Orug Disposition
`
`Cion. I'tIarmarol"MI 20 (I): 18-49. 1991
`OlI2· ~96J!9 I /OOO I .()(l38/S06.00/O
`C Ad"ln!rmahOnal llmllro
`All nlhls l"C'SCT'Ved.
`cPl<OOS :M ' .
`
`Clinical Pharmacology of Omeprazol.
`
`Colin W. Howden
`Unlv~rsll y Departmenl of Medicine and Therapt'ul1cs. WC'Slrm Infirmary.
`Gl1S10W Gil 6NT. Scotland
`
`Cont~ntJ
`
`.. 39
`J9
`.... 39
`. .. 39
`J9
`. ......... 39
`. ........... 40
`
`"
`
`SummaI)' .......................••....•...•......••.....•.....••••....•.....•••.......•...
`I. Chcml51ry and Pharmaoolos,y of OmeprlIlolr
`1.1 Ow-mlSlry
`..................... .
`1 2 Mrxk of A1'"lIl)n
`2. Pharmacodynamics m Humans ........................... . , ..... .
`2.1 Effect on Basal ACid Ou tput. ....................
`. ........................................... .
`2.2 Effect on Peniapsmn-Slimuilled Acid Output ......................................... ..
`2. 1 Effect on Insuiln·St,mlllatro ACid Olltput ..................................................... .
`2.4 Effect on 24-HOllr Intnp$tnc: At ldll y ..
`. ......... 41
`2.5 Effect on Pluma Gasmn Levels
`............................ .
`41
`. ...... 42
`2.6 Effect on I'cpsm Secretion
`..................... .
`.... 42
`2.7 Effect on Intrapstrie Bacteria and Bacterial Prodllcts
`. ..................................... 42
`...............................
`2.8 Effects on EndOCrine Flinction
`2.9 Effects on Renal TlIblilar Flinctlon .............................................................................. 42
`..... 42
`3. Pharmacokinetics In Hlimans .......................... .
`3.1 Absorption and ~TUm Cont"('ntntions
`........ 42
`3.2 Distriblition
`....................... .
`3.3 Metabolism and Elimination
`........... .
`. ... 44
`3.4 InnllCnce of Disease Stales o n tile Pharmacokinetics or Om~pn~olc ..........
`4. Drua Interactions ........................................................................... _ ...................................... 45
`4S
`4. 1 Diazepam ................................................................
`...................
`4.2 AmlnopllrnazollC (Aminopynnr) and PllrnazollC (AnllpYrlne) .................................. 45
`.. 45
`4.3 Pllrnytoin .
`4.4 Propnnolol
`...... 45
`4.5 warfarin
`.. 45
`4.6 Amo~ yclilin and Ibcampicillin ........ .
`4.7 Nlrc(!lplllC .......................................... .
`. ..... 45
`4.8 Anlllrnb and Mrtoclo pnmldr ........ .
`l Tllcrapclltic Uses of Omepn~olc ......... .
`. ..... 46
`. ............................... 46
`5. 1 Dliodenal Ulcer ............................... .
`. .................................... 46
`5.2 Gastric Ulcer ...............................................
`5.3 PePIiC Ulcerallon Refracl(lI"y to Treatmrnt ..............................................
`. ... 47
`S.4 Rrflll~ OcsoplllllliS ............................................................. ........................
`. .... 47
`5.5 Zollinger-Ellison Syndrome ........................................................................
`. ..... 47
`
`" . 43
`
`.. 4S .,
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 1
`
`

