Eur J Clin Pharmacol (2000) 56: 665-670
`DOI 10.1007 /s002280000206
`
`+ptt-f +itM·'l'l'*'liii'·'"~,,.H''"'I'
`
`M. Hassan-Alin · T. Andersson· E. Bredberg · K. Rohss
`Pharmacokinetics of esomeprazole after oral and intravenous
`administration of single and repeated doses to healthy subjects
`
`Received: 30 March 2000 /Accepted in revised form: 18 August 2000 / Published online: 25 October 2000
`© Springer-Verlag 2000
`
`Abstract Objective: To study the pharmacokinetics of
`esomeprazole, one of the optical isomers of omeprazole,
`after 20 mg or 40 mg single and repeated oral and in(cid:173)
`travenous administration to healthy subjects. The main
`metabolites of esomeprazole were also assessed after the
`40-mg oral dose.
`Methods: In two separate studies, 16 healthy male sub(cid:173)
`jects and 16 healthy male and female subjects received
`intravenous doses of 20 mg and 40 mg esomeprazole,
`respectively, on the first investigation day. After a wash(cid:173)
`out period of 5-14 days, the same doses (20 mg as a
`solution and 40 mg as a capsule) were given orally for
`5 days and then again intravenously on day 6. Blood
`samples for determination of esomeprazole and its me(cid:173)
`tabolites were collected 12 h or 24 h post-dose and were
`analysed using normal-phase liquid chromatography
`with ultraviolet (UV) detection. Pharmacokinetic pa(cid:173)
`rameters of esomeprazole and its metabolites were esti(cid:173)
`mated using non-compartmental analysis. Geometric
`means and ratios of the geometric means together with
`95% confidence intervals (CI) of the pharmacokinetic
`parameters were calculated using analysis of variance
`(ANOVA).
`(CL) of esomeprazole
`Results: Plasma clearance
`decreased from 22 l/h to 16 l/h and from 1 7 l/h to 9 l/h
`following repeated dosing of 20 mg and 40 mg, respec(cid:173)
`tively. Total area under the plasma concentration-time
`
`M. Hassan-Alin (1:8J) · K. Rohss
`Experimental Medicine,
`AstraZeneca Research and Development Molndal,
`S-431 83 Molndal, Sweden
`e-mail: mohammed.hassan-alin@astrazeneca.com
`Tel.: +46-31-7762339; Fax: +46-31-7763715
`
`T. Andersson
`Clinical Pharmacology,
`AstraZeneca LP, Wayne, PA, USA
`
`E. Bredberg
`Gastrointestinal Therapeutic Area,
`AstraZeneca Research and Development Molndal,
`S-431 83 Molndal, Sweden
`
`to
`increased (from 1.34 µmol x h/l
`curve (AUC)
`2.55 µmol x h/l) with absolute bioavailability (F) being
`50% on day 1 and 68 % on day 5 after the 20-mg oral dose.
`AUC increased (from 4.32 µmol x h/l to 11.21 µmol x h/
`1) with F being 64% on day 1 and 89% on day 5 after the
`40-mg oral dose. The plasma levels for esomeprazole
`sulphone were substantially higher on day 5 than on day 1,
`while those for 5-hydroxy esomeprazole were marginally
`higher on day 5 than on day 1 following repeated oral
`dosing of 40 mg esomeprazole. No side effects attributable
`to esomeprazole were noticed.
`Conclusion: The increased AUC of esomeprazole with
`repeated dosing is probably due to a combination of a
`decreased first-pass elimination and a decreased systemic
`clearance.
`
`Key words Esomeprazole · Pharmacokinetics ·
`Single dose · Steady state
`
`Introduction
`
`Esomeprazole is the first proton pump inhibitor (PPI)
`developed as an optical isomer (S-omeprazole) for the
`treatment of acid-related diseases. Like other PPis [l],
`the metabolism of esomeprazole is mediated by the
`cytochrome P450
`(CYP)
`isoforms CYP3A4 and
`CYP2Cl9, which form two main metabolites, esomep(cid:173)
`razole sulphone and 5-hydroxy esomeprazole, respec(cid:173)
`tively [2], both pharmacologically inactive. Esomeprazole
`is a potent inhibitor of gastric acid secretion. The com(cid:173)
`pound accumulates in the acidic compartment of the
`parietal cells where the molecule is transformed to its
`active form, the suphenamide.
