Clinical pharmacology and safety profile of esomeprazole, the first enantiomerically pure proton pump inhibitor PDF

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WI. Tonini Awareness of important differences in the pharmacological profile of S. Vigneril individual optical isomers of chiral drugs led to the development of es- V. Savarino* omeprazole, the S-isomer of omeprazole, a new pharmacological enti- ty designed to improve the clinical outcome of availab...

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Clinical pharmacology and safety profile of esomeprazole, the first enantiomerically pure proton pump inhibitor V. Savarino Digestive and Liver Disease

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WI. Tonini S. Vigneril V. Savarino* C. Scarpignato3

Awareness of important differences in the pharmacological profile of individual optical isomers of chiral drugs led to the development of esomeprazole, the S-isomer of omeprazole, a new pharmacological entity designed to improve the clinical outcome of available proton pump inhibitors in the management of acid-related disorders. The superior acid control achieved by esomeprazole is mainly due to an advantageous metabolism compared with racemate omeprazole, leading to improved bioavailability and to enhanced delivery of the drug to the gastric proton pump.

Digest liver Dis 2001;33:600-6 Key words: acid-related disorders; clinical pharmacology; esomeprazole; proton pump inhibitors

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Department of Physiological and Pharmacological Sciences, University of Pavia; I Department of Internal Medicine, Division of Gastroenterology, University of Palermo; 2 Department of Internal Medicine, Division of Gastroenterology, University of Genoa; 3 Department of Internal Medicine, Laboratory of Clinical Pharmacology, University of Parma, Italy. Address for correspondence

Prof. M. Tonini, Dipartimento di Scienze Fisiologiche-Farmacologiche, Universitk di Pavia, Piazza Botta, IO, 27100 Pavia, Italy. Fax:+39-0382-5064 I 9 E-mail: marcello. [email protected]

Acid-related disorders of the upper gastrointestinal tract comprise diseases of the oesophagus, stomach and duodenum such as gastro-oesophageal reflux disease (GERD), gastric and duodenal ulcers, drug-induced ulcers, and Zollinger-Ellison syndrome. It is well known that gastric acid and pepsin are largely involved in their etiology and pathophysiology, both factors acting in concert with Helicobacter pylori (H. pylori) or with either nonsteroidal anti-inflammatory drugs (NSAIDs), stress or smoking. All these diseases can be beneficially affected by neutralizing gastric acid or by inhibiting its secretion I. Proton pump inhibitors (PPIs) have been one of the most important advances in the field of gastrointestinal pharmacology in the past 20 years, and their greater efficacy in acid-related disorders over other acid reducing drugs has been demonstrated in many studies *. For this reason, PPIs are now considered as the most effective compounds for the control of gastric acid secretion in clinical use. Currently, four PPIs are commercially available (omeprazole, lansoprazole, pantoprazole and rabeprazole). Esomeprazole 3, the first PPI developed as an isomer (the S-enantiomer of omeprazole), will soon gain the market. This review is mainly intended to survey the pharmacodynamic, pharmacokinetic and tolerability profile of PPIs, with special reference to the novel compound esomeprazole.

The most effective target of acid-inhibitory drugs is the H+/K+-ATPase, the gastric acid pump or proton pump located in the canalicular membrane of gastric parietal cells. This enzymatic pump, which is the final common pathway for acid secretion in the stomach, secretesHCl and the resulting H’ (H30+) is exchanged for K+ with ATP breakdown 4. In fact, the proton pump extrudes H30+ at a concentration of 160 mM and reabsorbs K’ into a cytosolic concentration of 140 mM. The reason why PPIs display a higher an-

tisecretory efficacy compared to other drugs (e.g. HZreceptor antagonists) stems on the blockade of this final step in acid production 4. The mode of action of PPIs, which is relatively similar independently of the nature of each individual agent, can be described by taking into account the structure of the gastric proton pump and that of PPIs 2. The gastric proton pump contains two transmembrane sub-units, called alpha and beta, of 1034 and 291 aminoacids, respectively. The alpha sub-unit consists of 10 transmembrane spanning segments and is responsible for the transport and the catalytic function of the pump. It is also present as an inactive form in the cytoplasm and has to be transported to the canalicular cell membrane surface of gastric parietal cells to become active. The alpha sub-unit contains a total of 28 cysteine residues, whereas the content of the beta subunit is 9. In their active form (see below), PPIs form disulfide covalents bonds with exposed SH-groups of extra-cytoplasmatic (i.e. luminal) cysteine residues in the alpha sub-unit leading to blockade of proton pump activity 5. The PPIs are pyridyl methylsulfinyl benzimidazole prodrugs that are converted by the acid environment inside the canaliculus of the parietal cells into a cyclic protonated sulphenamide. In detail the reaction occurs as follows. Inside the canaliculus of a secreting parietal cell the pH is in the order of 1. This is the ideal environment to cause fast protonation of the PPI pyridine nitrogen and thereby drug accumulation relative to the blood by a factor of 1000, which is strictly dependent on the pKa of PPIs (between 4 and 5 for all compounds). This reaction is followed by rapid conversion of the prodrug into a cyclic sulphenamide, a highly reactive thiophile compound, which is the active form of all the PPIs 4.With regard to the mode of action, cyclic sulphenamides react covalently with cysteine 813 in the fifth and sixth transmembrane region of the alpha sub-unit. This reaction, which is extremely fast especially at low pH values, is apparently the only reaction required to block the pump. Apart from this common mode of action, each individual agent can bind to other cysteine residues. For example, omeprazole has been shown to bind to cysteine 892; lansoprazole to cysteine 321; pantoprazole to cysteine 822; rabeprazole to cysteine 892 and 321 6. However, the pharmacological relevance of these additional bindings is at present unknown. As mentioned above, the binding of cyclic sulphenamide with SH-groups of the alpha sub-unit is covalent and thus chemically irreversible. In a functional sense,however, the PPI-induced acid inhibition is reversible, due to the turnover of the proton pump and the parietal cell, respectively. Based on this, the duration of action of PPIs is related principally to the regeneration of new

