DRUG DISPOSITION
`
`Clin Phormacokinet2001; 40 (6): 411-426
`0312-5963/01/0006-0411/$22.00/0
`
`© Adis International Limited. All rights reserved.
`
`Pharmacokinetic Studies with
`Esomeprazole, the (S)-Isomer
`of Omeprazole
`
`Tommy Andersson, 1 Mohammed Hassan-Alin, 2 Goran Hasselgren, 2
`Kerstin Rohss2 and Lars Weidolf'
`1 Clinical Pharmacology, AstraZeneca LP, Wayne, Pennsylvania, USA
`2 Clinical Research, AstraZeneca Molndal, Molndal, Sweden
`3 Preclinical Research, AstraZeneca Molndal, Molndal, Sweden
`
`2.
`
`Contents
`. . . . . . . . . . . . . . . . . . . . .
`Abstract
`. . . . . . . . . . . . . . . . . .
`l. In Vitro Studies
`l. l Metabolism in Human Liver Microsomes .
`1.2 Plasma Protein Binding Studies
`. . . . . .
`In Vivo Studies
`. . . . . . . . . . . . . . . . . .
`2. l Pharmacokinetics of Esomeprazole in Young Healthy Volunteers
`2.1. l Studies on Potential for Inversion . . . . . . . . . . . . . . .
`2.1.2 Single and Repeated Administration of Esomeprazole, (R)-Omeprazole
`and Omeprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2. 1.3 Metabolic and Excretory Pattern After a Single Oral Dose
`. . . . . .
`2.1.4 Single and Repeated Administration of Intravenous and Oral Doses
`2. l .5 Single and Repeated Administration of Different Oral Doses
`2.2 Pharmacokinetics of Esomeprazole in Patients with
`. . . . . . . . .
`Symptomatic Gastro-Oesophageal Reflux Disease
`2.3 Pharmacokinetics of Esomeprazole in Special Populations . . . . .
`2.3. l Single and Repeated Oral Administration in Healthy Elderly Individuals .
`2.3.2 Repeated Oral Administration in Patients with Impaired Liver Function
`2.3.3 Single and Repeated Oral Administration, Pooled Data from Females
`Versus Males . . . . . . .
`3. Discussion and Clinical Relevance .
`4. Conclusions . . . . . . . . . . . . . .
`
`. 411
`413
`. 413
`. 415
`. 415
`415
`415
`
`415
`416
`417
`419
`
`420
`. 421
`. 421
`422
`
`423
`423
`. 425
`
`Abstract
`
`This article reviews the pharmacokinetics of esomeprazole, the (S)-isomer of
`the proton pump inhibitor (PPI) omeprazole. Esomeprazole is the first single
`isomer PPI developed for the treatment of patients with acid-related diseases.
`In vitro experiments in human liver microsomes demonstrated that the forma(cid:173)
`tion of the hydroxy and 5-0-desmethyl metabolites of esomeprazole is via cyto(cid:173)
`chrome P450 (CYP) 2Cl9, whereas that of the sulphone metabolite is via CYP3A4.
`The formation rate of the hydroxy metabolite from esomeprazole is lower than
`for (R)-omeprazole, but that of the 2 other metabolites is higher, demonstrating
`stereoselective metabolism. The sum of the intrinsic clearances of all 3 metabo-
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`412
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`Andersson et al.
`
`lites for esomeprazole was one-third of that for (R)-omeprazole, suggesting lower
`clearance of esomeprazole in vivo.
`In vivo investigations demonstrated that esomeprazole is chirally stable after
`administration. Esomeprazole is 97% bound to plasma proteins. In normal (ex(cid:173)
`tensive) metabolisers with regard to CYP2Cl9, esomeprazole is metabolised
`more slowly than omeprazole, resulting in a higher area under the concentration(cid:173)
`time curve (AUC) after administration of the same dose. This is more pronounced
`after repeated administration rather than after a single dose. In poor metabolisers,
`the AUC is lower for esomeprazole than for omeprazole, contributing to less
`overall interindividual variability for esomeprazole than for omeprazole.
`In general, esomeprazole and omeprazole are subject to the same metabolic
`transformations. Almost complete recoveries were reported and the ratio between
`urinary and faecal excretion is about 4 : I for both compounds. The dose-depend(cid:173)
`ent increase in AUC of esomeprazole with repeated administration results from
`a combination of decreased first-pass elimination and decreased systemic clear(cid:173)
`ance. Patients with gastro-oesophageal reflux disease exhibit a pharmacokinetic
`pattern similar to that in healthy individuals, whereas elderly individuals exhibited
`a slightly lower metabolism rate.