`One recent study in which each of the optical isomers of
`omeprazole, esomeprazole and R-omeprazole was incu(cid:173)
`bated with human liver microsomes [2] indicated a rela(cid:173)
`tively higher dependence on CYP2C 19 for the metabolism
`of R-omeprazole than esomeprazole. The data from hu(cid:173)
`man liver microsomal experiments also showed that the
`intrinsic clearance for esomeprazole was substantially
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`lower than that for R-omeprazole and, consequently,
`lower than that for the racemate [2]. In an in vivo study in
`healthy subjects [3], the plasma levels of esomeprazole
`were higher than those of omeprazole, while those of
`R-omeprazole were lower. The mean AUC (area under
`the plasma concentration-time curve) of esomeprazole on
`day 7 was almost twofold higher for esomeprazole than
`that for omeprazole, whereas the mean AUC of R(cid:173)
`omeprazole was approximately 50% of that for omep(cid:173)
`razole. Furthermore, an almost twofold higher AUC with
`resulting higher intra-gastric pH for esomeprazole than
`for omeprazole was shown in patients with symptomatic
`gastroesophageal reflux disease (GERD) [4]. The intrinsic
`clearance being lower for esomeprazole than for R(cid:173)
`omeprazole and the racemate resulting in a twofold higher
`AUC may therefore provide better clinical effect in the
`treatment of acid related diseases.
`The objective of the present investigation was to
`study the pharmacokinetics of esomeprazole after oral
`and intravenous (i.v.) administration of single and
`repeated doses to healthy subjects.
`
`Materials and methods
`
`Subjects
`
`In two separate studies, 16 healthy male subjects (study A) with a
`mean age of 28 years and mean weight of 76 kg and 16 healthy
`subjects (8 male and 8 female, study B) with a mean age of 27 years
`and a mean weight of 72 kg were included. The two studies were
`conducted in accordance with the Declaration of Helsinki and
`approved by the ethics committees of the University of Goteborg
`and the University of Uppsala and by the Swedish Medical Prod(cid:173)
`ucts Agency. Written informed consent was received from all
`subjects prior to participation.
`All subjects underwent a full clinical examination, including
`past medical history, physical examination and electrocardiogram
`(ECG) at pre-entry. Laboratory screen for haematology and serum
`biochemistry was also performed prior to participation in the
`studies.
`
`Study design
`
`The two studies were conducted according to an open design and
`each consisted of four investigation days. In studies A and B,
`subjects received i.v. doses of 20 mg and 40 mg esomeprazole,
`respectively, on the first investigation day (first i.v). After a wash(cid:173)
`out period of 5-14 days, the same doses (20 mg as a solution and
`40 mg as a capsule) were given orally for 5 days and then again
`mtravenously on day 6 (second i.v.). Blood samples for determi(cid:173)
`nation of esomeprazole in plasma were taken up to 12 h (study A)
`or 24 h (study B) post-dose after the first and second i.v. doses
`and on day 1 and day 5 of oral dosing. Plasma samples for
`esomeprazole main inactive metabolites were also assessed in
`study B.
`Alcohol intake was not allowed for 2 days prior to or during the
`treatment period. Drugs available on prescription had not been
`allowed during the last 2 weeks preceding the studies. Oral con(cid:173)
`traceptives were not allowed. On the four investigation days, the
`subjects arrived at the laboratory in the morning, having fasted
`since the previous evening, for administration of drug and for
`collection of repeated blood samples. On these days, standardised
`meals were served 4 (lunch), 7 (light meal), and 10 h (dinner) after
`drug administration.
