`clinically significant association between blood/plasma
`concentrations and pharmacodynamic effects that is not
`neces sarily always the case. However, for cyclosporine
`the relationship between pharmacokinetics and safety
`has been extensively studied and provides the basis for
`the generally accepted blood-level-guided dosing regi(cid:173)
`mens. Several other potential issues regarding the inter(cid:173)
`changeability of cyclosporine formulations are of con(cid:173)
`cern to clinicians. There is doubt that the results of piv(cid:173)
`otal bioequivalence studies that are conducted in healthy
`volunteers are extrapolatable to transplant patients who
`exhibit several factors affecting cyclosporine pharmaco(cid:173)
`kinetics that are not present in healthy volunteers (see
`below and Fig. 1). This applies especially for subpopu(cid:173)
`lations of patients who are known poor absorbers. Intra(cid:173)
`individual variability of cyclosporine is a critical clinical
`issue that has been associated with acute and chronic
`rejection (18,19) and cannot be addressed by pivotal
`healthy volunteer trials . This translates into suspicion
`that standard bioequivalence testing may not be a valid
`approach to establishing long-term safety and efficacy in
`transplant patients.
`
`age
`disease
`race
`lliet
`
`pre-existing
`~ tors
`~
`
`clinical
`statu
`/
`
`-------=-
`
`ac tiv ity of:
`•CYP3A enzymes
`•ABC protein
`, ,
`transporters
`" - - - - ' - - - - - - - - - - ' concomitant
`CYP3J\/ ABC protein
`therapy
`•induc rs
`· inh ibitors
`
`time after
`transplantation
`r ejection
`infection
`liver function
`gut fun ction
`
`FIG. 1. Fac tors potentially affec ti ng cyclo(cid:173)
`spori ne p h~rnwcokinc ti cs in transplant
`p:1tients.
`
`Ther D1t1g Monit. \lul. 22, No. 3. 200/J
`
`'
`
`transplant
`organ
`
`liver
`heart
`smaJJ bowel
`
`Bausch Health Ireland Exhibit 2007, Page 3 of 17
`Mylan v. Bausch Health Ireland - IPR2022-01102
`
`

`

`332
`
`U. CHRISTIANS ET AL
`
`TABLE 1. Comparison of guidelines and reco111me11dations to establish bioequivalence and to switch between
`cyclospori11e f ormulations
`
`Recommendation
`
`Johnston et al., 1997 10
`
`Sabatini et al., 1999 13
`
`Kahan, 1999 14 ·'.? 1
`
`Average/individual
`bioequivalence
`
`Validity of average
`bioequivalence questionable
`
`Demonstration of individual
`bioequivalence should be
`mandatory for FDA approval
`
`Should be required for all CsA
`generics
`Should be required for all CsA
`generics
`
`Should be required for FDA
`approval of all CsA generics
`Should be required for FDA
`approval of all CsA generics
`
`Should be required (study period
`>3 months)
`Not addressed
`
`Not addressed
`
`Yes
`
`Bioequivalence studies in
`paticnis af1cr transplantation
`Biocqui\'alen e studies in
`subpopulations that are poor
`absorbers ,
`Long-term efficacy and safety
`studies in transplant patients
`Physicians and patients must
`approve switch of CsA
`formulations even if
`bioequivalent
`
`CsA, cyclosporine.
`
`Average bioequivalence is a
`valid approach to establish
`interchangeability, individual
`bioequivalence should be
`demonstrated for the first CsA
`generic approved
`Recommended for first CsA
`generic approved
`Recommended for first CsA
`generic approved
`
`6-months pre-marketing
`follow-up
`Not required
`
`The question has been raised by several authors (10,
`12,14,20) as to what extent the standard bioequivalence
`criteria used by the FDA and most drug agencies in other
`countries address these concerns and the sufficiency of
`these criteria to establish the safety of substituting cy(cid:173)
`closporine formulations. This has also been discussed in
`recent meetings (13,21 *). This has resulted in several
`different and sometimes contradictory guidelines and
`recommendations (Table 1). It was our goal to critically
`review cyclosporine bioequivalence issues and the dis(cid:173)
`cussed recommendations in light of bioequivalence and
`clinical data that is presently available for several generic
`cyclosporine formulations and in light of the extensive
`experience with switching transplant patients between
`the innovator's bioequivalent cyclosporine formulations
`as well as between the bioinequivalent Sandimmune and
`Neoral formulations .