`Patients with a severe deficit in their liver function had a lower rate of meta(cid:173)
`bolism, as would be expected, whereas those with mild to moderate liver disease
`did not exhibit any alteration in the pharmacokinetics. The pharmacokinetics of
`esomeprazole in individuals with impaired renal function is unlikely to differ
`from that in healthy individuals. A slight sex difference in the pharmacokinetics
`of esomeprazole was demonstrated in that the AUC and peak plasma drug concen(cid:173)
`tration were slightly, but not statistically significantly, higher in females than in
`males.
`
`The proton pump (H+, K+-ATPase) inhibitor ome(cid:173)
`prazole is a racemic mixture of the 2 optical isomers
`(R)- and (S)-omeprazole (esomeprazole). Like the
`other proton pump inhibitors (PPis) lansoprazole,
`pantoprazole and rabeprazole, omeprazole is a sub(cid:173)
`strate for the polymorphically expressed cytochrome
`P450 (CYP) enzyme CYP2Cl9.[1,2l A small propor(cid:173)
`tion of the population (approximately 3% of Cauca(cid:173)
`sians and 15% of Asians) do not express a functional
`form of this particular enzyme and, hence, these
`individuals exhibit several-fold higher than average
`area under the plasma concentration-time curves
`(AUC) after the administration of these drugs.[31
`The metabolism of omeprazole is stereoselective,
`and the metabolism rate of the (S)-isomer is lower
`and less variable than that of the (R)-isomer, result(cid:173)
`ing in higher plasma concentrations of the (S)-isomer
`following administration of the same dose.[4,51 Im-
`
`portant in this context is that omeprazole and es(cid:173)
`omeprazole are protonated and converted in the acidic
`compartment of the parietal cell to form the active
`inhibitor, the achiral sulphenamide. This structure
`is identical for the 2 drugs and acts identically on
`the H+, K+-ATPase. This means that the AUC of the
`drug, irrespective of whether it originates from ad(cid:173)
`ministered omeprazole or esomeprazole, is correlated
`to the acid inhibitory effect. Hence, the pharmaco(cid:173)
`kinetic parameter that is best correlated to the acid
`suppressive effect, the AUC,[61 was almost 2-fold
`higher after esomeprazole than after an equivalent
`dose of omeprazole, resulting in a more pronounced
`acid suppressive effect for esomeprazole, with a
`longer time with pH> 4.[71 In addition, the time with
`intragastric pH > 4 was significantly longer for es(cid:173)
`omeprazo le 40mg than for 20mg.
`The time with pH > 4 is usually considered to be
`
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`Esomeprazole
`
`413
`
`correlated with clinical effect on gastric acid-re(cid:173)
`lated diseases, and is used as a surrogate end(cid:173)
`point in that respect. Thus, these results were the
`main reason for the decision to use esomeprazole
`40mg in the clinical programme. The advantageous
`pharmacokinetic profile of esomeprazole com(cid:173)
`pared with omeprazole has been shown to translate
`into superior efficacy in the clinical situation. In
`clinical studies, esomeprazole has been shown to
`be more effective than omeprazole in the treatment
`of gastro-oesophageal reflux disease (GORD) in
`patients with erosive oesophagitis, and, in addi(cid:173)
`tion, esomeprazole 40mg demonstrated better effi(cid:173)
`cacy than esomeprazole 20mg.l8l
`The pharmacokinetics of esomeprazole have
`been studied after single and repeated administra(cid:173)
`tion in healthy individuals as well as in patients
`with symptomatic GORD, and in special popula(cid:173)
`tions, such as patients with hepatic impairment,
`and elderly, but otherwise healthy, individuals. The
`potential influence of gender on the metabolism of
`esomeprazole has also been studied.
`
`1. In Vitro Studies
`
`The in vitro investigations explored the meta(cid:173)
`bolic routes and mapped which enzymes are re(cid:173)
`sponsible for the different transformations of the 2
`optical isomers of omeprazole. The plasma protein
`binding of the 2 optical isomers was also deter(cid:173)
`mined with in vitro experiments.
`
`l . l Metabolism in Human Liver Microsomes
`
`The metabolism of esomeprazole and (R)(cid:173)
`omeprazole were studied using in vitro test sys(cid:173)
`tems, including human liver microsomes and in
`vitro expressed human CYP isoforms.[4l The rate
`and extent of formation of the 3 major metabolites,
`the hydroxy, sulphone and 5-0-desmethyl meta(cid:173)
`bolites, were assessed in these systems.
`In the first set of experiments, liver tissue from
`3 separate livers was used to prepare human liver
`microsomes for determination of the maximum
`rate of metabolism (V max) and the Michaelis-Menton
`constant (Km), which inversely reflects the affinity
`
`of drug for enzyme. Intrinsic clearance (CLint) was
`calculated as the ratio between V max and Km.