`
`Study drugs
`
`For esomeprazole 20 mg, the oral and the i.v. study formulations
`were present as its corresponding sodium salt in solution, (5 mg/ml,
`AstraZeneca R and D Molndal, Sweden). The oral esomeprazole
`40 mg was present as its corresponding magnesium salt as enteric(cid:173)
`coated pellets dispensed in a hard gelatin capsule, while the
`i.v. 40 mg formulation was present as its sodium salt in solution,
`(5 mg/ml, AstraZeneca R and D Molndal). The concentration
`of esomeprazole is stated with respect to the neutral form.
`For the 20-mg oral dose, 4 ml of the drug solution was diluted
`with distilled water to a volume of 50 ml and was given to the
`subject to swallow. The beaker was rinsed twice with 50 ml buffer
`solution (0.16 mmol/l). For the i.v. 20-mg dose, 4 ml of the solution
`was added to a 96-ml sodium chloride i.v. infusion to give a final
`concentration of 0.2 mg/ml esomeprazole. A volume of 100 ml was
`administered intravenously over 30 min.
`The 40-mg capsule was taken orally with 200 ml water. For the
`i.v. 40-mg dose, 8 ml of the drug solution was added to a 192-ml
`sodium chloride i.v. infusion to give a final concentration of0.2 mg/
`ml esomeprazole. A volume of 200 ml was administered intrave(cid:173)
`nously over 30 min.
`
`Blood sampling
`
`On each of the four investigation days a reference blood sample
`was drawn from an indwelling cannula in a forearm vein followed
`by i.v. or oral administration of esomeprazole. The i.v. doses were
`infused for 0.5 h through a second indwelling cannula. Thereafter,
`blood samples for the assay of esomeprazole and its metabolites
`were taken at pre-dose and at 0.08, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2,
`2.5, 3, 4, 5, 6, 7, 8, 10, 12 or 24 h post-dose, collected in heparinised
`tubes, centrifuged and the plasma stored frozen until analysis.
`In study A (20-mg dose), the plasma samples were analysed for
`esomeprazole using normal-phase liquid chromatography with ul(cid:173)
`traviolet (UV) detection at AstraZeneca R and D Molndal [5]. In
`study B (40-mg dose), the plasma samples were analysed for
`esomeprazole and its metabolites (esomeprazole sulphone and
`5-hydroxy esomeprazole) using normal-phase liquid chromatogra(cid:173)
`phy with UV detection with some modifications. The compounds
`were detected in the elute using UV at 302 nm and the retention times
`were 3.5, 4.5, 8.0 and 5.5 min, respectively, for esomeprazole,
`esomeprazole sulphone, 5-hydroxy esomeprazole and the internal
`standard. The absolute recovery for esomeprazole and the sulphone
`metabolite at 25-2500 nmol/l was greater than 90% and for the hy(cid:173)
`droxy metabolite at 50-3000 nmol/l was 70%. The limit of quanti(cid:173)
`fication for esomeprazole and esomeprazole sulphone was 25 nmol/l
`with coefficient of variation (CV) less than 20% and for 5-hydroxy
`esomeprazole 50 nmol/l (CV< 20% ). The plasma samples were
`analysed for the compounds at AstraZeneca Rand D Molndal.
`
`Pharmacokinetic and statistical analyses
`
`its main
`Pharmacokinetic parameters of esomeprazole and
`metabolites, esomeprazole sulphone and 5-hydroxy esomeprazole,
`were estimated using non-compartment analysis with WinNonlin
`computer software. The total AUC was calculated according to the
`log-linear trapezoidal method and extrapolated to infinity using
`the last determined plasma concentration and A, which is the
`elimination rate constant determined using log-linear regression
`analysis of the terminal slope of at least three last plasma con(cid:173)
`centration-time data. The terminal plasma elimination half-life
`(t 1; 2) was calculated as:
`ln2
`A
`The absolute bioavailability (F) of esomeprazole following the oral
`doses was calculated as:
`
`_ AUCpa,Doy I Dose;v, !"dose
`Fi
`A uciv, 1st dose Dose pa, Day 1
`Day! -
`·
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`FDay5 =
`
`A UC pa, Day 5 Doseiv, 2nd dose
`· --~-
`A uciv, 2nd dose Dose po, Day 5
`
`For the oral doses, the observed maximum plasma concentra(cid:173)
`tion (Cmax) as well as the time to reach Cmax (tmax) was also
`recorded. For the i.v. doses
`the plasma clearance (CL) of
`esomeprazole was estimated as CL = ~'J~w and the apparent volume
`of distribution at steady state (Vss) as MRT x CL, where MRT is
`the mean residence time (AUMC/AUC-T/2). AUMC is the area
`under the first moment curve and T is the infusion time.