`

`Clinical Pharmacolog~ of Omeprazo!t·
`
`J9
`
`Su mm(uJ'
`
`Omcprazo!c IS a spc(iflc inhibitor of H-. K '-ATPase or 'prmoll pump' In parlctal cclls.
`This cnz) me IS responsibk for the final step In the process of ac .d SCCTetlOn: omeprazoic
`blocks aCid !.Ccr('tlon In responsc to all stimuli. Single doses produce dosc-dependen t
`inhibition with mereasmg elTcrt O\er the first fcv. days. reachmg a ma\lmum after about
`5 da) s. Doscs of omeprazole 20mg dall~ or greater arc able 10 qrtually abohsh mtragastnc
`aeldl[~ In most mdl\lduals. although lov.cr do!.Cs ha'c a much more vanable effect
`Omepra10le causcs a dosc-depcndcnt Incrcasc In gastrin le\'els.
`OmepraLOk mUSl be protected from Intra gastric aeld v. hen ginn oral I). and IS there(cid:173)
`for;.' admmlstcred as encapsulated entenc-coatcd granules. :\bsorpllon can be crratlc but
`IS gcnerall~ rapid. and Illluall~ the drug IS \lldel) dlstnbutcd. IllS high!) protcm-bound
`and cxtcnSl\cl) metabolised. Its elimmatlon half-life IS about lh but Its pharmacotoglcal
`elTl'Ct la~ts much longer. smCl' !lIS prcfcrcnllaH~ concentrated m panetal cells v.here 1\
`forms a co' aiI'm lin kage v. IIh H'. K' -ATPase. \lhlch 11 Irre'crSlbl) mhlbllS. Omeprazole
`binds to hepatiC cytochrome P450 and mhlblts o.\ldaIlH metabolism of some drugs. the
`mosl important helllg phen)lOlll.
`Omcprazote has produced short tefm healing rates superior to the hlstammc ti ~·
`reccptor antagolllsts 10 duodenal ulcer. gastric ulcer and rcnu ~ ocsophag1\ls. It has also
`been shov.·n t o be hlghl) elTectlve III heali ng ulcers v.hlch ha,-c failed to respond 10 ti 1-
`receplOr antagonists. and has l)l"Cn e.,tremcl) \'aluable In treallng pallenlS v. IIh Zolllngcr(cid:173)
`Etlison s)ndromc.
`
`I. C hemistlJ' and Pharmacology of
`Omepra;-.ole
`1.1 Chemistr)
`
`The molecular structure of omcprazok is com(cid:173)
`posed of a substituted p)ridine ring li nked 10 a
`benzimidazole by a sulfoxide chain (fig. I). I t s mo(cid:173)
`lecular weight is 345 daltons. Omeprazok is a lipo(cid:173)
`philic weak base, and will thcrefore prcferentiall}
`accumulatc in an acidic environment such as the
`secretory me mbrane of the parietal cell.
`
`1.2 Mode of Action
`
`Omeprazole is avidly taken up by thc parietal
`cell. In an addic pH it becomcs converted to its
`activc form, a sulphenamlde. b) protonation. In
`
`Fig. 1. Chcmlcal structure of omrpralO!c
`
`this form, the drug produces an irreversible linkage
`via a disulfide bond with the e nzyme H'. K'(cid:173)
`AT Pa~ or 'proton pump' (fig. 2) which is rcspon(cid:173)
`sible for the active ~cre t ion of h ydrogen i o ns by
`the parietal cells (Sachs & wall mark 1989: Wall(cid:173)
`mark 1989) .
`This action makes omcprazok unique a mong
`cxisting gastric an tlsccretory drugs which arc com(cid:173)
`petith'e antagonists at specific cellular receplOrs on
`the basolateral aspect of the parieta l cell. Th rough
`its irreversible inhi bition of H+. K·-ATPase. orne(cid:173)
`prazok blocks gastric acid secretion in response to
`all known stim uli incl uding a~en t s such a s dibu tryl
`cyclic adenosine monophosphate (d\)<A MP). which
`acts intracellularly (Wolfc & Soli 1988).
`Omeprazole 15 degradcd by acid. and so must
`be protected from gastric acid whcn given orall y:
`this is achieved b) the use of encapsu lated enteric(cid:173)
`coatcd granu les.
`
`], Pharmacod),namics ill Humans
`2.1 Effect on Basal Acid Output
`
`Following oral admi nistration of o meprazole in
`ils enca psu lated enteric<oated gra nule fo rm ula(cid:173)
`tion. its maxi mal effect on gastric acid secretion is
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 2
`
`