pumps (trj2g 50 hours) rather than to their pharmacokinetic properties 7. Nevertheless, differences between PPIs in their binding to various SH-groups, lipid solubility, chemical instability of the parent compound leading to fast formation of cyclic sulphenamides at high pH values (up to 5) may influence their onset of action 2. Rabeprazole is less dependent, compared to other drugs, on pH for conversion into the active sulphenamide. This low pH selectivity, which would allow rabeprazole to covalently react with the pumps of either secreting or non-secreting (i.e., less acidic) parieta1cells, is usually accounted to explain its faster onset of action, as indicated by a more pronounced elevation of intragastric pH upon a single dose of the drug 8. Apparently, this is only a transient benefit, since acid suppression after one week, or the rate of GERD and active gastric or duodenal ulcer healing is comparable to that of other PPIs 29lo.A compound with these chemical properties, other than to bind to SH-groups in the proton pump, may avidly bind to SH-groups in moderately acidic compartments (e.g. pH = 5), such as lysosomes, chromaffin granules and mitochondria. To date, the clinical relevance, in terms of side-effect generation, of the latter interactions is not known.

The pharmacokinetic profile of each individual PPI largely depends on the dose and the route of administration 2. PPIs administered as enteric coated preparations undergo rapid oral absorption with peak concentrations of approximately 0.5 to 2 mg/l occurring within 2-4 hours at the usually prescribed oral doses. Oral bioavailability is in the range of 50-80% with a low rate of hepatic first pass extraction. Since PPIs are highly protein bound, their volume of distribution is relatively low. PPIs are eliminated from serum with a half-life of approximately 1 hour (range 0.5 to 2 hours). However, due to their irreversible mode of action, such a short half-life does not interfere with their antisecretory eficacy. In fact, all PPI prodrugs are activated at pH 1 within a few minutes and, therefore, all of them could be efficiently activated during systemic drug exposure. With the exception of rabeprazole, all the other PPIs are activated much more slowly at pH values >3. For more detailed information on the pharmacokinetics of each individual PPI, the readers are referred to the folliowing exhaustive reviews * r1-r3.

Omeprazole, like other proton pump inhibitors, is a substituted benzimidazole that exists as a racemic mix-

ture of the R- and S-isomers, based on the chirality of sulphur atom. Esomeprazole is the optically stable Sisomer of omeprazole l4 15.This molecule is the first PPI to be developed as a single isomer for the treatment of acid-related disorders. It provides a better acid suppression, through inhibition of basal and stimulated gastric acid secretion, and shows a better phamacokinetic profile compared to omeprazole. Like omeprazole, esomeprazole acts by inhibiting the gastric H+/K+-ATPase 2r6. As mentioned above, all the available PPIs are racemic mixture of two isomers. The rationale for developing single PPI isomers stems from the fact that drug chirality can have a considerable clinical significance, since enzymes and receptors generally have a stereochemical preference for one optical isomer. This may result in important differences in the pharmacodynamic and pharmacokinetic profile of optical isomers, and thus in their clinical efficacy 17.Esomeprazole is the result of an extensive research programme aimed at developing a drug able to improve the clinical outcome of available antisecretory agents 18,including that of omeprazole, the current gold standard PPI in the management of acid-related diseases.

In a randomized double blind crossover trial, esomeprazole 20 and 40 mg/day for 5 days maintained intragastric pH values above 4 for longer (> 12 or 16 hours) than omeprazole 20 mg in patients with symptoms of GERD r9. It is well known that the healing of reflux oesophagitis is directly related to the proportion of time during the 24-hour period for which the intragastric pH is maintained above 4 2o(Fig. 1). A greater acid inhibitory effect of esomeprazole vs R-omeprazole

Fig. 1. In GERD patients, the healing of reflux oesophagitis is directly E $ related to the proportion of time during the 24-hour period for which \ the lntragastric pH is maintained above 4 [adapted from ref. 201.