`The pharmacokinetic parameters were analysed using a mixed
`model analysis of variance (ANOV A) with day as a fixed effect and
`subject as a random effect. Comparisons between the first and
`second i.v. administrations and between day 1 and day 5 of the oral
`dosing were performed. The pharmacokinetic parameters were log(cid:173)
`transformed prior to the analysis. Estimates and 95% confidence
`limits of log-transformed parameters were anti-logarithmised, and
`the results are presented as geometric means and the ratio thereof
`with confidence intervals.
`
`Results
`
`Intravenous doses of 20 mg or 40 mg
`
`The mean plasma concentrations of esomeprazole after
`i.v. administration of20 mg or 40 mg are shown in Fig. 1
`and the corresponding pharmacokinetic parameters are
`presented in Table 1 and Table 2, respectively. The
`plasma levels were higher after the second i.v. dose than
`the first dose both after the 20-mg and the 40-mg doses.
`The CL decreased by 29% after the second 20-mg dose
`and by 46% after the second 40-mg dose. The t 112 was
`prolonged by approximately 50% for both doses. The
`Vss was approximately 18 1 for both dose levels and on
`day 1 and day 5.
`
`Oral doses of 20 mg or 40 mg
`
`The mean plasma concentrations of esomeprazole after
`oral administration of 20 mg as a solution or 40 mg as a
`capsule are shown in Fig. 2, and the corresponding
`pharmacokinetic parameters are presented in Table 1
`and Table 2, respectively. The pharmacokinetics for the
`main metabolites esomeprazole sulphone and 5-hydroxy
`esomeprazole are shown in Table 3.
`Esomeprazole 20 mg given as an oral solution was
`rapidly absorbed, reaching Cmax at 0.5 h. The Cmax for
`the 40-mg capsule was reached at a later time than the
`solution but within 1-3.5 h.
`The plasma levels of esomeprazole after the 20-mg
`dose were higher after repeated dosing (day 5) than after
`a single dose (day 1) as reflected in a 43% higher Cmax
`(1.9 µmol/l versus 2.6 µmol/l) and a 90% higher AUC
`(1.34 µmol x h/l versus 2.55 µmol x h/l). F was 50% on
`day 1 and 68% on day 5. Following 40-mg oral ad(cid:173)
`ministration, the Cmax increased by 95% (2.38 µmol/l
`versus 4.64 µmol/l)
`and
`the AUC by 159%
`( 4.32 µmol x h/l versus 11.21 µmol x h/l) on day 5
`
`8 s 7
`Q e ::l 6 -= Q 5 ~ E
`.... 4 = II,) u
`= 3
`Q
`u
`e ..,
`1111 2
`is: 1
`0
`
`1111
`
`667
`
`-tr- 20 mg (1st dose)
`__.._ 20 mg (2nd dose)
`-o- 40 mg (1st dose)
`- - 40 mg (2nd dose)
`
`0
`
`2
`
`4
`8
`6
`Tune after dose (h)
`
`10
`
`12
`
`Fig. 1 Mean plasma concentrations of esomeprazole following
`intravenous administration of 20 mg (n = 16 male subjects) or 40 mg
`(n= 16 male and female subjects) as a single dose (1st dose) and
`after 5 days of oral dosing (2nd dose)
`
`compared with day 1. F was 64% on day 1 and 89% on
`day 5.