`
`CYCLOSPORINE FORMULATIONS
`
`Recognizing the limitations of the original cyclospor(cid:173)
`ine formulation Sandimmune, a crude oil-in-water drop(cid:173)
`let mixture (22), the innovator (Novartis Pharma, Basel,
`Switzerland) developed a microemulsion preconcentrate,
`Neoral, that improved emulsification and dispersion of
`cyclosporine in the small intestine and resulted in better
`and more reproducible absorption (23,25). From the be(cid:173)
`ginning, Neoral was developed to increase cyclosporine
`bioavailability and, therefore, to be bioinequivalent (i.e.,
`
`*Generic Immunosuppressants: Should you be worried? Transplan(cid:173)
`tation Society sponsored symposium. Montreal, Canada, July 12. Pre~
`sentations were published in Transplant Proc 1999; 31 [supplement].
`
`Ther Drng Mo11it, Vol. 22, No. 3, 2000
`
`suprabioavailable) to Sandimmune (10,20,24). In fact,
`Sandimmune and Neoral should be considered different
`drug products (20) .
`In healthy volunteer studies (25,26) as well as in clini(cid:173)
`cal studies in transplant patients (23-25,27) and psoriasis
`patients (28,29), Neoral cyclosporine pharmacokinetics
`differed from those of Sandimmune, yielding increased
`maximum blood concentration (Cmax), decreased time to
`reach Cmax (tmax), and increased area-under-the-time(cid:173)
`concentration curve (AUC) (23). Depending on the dose,
`the relative bioavailability of Neoral in healthy volun(cid:173)
`teers was 1.7-fold to 2.4-fold and the Cmax 1.9-fold to
`2.1-fold higher than after the same Sandimmune cyclo(cid:173)
`sporine dose (26). In de novo recipients of kidney trans(cid:173)
`plants, depending on the time after transplantation, dose(cid:173)
`normalized AUCs were 32-63% higher than in Sandim(cid:173)
`mune-treated patients (27). The mean increases of AUC
`and Cmax of 39% and 15%, respectively, in stable recipi(cid:173)
`ents of kidney transplants after switching from Sandim(cid:173)
`mune to Neoral (30) were smaller than in the healthy
`volunteer studies (26). Although based on healthy vol(cid:173)
`unteer studies, a conversion factor of 0.6 (Netiral:Sand(cid:173)
`immune) was estimated, tr~nsplant patients were
`switched 1: 1(25). In a clinical study in 55 stable recipi(cid:173)
`ents of kidney transplant, switching from Sandimmune to
`Neoral on a 1: 1 basis resulted in 22% higher cyclospor(cid:173)
`ine trough blood concentrations (31). However, patients
`with higher cyclosporine doses before conversion from
`Sandirnmune to Neoral are more likely to require dose
`reduction in the postconversion course. When switched
`from Sandimmune to Neoral, good absorbers remain
`good absorbers whereas poor absorbers become good
`absorbers (32). The higher bioavailability and different
`
`J
`
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`
`

`

`CYCLOSPORINE B!OEQUIVALENCE
`
`333
`
`and lower intraindividual pharmacokinetic variability,
`Neoral is generally considered to have proven benefits to
`patient care over Sandimmune (2, 10,24,27).
`In October 1998, the FDA approved SangCya (Sang(cid:173)
`stat Medical, Menlo Park, CA, USA) as the first generic
`cyclosporine formulation in the United States. SangCya
`is a nano-dispersion formulation based upon Sangstat' s
`CPLF formulation technology (37). Bioequivalence with
`Neoral was not only established in pivotal healthy vol(cid:173)
`unteer studies (38), but also in recipients of kidney and
`liver transplants (39,40) (Table 2, Fig. 2). In addition,
`individual bioequivalence between SangCya and Neoral
`was demonstrated (41) (Table 3, see below) following
`the draft FDA procedures (11,42). Safety and efficacy of
`SangCya was established in patients with kidney grafts
`during a 9-month observation period (43).