`Stereoselectivity in the metabolism of the 2 optical
`isomers of omeprazole was clearly demonstrated
`in these experiments (fig. 1). For (R)-omeprazole
`the dominant metabolic step is the formation of
`hydroxy-omeprazole, whereas for esomeprazole
`the formation of each of the 3 metabolites seems to
`be equally important. Similar affinities of the 2 op(cid:173)
`tical isomers for the enzymes that are responsible
`for the formation of the 3 metabolites were ob(cid:173)
`served. The highest affinity seemed to be for the
`enzyme that mediates the formation of the hydroxy
`metabolite, and the lowest affinity for the enzyme
`that mediates the formation of the sulphone.
`
`e Sulphone
`•
`5-0-Desmethyl
`-"' Hydroxy
`
`a
`
`0.4
`
`0.3
`
`0.1
`
`0
`
`150
`100
`50
`Substrate concentration (µmol/L)
`
`200
`
`Fig. 1. Formation of the sulphone, hydroxy and 5-0-desmethyl
`metabolites from esomeprazole (a) and (R)-omeprazole (b) in hu(cid:173)
`man liver microsomes from one representative liver (HL 102)
`[this includes new data and data from Abela et al.[41].
`
`© Adis International Limited. All rights reserved
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`414
`
`Andersson et al.
`
`CL;n1
`
`Metabolites
`
`CL;n1
`
`
`
`Esomeprazole ~ Hydroxy ~R-isomer
`
`5-0-Desmethyl ~--:1 _3_A_4_
`4 0.8
`.
`
`--3A-4~l _ _ _
`3.9 •
`
`~
`
`Sul phone
`
`Total CL;n1 = 14.6
`
`Total CL;n1 = 42.6
`
`Fig. 2. Metabolism scheme illustrating the intrinsic clearance values (CL;nt) for the different metabolic pathways of esomeprazole and
`(R)-omeprazole from in vitro experiments on human liver microsomes.[41 Values of CL;nt are expressed as µI/min per mg of protein.
`
`The CLint for the hydroxy metabolite formed
`from esomeprazole was 10 times lower than that
`from (R)-omeprazole, whereas for the sulphone
`and 5-0-desmethyl metabolites this value was
`higher. The relative proportion of the sums of the
`CLint values of all 3 metabolites was 1 : 3 for esome(cid:173)
`prazole versus (R)-omeprazole (fig. 2), suggesting
`that esomeprazole would be cleared more slowly
`than the other optical isomer in vivo.
`In the second set of experiments, a test kit of
`human liver microsomal samples from 10 different
`livers was used in correlation experiments. In these
`experiments, the rates of formation of the 3 differ(cid:173)
`ent metabolites of esomeprazole were tested for
`correlation with the formation rate of metabolites
`of drugs with a CYP isoform-specific metabolism.
`Using this method, it is possible to map the meta(cid:173)
`bolic routes of esomeprazole to specific CYP en(cid:173)
`zymes. The results indicated that the hydroxy as well
`as the 5-0-desmethyl metabolites of both optical
`isomers are formed mainly by CYP2Cl9. The sul(cid:173)
`phoxidation is catalysed by CYP3A4.
`Lastly, in the third set of experiments, microsomes
`from a human lymphoblastoid cell line expressing
`CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9-
`Arg, CYP2C 19, CYP2D6-Val, CYP2El and CYP3A4
`were used to determine the kinetic parameters of
`esomeprazole and (R)-omeprazole. Each set of micro(cid:173)
`somes contains only 1 specific CYP enzyme. The
`results of the experiments with cDNA-expressed
`enzymes indicated that the hydroxy as well as the
`5-0-desmethyl metabolites of both optical isomers
`
`are formed mainly by CYP2C 19 (Km approximately
`5 µmol/L), whereas the sulphoxidation is catalysed
`by CYP3A4 (Km approximately 80 µmol/L). These
`results are in agreement with the results of the cor(cid:173)
`relation experiments described above.
`It is obvious that the rate at which CYP2Cl9
`forms the hydroxy metabolite from esomeprazole
`is lower than that from (R)-omeprazole, while the
`rate by which this enzyme forms the 5-0-
`desmethyl metabolite from esomeprazole is higher.
`It was also shown that the rate at which CYP3A4
`forms the sulphone metabolite was higher for esome(cid:173)
`prazo le than for (R)-omeprazole. This is in agree(cid:173)
`ment with the results obtained in the human liver
`microsomal experiments with the 3 liver samples.