`In the investigation of the 40-mg dose of esomep(cid:173)
`razole, eight male and eight female subjects participated.
`Female subjects generally had higher AUC of esomep(cid:173)
`razole
`than male subjects (6.28 µmol x h/l versus
`2.97 µmol x h/l) following a single dose of esomepraz(cid:173)
`ole. There was a
`tendency
`for a higher AUC
`(13.37 µmol x h/l versus 9.40 µmol x h/l) following re(cid:173)
`peated administration but there was no statistically sig(cid:173)
`nificant difference.
`The AUC for the inactive esomeprazole sulphone in(cid:173)
`creased from 4.06 µmol x h/l to 16.17 µmol x h/l from
`day 1 to day 5, and that for the 5-hydroxy esomeprazole
`increased from 0.71 µmol x h/l to 0.97 µmol x h/l fol(cid:173)
`lowing repeated oral administration of 40 mg esomep(cid:173)
`razole. The t 112 values for the sulphone and 5-hydroxy
`esomeprazole were prolonged from 2.6 h to 3.8 h and
`from 1.3 h to 2.2 h, respectively. Esomeprazole, given in
`daily repeated doses of 20 mg or 40 mg was well toler(cid:173)
`ated.
`
`Discussion
`
`Esomeprazole 20 mg given as an oral solution was more
`rapidly absorbed than after 40 mg given as a capsule,
`which is an expected difference between a capsule for(cid:173)
`mulation and an oral solution. Esomeprazole oral for(cid:173)
`mulations were present as capsules or solution
`containing different salts (magnesium and sodium salts,
`respectively). However, since the bioavailability of a
`capsule formulation of esomeprazole relative to that of a
`solution containing magnesium and sodium salt, re(cid:173)
`spectively, was complete (AstraZeneca AB, data on file),
`the different formulations and salts used in esomepraz(cid:173)
`ole in the present investigation are unlikely to have any
`influence on the results.
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`Table 1 Pharmacokinetic parameters [geometric mean values with
`95% confidence intervals (95% Cl)] of esomeprazole following
`intravenous (1st and 2nd doses) and oral (day 1 and day 5) routes
`of administration of 20 mg esomeprazole to healthy male subjects
`
`(n = 16). Cmax observed maximum plasma concentration; I 1;2 plas(cid:173)
`ma elimination half-life; CL plasma clearance; V,s apparent volume
`of distribution at steady state; AUC area under the plasma
`concentration-time curve; F absolute bioavailability
`
`Route
`
`Pharmacokinetic parameter
`
`Intravenous route
`1st dose (95% CI)
`2nd dose (95% CI)
`Ratio 2nd dose/1st dose (95% CI)
`Oral route
`Day 1 (95% CI)
`Day 5 (95% CI)
`Ratio day 5/day 1 (95% CI)
`
`Cmax (µmol/l)
`2.51 (2.28-2.76)
`2.67 (2.43-2.94)
`1.07 (0.99-1.15)
`
`Cmax (µmol/l)
`1.86 (1.58-2.18)
`2.65 (2.26-3.11)
`1.43 (1.23-1.66)
`
`11;2 (h)
`0.78 (0.62-0.94)
`1.15 (0.99-1.31)
`1.56 (1.21-1.91)
`
`t1;2 (h)
`0.75 (0.58-0.91)
`1.01 (0.85-1.18)
`1.36 (1.23-1.49)
`
`CL (l/h)
`21.7 (17.7-26.8)
`15.5 (12.6-19.1)
`0. 71 (0.66--0. 78)
`AUC (µmol x h/l)
`1.34 (1.02-1. 77)
`2.55 (1.94-3.36)
`1.90 (1. 72-2.09)
`
`Yss (1)
`17 .8 (16.8-18.9)
`19.8 (17.0-23.3)
`1.16 (0.93-1.39)
`F (%)