`Healthy volunteer studies demonstrating bioequiva(cid:173)
`lence with Neoral (Table 2) have been published for two
`other generic cyclosporine formulations, Neoplanta
`(Hanmi Pharmaceutical, Seoul, Korea) ( 44,45) and Ci(cid:173)
`pol-NR (Chong Kun Dang, Seoul, Korea) (46). Like
`Neoral, both are microemulsion formulations (46,47).
`The difference between Neoplanta and Neoral is that
`Neoplanta uses dimethyl isosorbide instead of ethanol as
`the solvent (48). In de novo recipients of renal trans(cid:173)
`plants, Neoplanta and Neoral (n = 20 for each group)
`showed similar efficacy in preventing graft rejection and
`similar tolerability (48).
`
`pharmacokinetic pattern of Neoral raised several safety
`concerns that required clarification in clinical studies
`t23-25). The high cyclosporine Cm:.i-: after Neoral was of
`special concern because high cyclo purine C,mi., values
`have been related to short-term renal vasoconstriction
`and possi bly chronic cyc;lo ·purine nephropathy (33) . An(cid:173)
`other concern was the higher LotaJ exp() ure of patients
`during conversion from Sandimmune to NeoraJ (-3). Tbe
`conversion protocol recommends starti ng Neoral at the
`preconversion dose (I : I conversion) with s ub cque nr
`do e adju tments ace rding to cyc losporine trough blood
`co ncentrations . It was nece st1ry to assurn
`that the
`greater expo ure to cy losporine from the microemulsion
`fo rmulation might increase the nephroto ic risk. In fact,
`adverse events such as hypertension, nephrotoxicity, a nd
`acute rejection have been reported after conversion (30).
`However, as of today, despite the two products' signifi(cid:173)
`cant pharmacokinetic differences, clinical studies have
`established a safety and tolerability profile of Neoral
`comparable ro thaLof Sandimmunc (24). Long-term stud(cid:173)
`l show any stmistically ·ign ificant difference ·
`ies did 11
`between recipient of kidney tran. plants tre< led with
`Sandimmune and those treated with Neoral in Ler111s of
`safety, including creatinine concentrations, patient and
`graft survival, as well as the incidence of acute rejection
`(23,24,27 ,34,35 ). This is not surprising: because of the
`drug's highly intraindividually and interindividually
`varia_ble pharmacok.inetics and narrow therapeutic index,
`cyclosporine doses must be adjusted according to cyclo(cid:173)
`VARIABILITY OF CYCLOSPORINE
`sporine blood concentrations (36). Regular therapeutic
`PHARMA CO KINETICS
`drug monitoring is required, and the cyclosporine con(cid:173)
`The significantly lower pharmacokinetic variability of
`centrations are kept in a narrow target concentration
`cyclosporine after administration of Neoral compared to
`range that is independent of the cyclosporine formula(cid:173)
`Sandimmune is commonly regarded as the major im-
`tion. However, because of its improved dose linearity
`TABLE 2. Comparison rif' the results ci( bioequivalmce studies in healthy 1'0/1111/eers and patients who have fwd a
`tm11sp/antation with cydosporine for11111/ations (test) bioequivalem to Neoral (referencer
`
`Cyclospori ne
`
`Test Formulation
`SangCya
`SangCyat
`SangCya
`SandCya
`SangCya
`Neoplanta
`Cipol-N
`SangCya
`SangCya
`
`Subjects
`
`Fasted male healthy volunteers
`Fasted male and female healthy volunteers
`Fasted/fe d male healthy \'oluntecrs
`Fasted female healthy l'olunteers
`Fasted male Afric.in-Amcrican volunteers
`Fasted male Korean healthy Volunteers
`Fasted male Korean healthy volunteers
`Kidney transplant patients
`Li vcr tran splant patients
`
`11
`
`36
`20
`24
`28
`lO
`24
`24
`32
`26
`
`c""" ratio (%)
`Point
`Estimate
`
`90% CI
`
`AUC ratio(% )
`
`Poin t
`Estimate
`
`90% Cl
`
`Ref.