`

`40
`
`Clln. l'hurmU('QIi.III(,I. 10 (I) NYO
`
`similar group of6 subjects given omeprazolc 60mg
`daily, inhibition of basal acid output was 91.7%
`after the first dose and 99. [% after the seventh.
`In a separate study, the effects of7 days' admin(cid:173)
`istration of omeprazole IOmg daily were assessed
`(Howden et a1. 1985a). A single dose of IOmg did
`nOI significantly affect basal acid output. but after
`7 days of dosing mean basal acid output was reo
`duced by 93%. However. there was a high degree
`ofinterindividual variabili ty in response to this low
`dose.
`These studies show a dose-dependent effect of
`omeprazole on inhibition of basal acid output. They
`also show variability in response to low dose orne·
`prazole, and increased anti secretory effect with re(cid:173)
`peated dosing.
`
`2.2 Effect on Pentagastrin-Stimulated
`Acid Output
`
`Intravenous infusion of pentagastrin 1.2 ~g/kg
`for I hour increased gastric acid secretion in a group
`of 6 healthy male subjects fro m a mean ( ± SO)
`basal value o f 4.3 ± 3.4 mmol/ h to a plateau value
`of 35.4 ± 5.4 mmol/ h (Howden et al. 1984a).
`Omeprazole 30mg reduced the pentagastrin-stim(cid:173)
`ulated plateau acid outpu t t o 10.2 ± 10.1 mmol/
`h (-71.2%~ P < 0.05). After 7 days of dosing with
`omeprazole 30mg daily, this was further reduced
`to 0.6 ± 1.0 mmol/ h (-98 .4%~ p < 0.01).
`In subjects given omeprazole 60mg daily. pre(cid:173)
`treatment plateau acid output was 37.1 ± 10.6
`mmol/ h. After I dose this was reduced to L7 ±
`2.3 mmol/ h (-95.3%; p < 0.01); after the seventh
`dose, it was 0.4 ± 0.2 mmol/ h (-99%; p < 0.01).
`In subjects given omeprazole 10mg daily (Howden
`et al. 1985a). pretreatment plateau acid output was
`23.3 ± 8.2 mmol/h. Six hours after a single dose
`of 10mg, the figure was 23. 1 ± 8.6 mmol/h (not
`significant) but at a sim ilar time after the seventh
`daily dose it was 7.8 ± 6.7 mmol/ h (-66.5%; p <
`0.01). Again. there was a high degree ofi nterindiv(cid:173)
`idual variability in response to the low dose.
`In a group of patients with healed duodenal
`ulcer, pentagastrin-stimulated acid output after 7
`days of dosing with placeoo or omeprazole 5 or
`
`o
`
`Active intllbitor
`
`o
`
`Enzyme-SH
`
`Enzyme-inhib4tor comple~
`
`Fig. 2. Diagram of lilt InlNl'Iclion of lh~ aC1lv31Cd form of
`o mc pr.lzolc wilh gastTiC H·. K '-A TPasc:.
`
`achieved aftcr about 6 hours: in a group of6 healthy
`male subjects given omeprazole 30mg, basal acid
`output measured 6 hours later was reduced by 66%
`(Howden et a1. 1 984a). After I week of daily
`administration of the same dose, the inhibition of
`basal acid output had risen to almost 100%. In a
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 3
`
`

`

`('lIn1(al Pharmacology of Omcpra:wlc
`
`41
`
`10mg daily was measured 14 hours after the final
`dose (Howden et aL 1986a), Toml out put was 42.9
`± 4.9 mmol fo llowing placebo. and 34.5 ± 9.8 and
`32.3 ± 8.7 followi ng omeprazole 5 and IOmg, re(cid:173)
`spectivel), Neither of the reductions in output pro(cid:173)
`duced by these low doses of omeprazole was sig(cid:173)
`nificanl.
`
`same study. indicating some degree of interi ndiv(cid:173)
`idual vanabili ly in response to th is dose.
`Finally, a dosage regimen of omeprazole 5 o r
`10mg daily for 7 days did nOt have any significan t
`effect on 24-hour intragastric acid ity in a gro up o f
`6 patIen ts with healed duodenal ulcer (Howden et
`at. 1 986a).
`
`2.3 Effect on Insulin-Stimulated Acid Output
`
`1.5 Effect on Plasma Gastrin Levels
`
`Omeprazole 30mg as a single oral dose reduced
`the stimulated acid output induced by an inlTa(cid:173)
`venous infusion of insulin 0.03 U!kglh (Utley et
`a1. 1985) from 16.8 ± 2.2 to 4.3 ± 1.8 mmol!h
`(-74%: p < 0,05). A sim ilar group of subjects re(cid:173)
`ceived a single dose of omeprazole 60mg. and in
`this group the insulin-stimulated acid output was
`reduced from 12.3 ± 2.6 to 3.4 ± 2.1 mmol!h
`(-73%: p < 0.05).
`
`2.4 Effect on 24- Hour Intragastnc Acidity
`
`In a group of9 patients with duodenal ulcer in
`clinical remission. a regimen of omeprazole 30mg
`dall) for I week nrtually el iminated intragastric
`acidit). with mean hourly hydrogen ion activity
`falling from 38.5 to 1.95 mmol/ L (Walt et a1. 1983).
`The median tntragastric pH rose from 1.4 to 5.3.
`representing a much greater increase than that
`achieved b) conventional doses of existing hist(cid:173)
`amine H1-receptor antagonists.
`In another s t ud~. 12 duodenal ulcer patients re·
`cei\ed omeprazole 20mg daily for 28 days (Lan·
`zon-Miller et a1. 1987). AI the end of that lime.
`median tntegrated 24-hour tntragastric aCidity had
`fallen from 1148 to 36 mmol/ L ' h (-97%), The
`same pallen ts also receiv("d a separa te course of
`\T("alment .... ith ranitidin(" 150mg twice daily: Ihe
`m("dlan tn tegrated 24-hour tntragastric acidity with
`that treatm("nt was 490 mmol! L ' h (-57% com(cid:173)
`pared wllh pretreatment values).
`Omcprazole 20mg dai ly for 8 days reduced in(cid:173)
`tragastric acid It) by around 99% in 6 patients wi th
`healed duodenal ulcer (Naesdal et a1. 1987) but had
`a much smaller effect on another 4 patients in the
`
`Plasma conce ntrations of a wide variety of gas(cid:173)
`trointestinal pcptides were measured in 6 healthy
`subjects 6 hours after a single oral dose of ome(cid:173)
`prazo1c 40mg (Allen et al. 1984). The basal level
`of gastrin was significan tly (p < 0.05) increased
`fro m 13 ± 6.8 to 28.2 ± 8.3 pmol/ L The inte(cid:173)
`grated gastri n response to a meal was also in(cid:173)
`creased. but failed to reach statistical significance.
`No significa nt changes were found in the concen(cid:173)
`lTations of any of the olher peptides measured.
`In a group of 12 healt hy volunteers given ome(cid:173)
`prazole 4001g daily fo r 9 days by Festen et a l.
`(1986). fast ing serum gastrin levels increased from
`36 ± 3 to 49 ± 6 nglL (p < 0.0 1) after the firs t
`dose and to 59 ± 6 nglL after the nint h (p < 0.002).
`A nonsignificant increase in serum gastrin lev(cid:173)
`els was found in I study of 10 duodenal ulcer
`patients given omeprazo1c 20mg daily for 8 days
`(Naesdal et a1. 1987). Omeprazole 5 or 10mg dai ly
`for 7 days also produced no alteration in fasti ng
`gastrin levels in a group of6 duodenal ulcer patients
`(Howden et al. I 986a). However. the median in(cid:173)
`tegrated gastrin response to a meal was signifi(cid:173)
`cantl) increased from 29.210 67.0 pmol/ L· h (p <
`0.05) follo wing 7 days of omeprazoJc 10mg daily.
`The median integrated 24-hour plasma gastrin
`was SIgni fi cantly raIsed from 328 to 1519 pmoII
`L · h In a group of 12 duodenal ulcer patients given
`omeprazo1e 20mg daily for 28 days (Lanzon-Miller
`et al. 1987). The median integrated 2-hour plasma
`gastrin fo r the same group of pa tients given rani(cid:173)
`tidine I 50mg twice daily for 28 days was 799 pmoll
`L · h.
`Omeprazole produces a dose-dependent in(cid:173)
`crease in gastrin levels. The rise in integrated 24-
`hour gastrin is directly proportional to the reduc-
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 4
`
`