`50.0 (45.0-56.0)
`68.0 (62.0-76.0)
`1.35 (1.23-1.49)
`
`Table 2 Pharmacokinetic parameters [geometric mean values with
`95% confidence intervals (95% Cl)] of esomeprazole following
`intravenous (1st and 2nd doses) and oral (day 1 and day 5) routes
`of administration of 40 mg esomeprazole to healthy male and
`
`female subjects (n = 16). Cmax observed maximum plasma concen(cid:173)
`tration; 11;2 plasma elimination half-life; CL plasma clearance; Vss
`apparent volume of distribution at steady state; AUC area under
`the plasma concentration-time curve; F absolute bioavailability
`
`Route
`
`Pharmacokinetic parameter
`
`Intravenous route
`1st dose (95% CI)
`2nd dose (95% CI)
`Ratio 2nd dose/1st dose (95% CI)
`Oral route
`Day 1 (95% CI)
`Day 5 (95% CI)
`Ratio day 5/day 1 (95% CI)
`
`Cmax (µmol/l)
`5.53 (4.90-6.25)
`6.91 (6.36-7.52)
`1.25 (1.16-1.35)
`
`Cmax (µmol/l)
`2.38 (1.77-3.19)
`4.64 (3.80-5.66)
`1.95 (1.59-2.40)
`
`11;2 (h)
`0.85 (0.74--0.98)
`1.22 (1.07-1.38)
`1.43 (1.31-1.57)
`
`t1;2 (h)
`0.85 (0. 73--0.99)
`1.25 (1.09-1.44)
`1.48 (1.29-1.69)
`
`CL (l/h)
`17.05 (13.74-21.14)
`9.18 (7.66-11.01)
`0.54 (0.47-0.62)
`AUC (µmol x h/l)
`4.32 (3.04-6.14)
`11.21 (8.56-14.67)
`2.59 (2.11-3.19)
`
`Yss (1)
`17.98 (16.34-19.78)
`15.55 (14.71-16.44)
`0.87 (0.82--0.91)
`F (%)
`63.6 (54.10-74.74)
`88.9 (80.8-97.79)
`1.40 (1.23-1.59)
`
`The F of esomeprazole was higher on day 5 than on
`day 1 following repeated oral administration of 20 mg or
`40 mg. The CL of esomeprazole decreased after repeated
`i.v. dosing of 20 mg or 40 mg and t 1;2 was prolonged
`accordingly. The volume of distribution of esomeprazole
`was approximately 18 1, which equals the volume of
`extracellular body water, and was not altered by
`
`8
`~ 7
`a 6
`:t.
`.._..
`= Q
`5
`·.c = r.. 4
`.... = 41 ""
`= 3
`Q ""
`= 2
`E!
`..,
`=
`15::
`
`0
`
`0
`
`-tr-20~(dayl)
`
`_._20~(day5)
`-0-40~(day 1)
`
`--40~(day5)
`
`2
`
`4
`6
`Tune after<hse (h)
`
`8
`
`10
`
`12
`
`Fig. 2. Mean plasma concentrations of esomeprazole following
`oral administration of a single dose (day 1) and after five daily
`doses (day 5) of 20 mg as a solution (n = 16 male subjects) or 40 mg
`as a capsule (n= 16 male and female subjects)
`
`repeated dosing. The increased AUC during repeated
`dosing with esomeprazole observed here and previously
`[3] is probably caused by a combination of a decreased
`first-pass elimination and a decreased systemic clearance.
`In the investigation of the 40-mg dose of esomep(cid:173)
`razole, eight male and eight female subjects participated.
`Female subjects generally had higher AUCs of esomep(cid:173)
`razole than male subjects following a single dose.
`Somewhat higher AUCs, although not statistically sig(cid:173)
`nificant, were also observed following repeated admin(cid:173)
`istration. Esomeprazole
`is eliminated primarily by
`hepatic metabolism mediated by CYP2C 19 and
`CYP3A4 [2]. It has previously been shown that female
`subjects have a higher activity of CYP3A4 than male
`subjects, while the activity of CYP2Cl9 is lower [6, 7].