`
`99
`95
`97
`92
`96
`97
`l03
`90
`86
`
`97-10-1-
`9()-101
`91-104
`87-100
`81-108
`90-101
`10()-106
`84-102
`81-106
`
`99
`97
`100
`95
`90
`99
`100
`94
`95
`
`97-103
`92-102
`96--105
`92-102
`83-96
`94-102
`96-104
`86-106
`89-109
`
`38
`41
`38
`38
`38
`45
`46
`39
`40
`
`* The AUC rmio in healthy volunteer · tudic
`is b:isccl upon tht: /\UC()-'l., the AUC ratio studies on the AUC0 __.,. in patients after transplant.
`ipol• .i,, Jik~ Ne r:u:.:!. urc microcmul~ion cydospori11e formulations, whereas SangCya is a nano-dispersion formulation based
`. coplanrn•' and
`upon ~ngsi:ir's PLF l!lrmulation tc •hnnlogy3 7,
`,· Analy,b of individua l biocquivulem:c see T~blc 3.
`CI, confitlc n<.:c interval.
`
`Ther D111i; A!o11i1, \lo/, 11, No. 3, 1000
`
`Bausch Health Ireland Exhibit 2007, Page 5 of 17
`Mylan v. Bausch Health Ireland - IPR2022-01102
`
`

`

`334
`
`~ 220
`~
`.Q
`~ 200
`
`Q)
`(.)
`C
`~ 180
`~
`~
`17)
`2
`c::
`6 140
`t)
`::J
`<(
`
`160
`
`120
`
`100
`
`80
`
`60
`
`U. CHRISTIANS ET AL
`
`FIG. 2. Comparison of biocquivalcnce of dif(cid:173)
`fe rent cyclo~porioc formulati ns in healthy vol (cid:173)
`unteers and stable kidney transplant patients .
`The bars represent the 90% confidence intervals
`o f the /\UC0 ...., tcs!/r•fercncc ratio and Lhe lines
`across the bars represcnL the polnt e ti mutes. The
`dotted line represents cornplete equivalence
`( 100% ), wherea~ Lhc rl!IShetl lines nre at I '.!5~
`and 809'c, the bf1)cquivalence occcptnnce limits.
`Data is taken from references 38,39.
`
`Test/ Reference,
`study subjects
`
`(/)
`
`c
`Q.)
`~
`0.
`cifc
`'- m
`o-
`(!) 0.
`z~
`---m
`co ....
`>, ......
`(.) >,
`O'l (!)
`C: C
`co -0
`Cf) '52.
`
`(/)
`
`c
`-~
`ro
`a.
`c
`-- co
`m-
`.... a.
`0
`(/)
`a.) C:
`z~
`----
`-> ,
`~ Q.)
`QC
`a.) -0
`z~
`
`(/)
`
`-1:
`:g _~
`:::i-
`E g_
`E-·- C:
`'O co
`c -
`ro a.
`Cl)~
`-. ro
`n, ...
`>-, ...
`o>.
`0)(1)
`cc
`m-o
`Cl)~
`
`(/) -'-
`~ al o-(!) C z~
`
`-._O
`co >
`>.>,
`(.) .c
`oi-ccij
`co Q.)