`In conclusion, in vitro data show that the forma(cid:173)
`tion of the hydroxy, sulphone and 5-0-desmethyl
`metabolites of esomeprazole, the 3 major metabo(cid:173)
`lites formed, is mediated via CYP2Cl9, CYP3A4
`and CYP2Cl9, respectively, for both optical iso(cid:173)
`mers. The affinity for CYP2Cl9 is approximately
`10-fold higher than that for CYP3A4. However, the
`rate at which the hydroxy metabolite is formed
`from esomeprazole is lower, and the rate at which
`the sulphone and 5-0-desmethyl metabolites are
`formed is higher, compared with (R)-omeprazole,
`clearly showing the difference in metabolic profile
`between the 2 optical isomers. In addition, the sum
`of the CLint values of all 3 metabolites for esome(cid:173)
`prazole was one-third of that for (R)-omeprazole,
`predicting that esomeprazole would be cleared
`more slowly than (R)-omeprazole in vivo and, thus,
`
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`Esomeprazole
`
`415
`
`plasma concentrations would be higher for esome(cid:173)
`prazole than for omeprazole.
`
`l .2 Plasma Protein Binding Studies
`
`Plasma from 6 healthy volunteers (3 men and 3
`women) was used for individual determinations of
`the plasma protein binding of esomeprazole, (R)(cid:173)
`omeprazole and omeprazole, by an ultrafiltration
`method.l9l The 2 concentrations at which the bind(cid:173)
`ing was determined were selected to cover the
`anticipated therapeutic plasma concentrations in
`humans (2 to 20 µmol/L). Free compound was
`separated from protein-bound compound, and con(cid:173)
`centrations were determined by liquid chromato(cid:173)
`graphy. The results showed that the protein binding
`of esomeprazole, (R)-omeprazole and omeprazole
`are the same (97% ), and are independent of sex and
`concentration in the range studied.
`
`2. In Vivo Studies
`
`2.1 Pharmacokinetics of Esomeprazole in
`Young Healthy Volunteers
`
`The potential for chiral inversion of esomepra(cid:173)
`zole was investigated in vivo (section 2.1.1 ). One
`study compared the pharmacokinetics of esome(cid:173)
`prazole, (R)-omeprazole and omeprazole (see sec(cid:173)
`tion 2.1.2). In another study, the metabolic and ex(cid:173)
`cretory pattern of an oral dose of esomeprazole was
`compared with that of omeprazole (see section
`2.1.3). Complete pharmacokinetic investigations
`with both intravenous and oral administration have
`been performed at 2 dose levels, 20mg and 40mg
`(see section 2.1.4). Finally, the dose dependency in
`pharmacokinetics was demonstrated in one study
`using 3 different oral doses of esomeprazo le ( 5, 10
`and 20mg) and is presented in section 2.1.5.
`
`2. 1. 1 Studies on Potential for Inversion
`Eight healthy males received a single dose of
`esomeprazole 40mg as a capsule to determine if
`administered esomeprazole is chirally stable in
`humansV 0l Plasma samples were taken up to 8
`hours after administration for stereoselective de(cid:173)
`termination of esomeprazole and (R)-omeprazole
`
`for the calculation of AUC. The plasma profiles are
`shown in fig. 3. The geometric means with 95%
`confidence intervals for the AUC of (R)-omeprazole
`and esomeprazole were 0.018 (0.004 to 0.086)
`µmol · h/L and 4.844 (2.670 to 8.790) µmol · h/L.
`Thus, the degree of inversion based on the ratio of
`the AUC of (R)-omeprazole and esomeprazole was
`0.4%, demonstrating that esomeprazole is chirally
`stable.
`
`2. 1.2 Single and Repeated Administration of
`Esomeprazole, (R)-Omeprazole
`and Omeprazole
`The pharmacokinetics of esomeprazole, (R)-om(cid:173)
`eprazole and omeprazole were investigated in 9
`healthy males, 5 of whom were poor metabolisers
`(PMs), in a nonblind, randomised, 3-way crossover
`study consisting of 3 treatment periods.CSl In each
`treatment period either esomeprazole, (R)-omepra(cid:173)
`zole or omeprazole was given once daily over 7
`days. The PMs received doses of 60mg and extensive
`metabolisers (EMs) received doses of 15mg. The
`pharmacokinetics were studied on days 1 and 7.