`This could possibly be due to the different hormone
`pattern in females versus males and potential inhibitory
`effect of the female hormones on CYP2Cl9. This may
`also be the reason for a less pronounced increase in
`AUC observed with repeated dosing in female subjects,
`since the CYP2Cl9 activity may be already somewhat
`inhibited and the influence of an additional inhibitory
`effect on CYP2Cl9 would be limited and less than for
`male subjects. Nevertheless, this gender difference in
`CYP activity may explain the observed difference in the
`pharmacokinetics of esomeprazole between males and
`females in the present investigation.
`The plasma levels for the inactive esomeprazole sul(cid:173)
`phone were substantially higher on day 5 than day 1,
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`669
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`Table 3 Pharmacokinetic parameters [geometric mean values
`with 95% confidence
`intervals
`(95% Cl)] of esomeprazole
`sulphone (n=6) and 5-hydroxy esomeprazole (n= 15) following
`oral (day 1 and day 5) route of administration of 40 mg
`
`female subjects. Cmax
`to healthy male and
`esomeprazole
`observed maximum plasma concentration; 1112 elimination half(cid:173)
`life; AUC area under the plasma concentration-time curve
`
`Metabolite
`
`Pharmacokinetic parameter
`
`Esomeprazole sulphone
`Day 1 (95% CI)
`Day 5 (95% CI)
`Ratio day 5/day 1 (95% CI)
`5-Hydroxy esomeprazole
`Day 1 (95% CI)
`Day 5 (95% CI)
`Ratio day 5/day 1 (95% CI)
`
`Cmax (µmol/l)
`
`11;2 (h)
`
`AUC (µmol x h/l)
`
`0.76 (0.52-1.11)
`1.71 (1.30-2.25)
`2.25 (1.99-2.55)
`
`0.29 (0.24-0.34)
`0.28 (0.25-0.31)
`0.96 (0.82-1.12)
`
`2.55 (2.01-3.24)
`3 .84 (3 .26-4.51)
`1.50 (1.29-1.75)
`
`1.27 (1.07-1.52)
`2.15 (1.71-2.70)
`1.72 (1.41-2.09)
`
`4.06 (2.24-7.37)
`16.17 (10.89-24.01)
`3.98 (3.04-5.20)
`
`0.71 (0.58-0.87)
`0.97 (0.80-1.18)
`1.39 (1.23-1.57)
`
`while those for the inactive 5-hydroxy metabolite were
`only slightly increased from day 1 to day 5 of repeated
`oral dosing of 40 mg esomeprazole. The formation of
`the 5-hydroxy metabolite is dependent on CYP2Cl9,
`whereas the formation of the sulphone metabolite is
`dependent on CYP3A4 [2, 8, 9]. The higher plasma levels
`for esomeprazole sulphone after repeated dosing of
`esomeprazole is likely due to an inhibition of its further
`metabolism which is mediated by CYP2C 19. Higher
`plasma levels for the sulphone metabolite have also been
`reported after repeated administration of the omepraz(cid:173)
`ole racemate [10].
`The CL of esomeprazole was 22 l/h after a single i.v.
`dose of 20 mg and 17 l/h after a single 40-mg dose. The
`corresponding values for the same doses of omeprazole
`racemate, as reported in a previous study, were 28 l/h
`and 24 l/h, respectively [11 ]. Thus the CL of esomep(cid:173)
`razole seems to be lower than that of the omeprazole
`racemate. A lower CL of esomeprazole relative to that of
`omeprazole racemate was also indicated in human liver
`microsomal experiments with an
`intrinsic CL for
`esomeprazole substantially lower than that for R(cid:173)
`omeprazole (the other isomer) and, consequently, lower
`than that for the omeprazole racemate [2].