`Cf) .c
`
`TABLE 3. Comparison Q{ intrasubject variability* and individual bioequivalence of Sa11gCya (test) and Neoral (reference)-1 1
`Ratio
`(95% confidence
`interval)
`
`Parameter
`
`SangCya
`
`Neoral
`
`p-vrrlue
`
`Cm,, [µg · L- 1
`]
`CV
`AUCo..2• h [µg · L- 1
`CV
`AUC0_
`CV
`
`[µ.g · L- 1 · h]
`
`• h)
`
`0.0235
`15.4%
`0.01 1 I
`10.5%
`0.0127
`I 1.3%
`
`0.0327
`18.2%
`0.0124
`11.2%
`U.008 1
`9.0%
`
`0.50
`
`0.84
`
`0.43
`
`Tlwr Drug M o11ir, Vol. 21, Nn. 3, 2000
`
`0.71
`(0.22-1.76)
`0.89
`(0.36-2.20)
`1.56
`(0.36-3.83)
`lnu-:isubjecl ,·ar1:1bi li1y 11
`c:tll:ulntcd r II wing 1hc proccum·o d~ cribcd by Li u. lntrn. ubjcct v:irinhiliry bee, ccn
`11ng )'II (tc:n) nnd Ncnr.11
`(reference! 1 11. compared u:.ing rhc likellh
`ratio . ! t
`t. ln11 ~ubjcl."I variabi lity i~ h cc.I
`11 the I< garilhmil- .calc
`t Bioequivulo11 c wn~ 1cccptell when the upper 5"' cunfitlcncc in1crvi1I wn ::::. 1hc individunl binc,1uivn!c_ncc lin,il tl 1• which w11, cnl ulntotl nt 2.!4.'i
`using u I> t ~ trap mclllcl{) (_(kl{) :nmplc$J.
`C . cocf 1cicnt
`f imrasuhjcct \'lll'i hdity; C,,.,..,, maxi m11 111
`tood cm1ccntr. rion.
`
`'Upper 95%
`confidence
`interval for 61t
`1.277
`
`1.009
`
`0.935
`
`Bausch Health Ireland Exhibit 2007, Page 6 of 17
`Mylan v. Bausch Health Ireland - IPR2022-01102
`
`

`

`CYCLOSPORlNE BIOEQUIVALENCE
`
`335
`
`provement of Neoral over Sandimmune (10,13,14). Fluc(cid:173)
`tuating cyclosporine blood concentrations have been as(cid:173)
`sociated with chronic and acute rejection (18,19,49). ln
`comparison to Sandimmune, the more consistent absorp(cid:173)
`tion from the Neoral formulation may result in a reduced
`incidence of chronic rejection (18) and toxicity, it is ex.(cid:173)
`pected to make clinical management easier and safer
`(50), and it will reduce costs after transplantation (2).
`Demonstration of equivalent pharmacokinetic variability
`of generic cyclosporine formulations and Neoral has
`been a major concern (10,13,14,21).
`Factors· that play a major role in the low and variable
`oral bioavailability of cyclosporine include solubility,
`emulsification, countertransport of the drug by P 170-
`glycoprotein and other ATP-binding cassette (ABC) pro(cid:173)
`tein transporters from the gut mucosa back into the gut
`lumen, and first-pass metabolism in the small intestine
`and liver.
`After administration of cyclosporine as the original
`Sandimmune formulation, absorption of cyclosporine re(cid:173)
`quires the following subsequent steps: formation of an
`oil-in-water droplet mixture with gastrointestinal fluids,
`emulsification of this mixture by bile salts, digestion of
`the oil droplet, and solubilization of cyclosporine in
`monoglycerides and bile salts resulting in a mixed mi(cid:173)
`cellar phase from which cyclosporine is absorbed
`(22,25). Emulsification by bile salts has been identified
`as the step that causes most of the variability in intestinal
`absorption of cyclosporine after Sandimmune adminis(cid:173)
`tration. This step is dependent on food intake, bile flow,
`and gastrointestinal motility (51). Microemulsion and
`nano-dispersion cyclosporine formulations are hypoth(cid:173)
`esized to shortcut the critical emulsification step. In the
`Neoral microemulsion, cyclosporine is dissolved in a
`mixture of corn oil mono-, di- and triglycerides, the hy(cid:173)
`drophilic solvent propylene glycol, the surfactant poly(cid:173)
`oxyl-40 hydrogenated castor oil, and the antioxidant DL(cid:173)
`tocopherol (22). Upon contact with gastrointestinal fluid,
`a monophasic microemulsion is formed that has proper(cid:173)
`ties similar to the putative mixed micellar phase from
`which cyclosporine is absorbed.
`Cyclosporine is a substrate of cytochrome P450 3A
`enzymes and the ATP-binding cassette transporter Pl 70-
`glycoprotein (52-55). It is metabolized by CYP3A en(cid:173)
`zymes in the small intestine to its major metabolites (56).