`After repeated administration in EMs, the AUC
`of esomeprazole was 2-fold higher than that of
`omeprazole, and the AUC of (R)-omeprazole was
`half that of omeprazole (fig. 4 and table I). In the
`PMs, the pattern was reversed; the plasma concen(cid:173)
`trations of esomeprazole were lower than those of
`omeprazole, whereas the plasma concentrations of
`
`3.0
`~
`0 2.5
`E
`2:
`c 2.0
`0
`~ 1.5
`c
`Q) u
`c
`0 1.0
`u
`"' E
`en
`"' 0::
`
`0.5
`
`0
`
`0
`
`• Esomeprazole
`D
`(R)-lsomer
`
`2
`
`4
`Time after dose (h)
`
`6
`
`8
`
`Fig. 3. Mean plasma concentration versus time of esomeprazole
`and (R)-omeprazole following a single oral dose of esomeprazole
`40mg as a capsule to 8 healthy males.[1DJ
`
`© Adis International Limited. All rights reserved
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`416
`
`Andersson et al.
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`-" Esomeprazole
`•
`(R)-Omeprazole
`D Omeprazole
`
`a
`
`b
`
`~
`0
`E
`3
`c
`
`0 "" ~ c
`
`Q)
`u
`c
`1.6
`0 u
`"' 1.4
`E
`en
`"' 0:: 1.2
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`0
`
`2
`
`6
`8
`4
`Time after dose (h)
`
`10
`
`12
`
`Fig. 4. Mean plasma concentrations versus time of esomepra(cid:173)
`zole, (R)-omeprazole and omeprazole on day 7 of repeated
`administration of 60mg solutions to (a) 5 poor metabolise rs and
`15mg solutions to (b) 4 extensive metabolisers.[51
`
`(R)-omeprazole were higher, resulting in substan(cid:173)
`tially less overall variability for esomeprazole than
`for omeprazole. There was an increase in the
`AUC of esomeprazole and omeprazole, but not of
`(R)-omeprazole, in the EMs from day 1 to day 7.
`This increase was more pronounced with esome(cid:173)
`prazo le than with omeprazole (112 vs 52%). In
`PMs, no change in AUC was observed during re(cid:173)
`peated administration for any of the compounds.
`
`2. 1.3 Metabolic and Excretory Pattern After
`a Single Oral Dose
`Six healthy males, including 2 PMs, were given
`single 40mg doses of 14C-labelled esomeprazole
`
`and omeprazole, both in aqueous solutions, separated
`by a wash-out period of at least 2 weeks.[IIJ In this
`nonblind, randomised, crossover study the excretion
`in urine and faeces during a 48-hour period was
`assessed, and the pharmacokinetics and metabolic
`patterns of esomeprazole and omeprazole were
`evaluated.
`Both compounds were rapidly absorbed [peak
`plasma drug concentration (Cmax) < 0.5 hour, table
`II]. In EMs, the plasma concentrations of esome(cid:173)
`prazole were higher than those of omeprazole. The
`mean ratio of the AUC values was 1.6, and the
`mean ratio of the Cmax values was 1.2. The mean
`elimination half-life (ty2~) was 0.9 hours for esome(cid:173)
`prazole and 0. 7 hours for omeprazole. In the 2 PMs,
`the plasma concentrations of esomeprazole were
`lower than those of omeprazole (AUC ratio 0.8), but
`the Cmax was approximately the same. The mean t11i~
`was 1.9 hours for esomeprazole and 2.2 hours for
`omeprazole in the PMs.
`The mean recoveries in urine and faeces within
`48 hours after the administration of esomeprazole
`40mg in the EMs were 77.0% and 18.5% of the
`dose, respectively (fig. 5). In the PMs the corre(cid:173)
`sponding figures were 72.5% and 22.0%. For ome(cid:173)
`prazole, in the EMs, the urinary and faecal excre(cid:173)
`tions after 48 hours were 79.5% and 12.4% of the
`dose, respectively, and in the PMs the corresponding
`figures were 74.5% and 20.0%. Thus, oral doses of
`esomeprazole 40mg or omeprazole 40mg were al(cid:173)
`most completely excreted in urine and faeces with
`total recoveries of 92% to 96% within 48 hours of
`administration, and the ratio between urinary and
`faecal excretion was about 4 : 1 for both com(cid:173)
`pounds in both PMs and EMs.
`About 70 metabolites were identified in urine by
`mass spectrometric detection, whereas radiochem(cid:173)
`ical detection identified only 20 peaks. Of those, 9
`were considered major, each constituting >5% and
`together >59% of the radioactivity excreted within
`4 hours after the dose in both EMs and PMs. These
`metabolites, for example the hydroxy metabolite
`and its corresponding carboxy metabolite, were
`formed via different oxidative steps, followed by
`conjugation with glucuronic acid. Less than 1 % of
`
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`

`omeprazole
`
`(R)-omeprazole
`
`Day?