`

`42
`
`C/III. Pharmacolim('f. } O (I) 1990
`
`tion in integrated 24-hour intragastric acidity (Lan.
`zon-Miller & Pounder, personal communication).
`
`2.6 Effect on Pepsin Secretion
`
`Although omeprazole has a dramatic effect on
`secretion of gastric acid, it does not significantly
`affect that of pepsin. Such a finding is consistent
`with the specifi c action of the drug on parietal cells
`without an effect on the function of the pepsi n(cid:173)
`secreting chief cells.
`Thompson ct al. ( 1985) found no significant al(cid:173)
`teration in pepsin output after 4 weeks of omepra(cid:173)
`zoIc 20 or 40mg daily in 9 patients with duodenal
`ulcer disease. Omeprazo]e IOms daily for 7 days
`did not affect basal or pentagastrin-stimulated pep(cid:173)
`sin in 6 healthy volunteers (Howden et al. 1985a),
`and a higher dosage of 30 or 60mg daily for 7 days
`did not affect basal pepsin secretion in heallhy
`volunteers (Howden et a\. 1 984a). Similarly, 12
`healthy subjects given omeprazole 40mg daily for
`9 days did not display any alteration in pentagas(cid:173)
`trin-stimulated pepsin o utput (Festen et al. 1986).
`
`2.7 Effect on Intragastric Bacteria a nd
`Bacterial Products
`
`Ten healthy male subjects were given omepra(cid:173)
`zole 30mg daily for 2 weeks in the study of Sharma
`et a\. (1984). Gastric ju ice sampled 22 hours after
`the final dose of omeprazoie showed a significant
`(p < 0.01) rise in the concentrations of bacteria,
`nitrite a nd N-nitrosam ines and a nonsignificant re(cid:173)
`duction in nitrate levels. The profound inhibition
`of gastric acidity had allowed proliferation of in(cid:173)
`tragastric bacteria wit h consequent reduction of
`dietary nitrate to ni trite and the production of N(cid:173)
`nitrosamines. All these changes had resolved within
`3 days of stopping omeprazole.
`
`2.8 Effects on Endocrine Function
`
`The effects of high dose endocrine function have
`been st udied in healthy male subjects (Howden et
`al. 1986b; MacGilchrist et al. 1987). Omeprazole
`60mg daily for 8 days had no effect on t he basal
`
`levels of thyroid-stimulating hormone (TSH). fol(cid:173)
`licle-stimulating hormone (FSH). luteinising hor(cid:173)
`mone (LH), prolactin (PRL), thyroxine (T 4), tri(cid:173)
`iodothyronine (T), conisol or testosterone. In
`addition, the responses ofTSH and PRL to stimu(cid:173)
`lation with thyrotrophin-releasing hormone and the
`responses of FSH and LH to stimulation with lu(cid:173)
`tcinising hormone-releasing hormone were unaf(cid:173)
`fected by omeprazole.
`An in itial finding ofa reduction in the peak cor(cid:173)
`tisollevel in response to stimulation with synthetic
`corticotrophin (ACTH) in a g roup of healthy male
`subjects receiving omeprazole 60mgdaily for 8 days
`(Howden et al. 1986c) was not subsequently con(cid:173)
`firmed (MacGilchrist et al. 1987). However, in vi(cid:173)
`/fO studies using isolated bovine adrenocortical celts
`showed that incubation wi th omeprazole produces
`a marked dose-dependent inhibition of stimulated
`cortisol release (Howden et al. I 986c). This is un(cid:173)
`likely to have any sign ificance for the use of orne·
`prazole in humans, since extremely high concen·
`trations of omeprazole were necessary to produce
`the effect.
`
`2.9 Effects on Renal Tubular Function
`
`Omeprazole 60mg administered daily for 7 days
`did not affect 2~hou r urinary electrolyte excretion
`or urinary acidification in response to oral am·
`monium chloride in a g roup of8 healthy male sub(cid:173)
`jects ( Howden & Reid 1984).
`
`3. Pharmacokinetics in Humans
`3.1 Absorption and Serum Concentrations
`
`Since omeprazole is acid·labile, it must be pro(cid:173)
`tected from the action of acidic gastric juice when
`given by mouth. In some studies, this was achieved
`by administering the drug with oral sodi um bi·
`carbonate (e.g. Cederberg et al. 1989). Absorption
`of omeprazole was rapid, with peak plasma con(cid:173)
`centrations being reached within O.5h.
`This d rug is usually administered as encapsu·
`lated enteric-(oated granules. The release from this
`formulation and subseq uen t absorption are erratic
`and do not follow classic pharmacokinetic prinei-
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 5
`
`