`In patients, metabolites were found to account for as
`much as 50% of the measurable cyclosporine derivatives
`in portal vein blood after cyclosporine instillation into
`the small intestine (57). In microsomes isolated from the
`duodenum of patients, cyclosporine metabolism varied
`IO-fold (56,58). A clinical study using intubation tech(cid:173)
`niques to deliver cyclosporine to different parts of the
`
`gastrointestinal tract established a significant inverse
`correlation between cyclosporine absorption and Pl 70-
`glycoprotein messenger RNA at the administration site
`(59), suggesting that Pl 70-glycoprotein-mediated intes(cid:173)
`tinal countertransport significantly contributes to the in(cid:173)
`complete absorption of cyclosporine. In a recent clinical
`study in stable recipients of kidney grafts (58), it was
`found that hepatic metabolism was responsible for 56%
`of the interpatient variability in apparent oral cyclospor(cid:173)
`ine clearance and 32% of the variability in Cmax · After
`the liver effect was taken into account, the only other
`parameter significantly contributing to cyclosporine
`pharmacokinetic variability was intestinal Pl 70-glyco(cid:173)
`protein, which was estimated to explain 17% of the vari(cid:173)
`ability in apparent oral clearance and 30% of the vari(cid:173)
`ability in Cmax (58). In the same study, cytochrome P450
`3A enzyme activities in the liver varied 3-fold and Pl 70-
`glycoprotein in the small intestine IO-fold among pa(cid:173)
`tients. These studies demonstrate that cytochrome
`P4503A-dependent intestinal and hepatic first-pass me(cid:173)
`tabolism as well as Pl 70-glycoprotein-mediated intesti(cid:173)
`nal countertransport reduce the oral bioavailability of
`cyclosporine whereas hepatic metabolism and intestinal
`countertransport also contribute to its pharmacokinetic
`variability.
`
`A VERA GE BIOEQUIVALENCE TESTING
`In the 1970s it was recognized that, even when two
`drug products contained the same active component at
`the same dose, small changes in the product formulation
`could result in significant differences in oral bioavail(cid:173)
`ability. Several cases of lack of effect or intoxication
`after administration of pharmaceutically equivalent ge(cid:173)
`neric drug products were reported (60). Pharmaceutical
`equivalents contain the same active ingredient, are ad(cid:173)
`ministered by the same route in the same dosage form,
`and are of identical strength and concentration (61).
`These experiences triggered an international effort to de(cid:173)
`velop clinical and statistical procedures to establish bio(cid:173)
`equivalence between pharmaceutical equivalents. Today,
`drug regulatory authorities in the United States (62), the
`European Community ( 17), and most other countries re(cid:173)
`quire demonstration of average bioequivalence between
`the marketed and a generic drug product as the basis of
`approval. The rules to establish bioequivalence are basi(cid:173)
`cally similar in most countries with only minor differ(cid:173)
`ences. Bioequivalence studies typically aim to demon(cid:173)
`strate that two pharmaceutical equivalents have similar
`pharmacokinetics (63). The standard bioequivalence trial
`is conducted according to a randomized 2-period cross(cid:173)
`over design and includes from 12-36 healthy normal
`male adults with an appropriate wash-out between study
`
`Tlwr Drug Mcmir, Val. 22, Na. 3, 2000
`
`Bausch Health Ireland Exhibit 2007, Page 7 of 17
`Mylan v. Bausch Health Ireland - IPR2022-01102
`
`

`

`336
`
`U. CHRISTIANS ET AL
`
`periods. The key issue in bioequivalence testing is to
`demonstrate similar oral bioavailability. Because the
`pharmaceutical equivalents are orally administered, ab(cid:173)
`solute bioavailability cannot be directly determined.