`esomeprazole
`
`omeprazole
`
`(R)-omeprazole
`
`Day 1
`esomeprazole
`Extensive metabolisers (n = 4)"
`Cmax (µmol/L)
`0.85 (0.20-1.80)
`tmax (h)b
`0.25 (0.17-0.33)
`AUC (µmol • h/L) 0.64 (0.15-1.25)
`0.70 (0.51-0.88)
`t11,~ (h)
`Poor metabolisers (n = 5)
`10.2 (9.5-11.4)
`11.0 (9.5-12.7)
`9.7 (7.8-12.7)
`12.0 (10.9-13.8)
`10.5 (7.5-15.4)
`Cmax (µmol/L)
`9.7 (7.6-12.3)
`tmax (h)b
`0.43 (0.25-0.75)
`0.33 (0.17-0.50)
`0.33 (0.17-0.50)
`0.28 (0.17-0.33)
`0.23 (0.17-0.33)
`0.35 (0.17-0.75)
`AUC (µmol • h/L) 22.6 (21 .5-24.5)
`38.1 (32.6-43.5)
`31.2 (27.3-37.5)
`21.7 (19.4-24.7)
`37.9 (31.6-43.2)
`30.1 (26.3-36.9)
`2.4 (2.2-2.8)
`2.3 (2.2-2.4)
`1.8 (1.7-1.8)
`2.5 (2.3-2.7)
`2.3 (2.2-2.6)
`1.8 (1.7-2.0)
`t11,~ (h)
`a Plasma concentrations of omeprazole in one volunteer were below the limit of quantification at all time-points on day 1 and thus data
`from this volunteer were not included in the calculations.
`b Arithmetic mean.
`AUC = area under the plasma concentration-time curve; Cmax = peak plasma drug concentration; tmax =time to reach peak concentration
`following drug administration; t11,~ =elimination half-life.
`
`Esomeprazole
`
`417
`
`Table I. Geometric mean pharmacokinetic parameter values (range) on days 1 and 7 ofonce daily administration of esomeprazole, omeprazole
`and (R)-omeprazole as solutions to poor (60mg) and extensive (15mg) metabolisers
`
`Parameter
`
`0.57 (0.24-0.94)
`0.28 (0.25-0.33)
`0.44 (0.18-0.78)
`0.53 (0.41-0.76)
`
`0.55 (0.28-0.83)
`0.29 (0.17-0.50)
`0.34 (0.14-0.51)
`0.44 (0.29-0.54)
`
`1.55 (0.89-2.57)
`0.27 (0.17-0.50)
`1.36 (0.60-2.32)
`0.70 (0.49-1.00)
`
`0.88 (0.41-1.43)
`0.29 (0.25-0.33)
`0.67 (0.25-1.21)
`0.60 (0.48-0.88)
`
`0.47 (0.22-0.84)
`0.25 (0.17-0.33)
`0.31 (0.14-0.47)
`0.42 (0.28-0.52)
`
`the parent compound was found in urine. Metabolic
`patterns in plasma were less complex, with only 4
`to 7 metabolites detected. The sulphone metabolite,
`which was not found in urine, was an important
`metabolite in plasma. Other major metabolites in
`plasma, for example, the 5-0-desmethyl metabo(cid:173)
`lite, were also found in significant amounts in
`urine. However, none of these metabolites have
`been found to be active.
`In conclusion, the main differences in pharmaco(cid:173)
`kinetics between esomeprazole 40mg and om(cid:173)
`eprazole 40mg are that the AU Cs for esomeprazole
`in EMs are 60% higher and those in PMs are 20%
`lower than for omeprazole. Thus, there is less dif(cid:173)
`ference in plasma concentrations between EMs and
`PMs for esomeprazole than for omeprazole. This
`demonstrates a lower influence of CYP2C 19 on
`the metabolism of esomeprazole as compared with
`omeprazole. Also, the data imply that there are no
`major differences in excretion routes and recover(cid:173)
`ies following oral administration of esomeprazole
`or omeprazole in humans.