`

`Chnlcal Pharmacology of Omeprazole
`
`4J
`
`pies. Studies have shown marked interindividual
`vanability in both the rate and exten t of absorp(cid:173)
`tion,
`In most healthy male subjects given omeprazolc
`10. 30 or 60mg daily (Howden et a1. 1984b. I 985a).
`peak plasma omeprazole concentrations were
`achieved by 1.5 hours. although there was marked
`variation in individual peak concentrations. The
`ranges were 58 to 154,22310 1160 and 860 10 ]8]0
`.ugfL after single doses of 10. 30 and 60mg. re·
`spectively. The area under the plasma omeprazo[el
`time curve from administration until 8 hours after
`the dose (AUCW_SI) calculated by the li near trap.
`ezoidal rule also showed marked interindividual
`variation: the ranges after single oral doses of 10.
`]0 and 60mg were 156 10 428. ]]8 to 2270 and
`1380 to 5000 .ugfL· h. respectively.
`Arter 7 days of treatment with these doses ad.
`ministered daily. the AVCW_8) had increased from
`that of the first dose (Howden et a1. 1984b. 1985a):
`the mean increases were 45% after 10mg daily. 86%
`after ]Omg daily and 128% after 60mg dai ly. This
`implies a degree of nonlinearity which has alro ocen
`noted by others. In a group of healthy volunteers
`given omeprazole either 10. 20 or 40mg daily for
`5 days. the increases in AUC from days I to 5 av(cid:173)
`eraged 21. 69 and 182%. respectively (Andersson
`et a1. 1989).
`The most likely explanation fo r the observed rise
`in AUC is that omeprazole absorption increases
`With repeated dosmg due 10 a progressive suppres(cid:173)
`sion of acid secretion. Less omeprazole is degraded
`once acid secretion is inhibited. leaving more
`available for absorption. The increase in AUC can(cid:173)
`not be explained b) decreased elimination. since
`the clearance of omeprazole docs not change with
`continuous treatment (Ching et al. 1990).
`The true bioa vailability of omeprazolc has been
`estimated at 35% after a single dose. increasing to
`approximately 60% following repeated daily doses
`(Cederberg et al. 1989). The time of ad ministration
`docs not matenally influence its absorption. In 8
`healthy male subjects given omeprazole 40mg daily
`for 5 days. the parameters of time to peak concen(cid:173)
`trallon. peak concentration and AVC were similar
`
`whether the doses had been taken at 0900 or 2100h
`each day (Prichard et a1. 1985).
`
`].2 Distribution
`
`Omcprazole is. initially. rapidly distributed to
`extravascular sites. The mean volume of distribu(cid:173)
`tion in 8 healthy volunteers given 20mg ora lly was
`reported by Regardh et a1. ( 1985) to be 0.31 L/ kg.
`with a range of 0.19 to 0.45 L/ kg. This would be
`compatible with localisation of the major fraction
`of omeprazolc within extracell ular water. Pene(cid:173)
`tration of the drug into red blood cells is low. the
`ratio between whole blood concen trations and those
`in plasma being in the region of 0.6. Omeprazole
`is more than 95% bound to plasma proteins in hu(cid:173)
`mans. principally albumin and itt-acid glycopro(cid:173)
`tein (RegArdh el al. 1985). [t subsequently becomes
`preferentially concent raled within parietal cells.
`
`].] Metabolism and Elimination
`
`Omepra70le is almost entirely cleared by me(cid:173)
`tabolism. so that vinually no unchanged drug is
`excret('(! (Clissold & Campol i-R ichards 1986), After
`oral or In travenous administration of [14C]_ome_
`prazok. more than 80% of the radioactivity was
`recovered in the urine. with most of the remainder
`in the faeces. No unchanged drug was found in
`either urine or faeces (Cederberg el al. 1989:
`Regardh 1986). The main metabolites in humans
`are the sulfone and hydroxy-omeprazole (fig. ]).
`The sulfone metabolite docs not possess any anti(cid:173)
`secretor) activity. whilc hydroxy-omeprazole is only
`weakly antisecretory (Cederberg et al. 1989).
`Arter low dose omeprazole labelled with t4c was
`given intravenously to volunteers. 16% was re(cid:173)
`covered in the bile within the first 4 hours (Lind
`et al. [987). Negligible amounts of drug were re(cid:173)
`covered from gastric juice over this time. indicat(cid:173)
`ing that bi liary excretion is the only imponant gas(cid:173)
`trointestinal route of elimination.
`Elimination half·life after oral omeprazole has
`been estimated al about 1 h (Cederberg et al. 1989:
`RegArdh ct a1. 1985). Omeprazole is almost entirely
`cleared from plasma at 4 hours after oral admin-
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 6
`
`