`Area-under-the curve (AUC) measurements serve as a
`surrogate for the extent of absorption; the maximum
`plasma concentration (Cmax) and the time of its occur(cid:173)
`rence (tmax) together characterize the rate of absorption
`(64). Pharmacokinetic parameters used to establish bio(cid:173)
`equivalence in the FDA and European Committee for
`Proprietary Medicinal Products (CPMP) guidelines are
`shown in Table 4. Test and reference product are con(cid:173)
`sidered equivalent when the 90% confidence interval for
`the true formulation means (µ, tcslµrcfercnce) falls within
`the acceptance limits of 0.8-1.25 (17,62). In practice, the
`confidence interval approach is carried out using log(cid:173)
`transformed data (65). The 0.8-1.25 bioequivalence ac(cid:173)
`ceptance range translates into a difference in rate and
`extent of absorption between the two drug products of
`-20% to +25%. These acceptance limits are based on the
`medical decision that a -20%/+25% difference in the
`concentration of the active ingredient in blood will not be
`
`T BLE 4. Plmramm:nki11 etic parameters i11 the United
`SwteN 111,tl E11l"opca11 g11irfcJi11es for hioeq11ivale11ce testing9s
`
`Recommended
`pharmacoki netic
`parameters
`
`Single dose
`
`Multiple dose
`
`Uni ted States
`and Canada"'
`
`Cmax
`tmax
`AUC0_,
`AUC0 _~
`t,/2
`
`cmax
`
`cmin
`AUCT
`AUC0.~
`tm .:u.
`c.,.
`DF
`
`Europct
`
`Cma;,i;
`tma:-c
`AUC0 _,
`AUC 0 _~
`t,/2:j:
`MRT;j:
`Ae
`Ae0 .~
`dAe/dt
`Css,,,ax
`Cssmin
`AUCT
`
`* Food and Drug Administration
`t Committee for Proprietary Medicinal Products
`:j: Mentioned in the CPMP guideline 17 as optional parameters.
`Ae, cumulative urinary excretion from administration to the time
`point of the last measured concentration; Ae0_~ , cumulative urinary
`excretion extrapolated to infinity; dAe/dt, urinary excretion rate;
`AUC0 _,, area under the concentration time curve from administration to
`the time of the last measured concentration ; AUC0_~ , AUC extrapo(cid:173)
`lated to infinity ; AUCT, AUC during a dosing interval; Cm><' maximal
`blood/plasma concentration; Cssmax, maximum blood/plasma concen(cid:173)
`tration at steady state; Cm in, minimum blood/plasma concentration; C 0 ,. ,
`average blood/plasma concentration; Cssrnin• minimum blood/plasma
`concentration at steady state; OF, degree of fluctuation; MRT, mean
`residence time; t 112, blood/plasma concentration half-life; tm,w time
`from administration to Cmax·
`
`Titer Drug Monil, Vol. 22, No. 3, 1000
`
`clinically significant (61). It is important to recognize
`that it is the upper and Jower limit of the 90% confidence
`interval for the rrue mean ratios and not only the mean
`ratio (point estimate) that must be within the bioequiva(cid:173)
`!ence acceptance limits (61). The 90%-confidence inter(cid:173)
`val is a measure of total variability, which is influenced
`by both interindividual and intraindividual variability
`(11,66). Variability is a factor that has a significant im(cid:173)
`pact on acceptance or rejection in average bioequiva(cid:173)
`lence testing.
`It has been suggested that the standard procedures to
`establish bioequivalence may not be adequate for all
`drugs and that modified procedures and additional data
`may be necessary (9,60,63,67). Drugs for which the va(cid:173)
`lidity of the standard approach for establishing bio(cid:173)
`equivalence must be assessed and if necessary modified,
`are (1) those with a narrow therapeutic index, (2) those
`with high interindividual and intraindi vi dual pharmaco(cid:173)
`kinetic variability, (3) those for which pharmacokinetics
`does not correlate with phannacodynamic effects, and
`(4) those with nonlinear pharmacokinetics and/or con(cid:173)
`trolled modified-release formulations (60). The validity
`of standard average bioequivalence procedures to estab(cid:173)
`lish bioequi valence of cyclosporine generics has been
`challenged (10, 13 ), mostly because cyclosporine has
`been classified as a narrow-therapeutic-index, highly
`variable drug (11-14). A drug is commonly regarded as
`highly variable when it exhibits an intrasubject coeffi(cid:173)
`cient of variance 2::30% as estimated by analysis of vari(cid:173)
`ance (66,67). Thi