`
`2. 1.4 Single and Repeated Administration
`of Intravenous and Oral Doses
`The pharmacokinetics of esomeprazole after
`oral and intravenous administration of single and
`
`repeated doses to healthy individuals were investi(cid:173)
`gated in 2 separate studiesV 2l In the first study, a
`solution of esomeprazole 20mg was administered
`both orally and intravenously to 16 males. In the
`second study a 40mg dose was administered both
`orally, as enteric coated granules in capsules, and
`intravenously to 8 males, 8 females not using oral
`contraceptives and 8 females using oral contracep(cid:173)
`tives. The 2 studies were performed as nonblind,
`
`Table II. Geometric mean pharmacokinetic parameter values (range)
`after a single oral dose of 40mg of 14C-labelled esomeprazole and
`omeprazole as solutions in extensive and poor metabolisers
`
`Omeprazole
`
`Parameter
`Esomeprazole
`Extensive metabolisers (n = 4)
`Cmax (µmol/L)
`5.39 (3.34-7.88)
`tmax (h)"
`0.29 (0.25-0.33)
`AUC (µmol • h/L)
`5.59 (3.74-9.60)
`t11,~ (h)
`0.86 (0.69-1.37)
`Poor metabolisers (n = 2)
`Cmax (µmol/L)
`7.83 (6.60-9.30)
`tmax (h)"
`0.29 (0.25-0.33)
`AUC (µmol • h/L)
`17.0 (16.8-17.3)
`t11,~ (h)
`1.87 (1.85-1.90)
`a Arithmetic mean.
`AUC =area under the plasma concentration-time curve; Cmax =peak
`plasma drug concentration; tmax =time to reach peak concentration
`following drug administration; t11,~ =elimination half-life.
`
`4.47 (1.88-8.67)
`0.25 (0.17-0.50)
`3.47 (1.74-6.16)
`0.67 (0.52-0.95)
`
`7 .49 (6.82-8.22)
`0.34 (0.17-0.50)
`20.7 (20.2-21.3)
`2.15 (1.99-2.34)
`
`© Adis International Limited. All rights reserved
`
`Clin Pharmacokinet 2001; 40 (6)
`
`MYL-EN000523835
`
`Page 7 of 16
`
`Patent Owner Ex. 2033
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`418
`
`Andersson et al.
`
`1:,, Urine EM
`
`0 Faeces EM
`
`D Total EM
`
`... Urine PM
`100 • Faeces PM
`• Total PM
`
`80
`
`s 60
`i::'
`Q) >
`0
`u
`Q)
`o:'.
`
`40
`
`crease was 159% from day 1 to day 5. Also, there
`was a near doubling of the Cmax· The absolute bio(cid:173)
`availability increased from 64 to 89% during re(cid:173)
`peated administration, which not only shows a
`higher bioavailability for the 40mg dose than for
`the 20mg dose but also indicates a more pronounced
`increase with repeated administration of the higher
`dose.
`Following intravenous administration the CL
`was 17.0 L/h after the first dose and 9.2 L/h after
`the second dose. This decrease in CL of 46% is to
`be compared with the 29% decrease in CL observed
`following the 20mg dose. These results indicate a
`
`a
`
`8
`
`7
`
`6
`
`5
`
`4
`
`1:,, 20mg (day 1)
`.._ 20mg (day 5)
`D 40mg (day 1)
`•
`40mg (day 5)
`
`3
`~ 2
`0
`E
`2:
`c
`0
`
`0
`
`~ c
`
`Q)
`u
`c
`0
`u
`8
`Cil
`E 7
`rn
`Cil
`0:: 6
`5
`
`b
`
`1:,, 20mg (1st dose)
`.._ 20mg (2nd dose)
`D 40mg (1st dose)
`•
`40mg (2nd dose)
`
`4
`
`3
`
`2
`
`0
`
`0
`
`2
`
`8
`6
`4
`Time after dose (h)
`
`10
`
`12
`
`Fig. 6. Mean plasma concentrations versus time after oral ad(cid:173)
`ministration of single and repeated 20mg (solution) and 40mg
`(capsules) doses of esomeprazole in 16 healthy males and 16
`healthy males and females, respectively (a) and mean plasma
`concentrations over time after first and second intravenous ad(cid:173)
`ministration of esomeprazole 20mg and 40mg in 16 healthy
`males and 16 healthy males and females (b), respectively (from
`Hassan-Alin et al)121 with permission).
`
`20 ~
`
`0
`
`0
`
`6
`
`12
`
`30
`24
`18
`Time after dose (h)
`
`36
`
`42
`
`48
`
`Fig. 5. Mean cumulative excretion of total radioactivity(% recov(cid:173)
`ery of dose) after administration of a single oral dose of 14C(cid:173)
`labelled esomeprazole as a solution to poor (PM) and extensive
`(EM) metabolisers.[111
`
`1-way trials with a once daily oral dose of esome(cid:173)
`prazole given to each participant for 5 days. A single
`intravenous dose of esomeprazole was adminis(cid:173)
`tered to each individual 5 to 14 days before the first
`oral dose, and 1 day after the last oral dose. Blood
`samples for pharmacokinetic evaluation were taken
`on days 1 and 5 of oral administration and on the
`days of intravenous administration.