`

`44
`
`Om. Pharmarolwll't 10 (I) 1990
`
`Omeprnole .c:id Hydroxy(cid:173)
`omeprnoie
`-CH~H_
`
`-COOH _
`
`Fig. 3. Mc\abohsm or omcprazolc.
`
`H
`
`o
`II -5 - Omeprllole
`II o
`
`SUIlOM
`
`istmtion (Cederberg et al. 1989), The anti secretory
`effe(;t of the drug, however, lasts much l onger.
`Omeprazole becomes selectively concentrated in
`parietal cells (Cederberg et aJ. 1989; Wallmark 1989)
`where it acts as a noncompetitive inhibitor of
`H +,K+·ATPase. Suppression of acid secretion
`is not correlated with plasma o meprazole concen(cid:173)
`tratio ns, but there is an association between orne(cid:173)
`prazole A UC and anlisecretory effect (Cederberg c.
`al . 1989; Lind el 31. 1983).
`
`3.4 Influence of Disease States on the
`Pharmacokinetics of Omeprazole
`
`3.4./ Chronic Renal Failure
`The antisecretory effect o f omeprazole is main(cid:173)
`tained in patients with chronic renal failure under(cid:173)
`going regular haemodialysis (Howden e1 at I 985b).
`In 6 s uch patients given omeprazole 30mg by
`mouth, time to peak plasma concentration , peak
`plasma concentration and AUe did not differ be·
`tween nondialysis and dial ysis days. The drug was
`not detected in dialysis fluid . There was marked
`interindividual variability in these pharmacokin·
`etic parameters. The range in AUe (138 to 3248
`.IIg,lL· h) on the nondialysis day did not differ sig(cid:173)
`nificantly from that in 6 healthy male subjects given
`a single o ral dose of 30mg (338 to 2270 .IIg,lL· h:
`Howden et al. I 9 84b).
`In the study by Naesdal et at ( 1986), 12 patien ts
`with established chronic renal failure (creatinine
`
`to 62 ml/ m in) were given (14C)_
`clearance II
`labelled omeprazole 20mg intravenously and 40mg
`orally in random order. The pharmacokinetics of
`orneprazole in these patienls did not differ signifi(cid:173)
`cantly from values previously found in healthy
`subjetts. Mean elimination half-life was 0.6h, and
`mean systemic bioavai lability was 70%.
`
`3.4.2 Chronic Lil'er Disease
`The oral and intra venous pharmacokinetics of
`omeprazole were st udied in 10 patients with ci r(cid:173)
`rhosis (McKee et al. 1988). Patients received orne(cid:173)
`prazole 10mg intravenously, and a 7-day course of
`IOmg orally. Acid secretion was low in these
`patients but omeprazole was still able to signifi(cid:173)
`cantly reduce pentagastrin-stimulated acid output.
`The range of AUC(0-8) after the seventh oral dose
`was 3.97 to 10.61 .IImol/ L·h, again indicating a
`high degree of intersubject variability. The AUCs
`were higher than those recorded in a group of
`healthy male subjects given omeprazole I Omg orally
`for 7 days (Howden et al. I 985a). The mean elim(cid:173)
`ination half-life was 2.85h, which was higher than
`that reponed for health y subjects. There was no
`evidence ofattu mulation of omeprazole in the ci r(cid:173)
`rhotic patients since no o meprazole was detectable
`in plasma at the stan of the study on the sevenlh
`day of dosing. On the basis of these findings. spe(cid:173)
`cific dosage reduction is not necessary in patients
`with chronic liver disease. Doses of more than 20mg
`will not be needed in such patients.
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 7
`
`