`The plasma concentrations of esomeprazole after re(cid:173)
`peated oral administration of 20 mg were higher, almost
`twofold, than those observed after repeated oral ad(cid:173)
`ministration of the same dose of the omeprazole race(cid:173)
`mate
`[4]. The major reason for
`this
`is a more
`pronounced increase in AUC for esomeprazole than for
`omeprazole with repeated dosing. The CL of esomep(cid:173)
`razole decreased by 29% and 46% after repeated dosing
`with 20 mg and 40 mg of esomeprazole, respectively.
`After 40 mg of omeprazole given repeatedly as i.v. doses
`over 5 days CL was decreased by 47% [12]. The F of
`esomeprazole was 50% and 64% after 20-mg and 40-mg
`single doses, respectively. Previous studies with the
`omeprazole racemate 20-mg and 40-mg single dose in(cid:173)
`dicate that the bioavailability of the racemate (40%) is
`slightly lower than that of esomeprazole [11 ]. The F
`during repeated dosing of omeprazole racemate, 20 mg
`daily, approaches 60% [13], which is to be compared
`
`with the values of 68% for 20 mg esomeprazole in the
`present investigation. Thus, both at single-dose and at
`steady-state conditions, the bioavailability is higher for
`esomeprazole than for the omeprazole racemate mainly
`as a consequence of a lower first-pass elimination and
`lower systemic CL for esomeprazole. The higher bio(cid:173)
`availability is likely to provide a rational basis for an
`increased clinical efficacy of esomeprazole compared
`with the omeprazole racemate since the effect on gastric
`acid secretion is correlated to the AUC [14, 15].
`The changes in drug exposure after repeated admin(cid:173)
`istration of esomeprazole as well as the omeprazole
`racemate can be due to an inhibition of CYP2Cl9. An
`inhibition of CYP2Cl9 has previously been suggested as
`the explanation for the findings with the omeprazole
`racemate, both with regard to the increased AUC of
`omeprazole itself and the inhibition of the metabolism of
`diazepam [10]. Strong support for this explanation can
`be found in the unaltered omeprazole AUC as well as
`the lack of interaction with diazepam during repeated
`dosing of the omeprazole racemate in poor metabolisers
`lacking CYP2Cl9 [16, 17]. For the metabolism of
`esomeprazole, CYP2Cl9 has been shown to play a less
`dominant role than that for the omeprazole racemate or
`the other isomer, R-omeprazole. CYP3A4 seems to play
`a relatively more important role for the metabolism of
`esomeprazole than the racemate [2]. Nevertheless, the
`present investigation together with previous results
`seems to indicate that the increase in AUC at repeated
`dosing is more pronounced for esomeprazole than it is
`for the omeprazole racemate. One possible explanation
`is that the increase in AUC from day 1 to day 5 seems to
`be related to esomeprazole but not to R-omeprazole [3].
`Finally, it should be noted that because of the threefold
`difference in AUC of esomeprazole between extensive
`and poor metabolisers, CYP2Cl9 is probably responsi(cid:173)
`ble for approximately two-thirds of the total metabolism
`of esomeprazole. Whether an inhibition by CYP2Cl9 is
`caused by the esomeprazole or the sulphone metabolite
`that is further metabolised by CYP2Cl9 has not been
`explored. However, the most likely explanation for the
`increased plasma concentrations obtained during re-
`
`MYL-EN000523712
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`Patent Owner Ex. 2069
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`

`670
`
`peated dosing of esomeprazole is that in addition to the
`inhibitory effect of the parent compound there may also
`be some contribution from an inhibition by the sulphone
`of CYP2Cl9.
`
`Conclusion
`
`The increased AUC of esomeprazole with repeated
`dosing is probably due to a combination of a decreased
`first-pass elimination and a decreased systemic clear(cid:173)
`ance. Esomeprazole was not associated with any side
`effects in this investigation.
`
`Acknowledgements The authors are grateful to Per-Olof Lag(cid:173)
`erstrom for the esomeprazole analysis and to Ola Junghard for the
`statistical evaluation.
`
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`MYL-EN000523713
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`Page 6 of 6
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`Patent Owner Ex. 2069
`Mylan v. Pozen
`IPR2017-01995
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`