`In the 20mg study using the oral solution, there
`was rapid absorption after both single and repeated
`doses and Cmax was reached within 0.5 hour (fig. 6
`and table III). For repeated doses, the AUC of es(cid:173)
`omeprazole after oral administration increased by
`90%, and Cmax increased by 43%, compared with
`single dose values. The systemic bioavailability (F)
`increased from 50% after a single dose to 68% after
`repeated doses. Following the intravenous doses,
`the total body clearance (CL) was 29% lower after
`the second dose than after the first dose and the
`ti1i~ was longer, 1.2 versus 0.8 hours.
`In the study using the 40mg capsule formula(cid:173)
`tion, Cmax was reached later than for the solution
`(within 1.5 to 2 hours) [table IV]. For the 40mg
`dose, a more pronounced increase in AUC of esome(cid:173)
`prazole with repeated doses was observed than for
`the 20mg dose, and for the group of males together
`with females not using oral contraceptives the in-
`
`© Adis International Limited. All rights reserved
`
`Clin Pharmacokinet 2001; 40 (6)
`
`MYL-EN000523836
`
`Page 8 of 16
`
`Patent Owner Ex. 2033
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Esomeprazole
`
`419
`
`Table Ill. Geometric mean (95% confidence interval) pharmacokinetic parameter values after single and repeated oral (solution) and
`intravenous doses of esomeprazole 20mg in 16 healthy males
`
`Parameter
`
`Intravenous
`1st dose
`
`2nd dose
`
`2nd dose/1st dose
`
`Oral
`day 5/day 1
`day 5
`day 1
`1.86 (1.58-2.18) 2.65 (2.26-3.11) 1.43 (1.23-1.66)
`Cmax (µmol/L)
`tmax (h)a
`0.26 (0.17-0.35) 0.21 (0.18-0.25)
`-0.05 (-0.14 to 0.04)
`AUC (µmol • h/L) 1.34 (1.02-1.77) 2.55 (1.94-3.36) 1.90 (1.72-2.09)
`0.72 (0.61-0.83) 0.96 (0.80-1.14) 1.34 (1.23-1.47)
`t112~ (h)
`F(%)
`50 (45-56)
`68 (62-76)
`1.35 (1.23-1.49)
`CL (L/h)
`Vss (L/kg)
`a Arithmetic mean with difference between day 5 and day 1 in last column.
`AUC =area under the plasma concentration-time curve; Cmax = peak plasma drug concentration; F = bioavailability; tmax =time to reach peak
`concentration following drug administration; tv,~ = half-life; Vss =volume of distribution at steady state.
`
`2.67 (2.20-3.23)
`0.75 (0.65-0.86)
`
`3.74 (3.00-4.68)
`1.11 (0.95-1.29)
`
`1.40 (1.29-1.52)
`1.48 (1.26-1.74)
`
`21.7 (17.7-26.8)
`0.24 (0.22-0.25)
`
`15.5 (12.6-19.1)
`0.26 (0.23-0.30)
`
`0.71 (0.66-0.78)
`1.12 (0.98-1.27)
`
`more pronounced effect of repeated administration
`of the higher dose, not only on bioavailability but
`also on systemic clearance. This was also reflected
`in a prolonged ti1i~, from 0.8 hours after the first
`dose to 1.2 hours after the second dose.
`Similar to the results of the 20mg study, the re(cid:173)
`sults of the 40mg study indicate that the increased
`AUC observed after repeated doses of esomeprazole
`is because of a combination of decreased first-pass
`elimination and decreased systemic clearance. How(cid:173)
`ever, there is a more pronounced decrease in these
`parameters with the higher dose, which is reflected
`in the more pronounced increase in AUC.
`In the 40mg study, a separate comparison of the
`values for the different pharmacokinetic parameters
`was done for males versus females not using oral
`contraceptives. The values observed in females not
`
`using oral contraceptives were also compared with
`those in females using oral contraceptives. Oral con(cid:173)
`traceptives had no major impact on the pharmaco(cid:173)
`kinetics of esomeprazole after single or repeated
`doses of the compound, following either oral or
`intravenous administration. The differences between
`the sexes in the pharmacokinetics of esomeprazole
`are discussed in section 2.3.3.
`
`2. 1.5 Single and Repeated Administration
`of Different Oral Doses
`The pharmacokinetics after a single oral dose
`and after 5 days repeated administration of solu(cid:173)
`tions of 5, 10 and 20mg of esomeprazole and an
`enteric-coated granule formulation of omeprazole
`20mg in a capsule were assessed in 12 healthy
`males.[1 3] This study was a nonblind, randomised,
`
`Table IV. Geometric mean (95% confidence interval) pharmacokinetic parameter values after single and repeated oral (capsule) and
`