`

`Clinical I'harmacolog~ ofOmcprazoi<"
`
`45
`
`Other re~archer5 have reported mean val ues for
`elimination half-life of 2.68h (Cederberg et al. 1989)
`and 2.85h (Rondanelli et al. 1989) in cirrhotic
`patients.
`
`4. Drug Interactions
`
`Omeprazole can bind to hepatic cytochrome
`P450 and inhibi t the oxidative metabolism ofcer(cid:173)
`tain drugs. This section reviews drug..<frug inter(cid:173)
`actions reported in the literature.
`
`4.1 Diazepam
`
`Diazepam was the first drug reported to interact
`with omeprazole: Gugler and Jensen (1984) gave 8
`healthy male subjects intravenous diazepam 0.1 mg
`per kilogram of bodyweighl before and after a 9·
`day course of omeprazole 40mg daily. Following
`omeprazolc. the mean elimination half·life of di(cid:173)
`azepam was In(Tea~d from 36.9 to 85.0h (p < 0.01)
`and Ihe total body clearance was reduced from 1.34
`100.61 L/ h/ kg (p < 0.01).
`
`4.2 Aminophenazone (Aminopyrine) and
`Phenazone (Antipyrine)
`
`Elimination of the 2 model drugs aminophen.
`azone and phenazone was measured in a group of
`healthy male subjects given omeprazole 30 or 60mg
`daily for 2 weeks b~ Henry et oIl. (1984). The values
`for both drugs were not significantly altered in su))..
`jects receiving the lower do~. However. in 10 su))..
`jects given omeprazole 60mg daily. the half-life of
`aminophenazone was prolonged by 21% (p < 0.05)
`and that of phenazone by 10% (p < 0.025).
`
`4.3 Phen ytoin
`
`In 8 health y male subjects. the pharmacokin(cid:173)
`etics of phenytoin were studied before and after
`administration of omeprazole 40mg daily for 8 days
`(Gugler & Jensen 1985). The subjects were given
`phenytoin 250mg by intravenous infusion on each
`occasion. Phenytoin clearance was reduced from
`0.025 to 0.021 L/ h/ kg after omeprazole (p < 0.05).
`
`and mean elimination half-life was increased from
`20.710 26.3 h (p < 0.01). The volume ofdistribu(cid:173)
`tion and protein binding of phenytoin were unaf(cid:173)
`fected.
`In a separate study (Prichard et al. 1987), 10
`healthy male subjects received. in random order.
`placebo or omeprazole 40mg daily for 9 days.
`Phenytoin 300mg was given ora lly on the seventh
`day of each treatmen\. Phenytoin AUC(O-72) was
`significantly increased by omeprazole from 121.6
`to 151.4 mg/L ' h (p < 0.01). a finding which is of
`potential clinical importance in view of the narrow
`therapeutic index of phenytoin. There were non(cid:173)
`significant increases in the peak plasma phenytoin
`concentrations and in the apparent elimination half(cid:173)
`life.
`
`4.4 Propranolol
`
`Omeprazole 20mg daily fo r 8 days did not alter
`the pharmacokinetics of propranolol in a group of
`8 healthy subjects taking propranolol 80mg twice
`daily (Henry et al. 1987).
`
`4.5 Warfarin
`
`A group of 21 healthy male subjects received
`warfarin for 7 weeks in doses adjusted to reduce
`vi tamin K-dependent clotting factors to 10 to 20%
`of normal (Sutfin et al. 1989). For 2 weeks. Ihey
`were also given omeprazole 20mg daily. Omepra(cid:173)
`zole did nOI affect plasma concentrations of the
`S-enantiomer of warfarin but caused a 12% in(cid:173)
`crease in those of the R-enantiomer. Thrombotest
`values were sl ightly reduced during the concomi(cid:173)
`tant admin istration. from a mean of21.1% to 18.7%
`(p :: 0.04). No adjustment in warfarin dosage was
`required. It appears that omeprazole inhibits the
`hepatic metabolism of the pharmacologically less
`active R-enantiomer of warfarin , but (he effect was
`not great and is unlikely to be of major impon(cid:173)
`ance. Nevertheless, funher studies are indicated.
`
`4.6 Amoxycillin and Baca mpicillin
`
`The phannacokine(ics of oral amoxycillin 500mg
`and bacampicillin 800mg were studied in 8 healthy
`volunteers before and after I week of omeprazolc
`
`MYLAN PHARMS. INC. EXHIBIT 1027 PAGE 8
`
`

`

`46
`
`efm. Pharma('okmel. ;0 (JJ 1990
`
`lOmg daily (Paulsen el al. 1989). Although there
`was a slight delay in bacampicillin absorption. no
`significant effect was found on the AUe or elim(cid:173)
`ination half·life of either amoxycillin or bacampi(cid:173)
`cillin.
`
`4.7 Nifcdipine
`
`In 10 healthy male volunteers, omcprazolc 20mg
`administered daily for 7 days significantly (p < 0.02)
`reduced the clearance ofnifedipine from 7S to 59.4
`L/ h (Danhofct 31. 1989). Conversely, the clearance
`of omeprazole 40mg given intravenously was sig(cid:173)
`nificantly reduced (p < 0.03) from 28.8 to 24.9 L/
`h in the same subjects when they had been pre(cid:173)
`treated with niredipine IOmg 3 times daily for 5
`days.
`
`4.8 Antacids and Meloclopramide
`
`Concomitant administration of antacids does
`nOI affect the absorption of omeprazole (Howden
`& Reid 1988; Tuynman et at 1987). Similarly, there
`is no evidence for any interaction between orne·
`prazole and metoclopramide (Howden & Reid
`1988).
`
`S. Therapeutic UJeJ of Omeprazole
`5. 1 Duodenal Ulcer
`
`Duodenal ulcer healing rates for antise<:retory
`drugs arc directl y related to their degree of suppres(cid:173)
`sion of 24-hou r in tragastric acidity (Jones et al.
`1987). It is therefore not surprising that omepra(cid:173)
`zole has produced the highest recorded healing rates
`in duodenal ulceration. The fi rst dose-comparalive
`trial (Gustavsson et al. 1983) fou nd a healing rale
`of I()()% after 2 weeks of treatment with omepra(cid:173)
`zole 60mg daily in 16 patients. A similar group of
`16 pat ien ts was given omeprazole 20mg dai ly; after
`4 weeks, the healing rate was 93%.
`Omeprazole has been shown 10 be superior to
`conventional doses of ranitidine in healing duo(cid:173)
`denal ulcers (Bardhan et al. 1986; Classen et al.
`1985). However, a more reeent multicentre clinical
`trial from Canada fa iled to demonstrate a statis-.
`
`tically significant difference in healing rates be(cid:173)
`tween omeprazole 20mg daily and cimetidine in
`the high dose of 600mg twice daily (Archambault
`et al. 1988).
`In an extensi ve meta.analysis of published
`clinical trials of antisecretory drugs in the treat(cid:173)
`ment of duodenal ulcer (Jones et al. 1987). overall
`heali ng rates after 4 weeks of treatment with ome(cid:173)
`prazolc 60, 40, 10 and 20mg were 100% (n ::r:: 27).
`98.4% (n = 126), 92.8% (n '" 154) and 95.5%
`(n '" 177). respectively.
`
`5.2 Gastric Ulcer
`
`Omeprazole has been shown to be highly effec(cid:173)
`tive in healing benign gastric ulcers. In a detailed
`meta-analysis of published controlled trials of anti·
`secretory drugs in gastric ulcer (Howden & Hun t
`1990). omeprazole was associated with the highest
`overall healing rates. In addition. a significant re(cid:173)
`lationship was demonstrated between gastric ulcer
`healing rates and percentage suppression of 24-hour
`intragastric acidi ty.
`Walan el al. (1989) reponed that in a large
`multicentre trial omeprazole 20 or 40mg once daily
`was superior to ranitidine 150mg twice daily in the
`treatment of ulcers of the body of the stomach or
`prepyloric ulcers. O meprazole 20mg daily for 4
`weeks healed 69% of gastric ulcers in 203 patients;
`a dosage of 40mg daily healed 80% of gastric ulcers
`in 194 patients at 4 weeks. In 205 patients given
`rani tidine 150mg twice daily, only 59% healed after
`the same period. Omeprazole was also shown to be
`highl y effective in healing gastric ulcers in