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and omeprazole racemate was obtained on pentagastrin-stimulated peak acid output in healthy subjects 21. Studies in patients with GERD, as well as in healthy subjects, have revealed that esomeprazole 40 mg once daily provides a more effective acid control (pH >4) than omeprazole (20, 40 mg), pantoprazole (40 mg), lansoprazole (30 mg) and rabeprazole (20 mg). In patients with GERD, once daily administration of 40 mg esomeprazole increased intragastric pH to >4 for a longer period than omeprazole 20 and 40 mg. The percentage of the 24-hour period with pH >4 on day 1 was 49 and 41%, whereas on day 5 it was 68.4 and 62% for esomeprazole 40 mg and omeprazole 40 mg, respectively. On day 5, a greater percentage of esomeprazole recipients (88%) had pH values above 4 for more than 12 hours compared with omeprazole (77%) 19.

In patients with GERD, esomeprazole (40 mg) recipients had a higher 24-hour median pH value (4.7) compared with pantoprazole 40 mg (3.7) on day 5. On the same day, a greater percentage of patients given esomeprazole maintained pH above 4 for >12 or 16 hours compared to pantoprazole 22. In a randomized open crossover trial enrolling 20 healthy subjects, esomeprazole 40 mg once daily for 5 days provided a greater control of 24-hour intragastric pH than lansoprazole 30 mg. On day 5, 90% of esomeprazole recipients had an intragastric pH >4 for 12 hours, while the percentage of lansoprazole recipients was 57%. The 24-hour median pH was 4.8 and 4.2 in esomeprazole and lansoprazole recipients, respectively 23.

In a randomized open crossover trial enrolling 23 healthy subjects, esomeprazole 40 mg once daily for 5 days provided a greater control of 24-hour intragastric pH than rabeprazole 20 mg. On day 5, 77% of esomeprazole recipients had an intragastric pH > 4 for 12 hours, while those of the rabeprazolegroup were 36% 24. Figure 2 shows the control of acid secretion induced by esomeprazole compared with other PPIs. The more effective and predictable acid control achieved with esomeprazole may reflect peculiar pharmacokinetic properties of the drug, which shows an advantageous metabolism leading to a decreased firstpass effect and a lower systemic clearance compared with omeprazole. This, in turn, results in higher plasma levels with more ‘drug reaching and blocking the gastric proton pumps in the acid secretory pathways.

Like other PPIs, the metabolism of omeprazole is mediated by the hepatic cytochrome P-450 (CUP) isoforms CYP3A4 and CYP2C19, which produce three pharmacologically inactive metabolites, omeprazole sulphone and 5-hydroxy plus 5-0-desmethyl omeprazole, respectively. Based on studies in human liver microsomes and cDNA-expressed enzymes, a significant stereoselectivity in the metabolism of optical isomers of omeprazole was observed. The R-isomer is almost exclusively metabolized (98%) via CYP2C19, 94% transforming to the 5-hydroxy metabolite, and 4% to the 50-desmethyl metabolite. Only 2% of the metabolism is via the CYP3A4 isoform. The S-isomer (esomeprazole) is metabolized primarily (73%) via the CYP2C19 isoform (46% going to the 5-0-desmethyl metabolite; 27% going to the 5-hydroxy metabolite), and by 27% via the CYP3A4 isoform to the sulphone metabolite. The intrinsic clearance (CL) of S-omeprazole is approximately one third of that of R-omeprazole, because of the considerably lower CL for formation of the 5-hydroxy metabolite (15 vs 43 pl/min) via CYP2C19. This implies that the total metabolic clearance for S-omeprazole is lower than that for R-omeprazole, resulting in higher plasma levels of the S-isomer in vivo 25and enhanced delivery to the proton pump (Fig. 3). Studies of pharmacokinetics in 32 healthy subjects revealed that plasma CL of esomeprazole decreasedfrom 22 l/h to 16 l/h and from 17 l/h to 9 l/h following repeated (5 days) dosing of 20 and 40 mg, respectively. The area under the plasma concentration-time curve (AUC) increased from 1.34 pm01 x h/l to 2.5 pmol x h/L, and from 4.32 ymol x h/l to 11.21 pm01 x h/l after 20 and 40 mg esomeprazole oral dose, respectively. The absolute bioavailability increased from 50 to 68% with a dosage of 20 mglday, and from 64 to 89% with

Fig. 3. Schematic representation illustrating the delivery of the same dose [indicated as ‘I 00 units1 of esomeprazoleand omeprazole racemate [a 500%mixture of the S- and the R-isomer) to the proton pump on the first day of treatment. The advantageousmetabolism of esomeprazoleresults in a higher percentage of the drug deliveredto the proton pump 64%) compared to omeprazole (38%1, which is more extensively metabolized in the liver. Quantitation is based on refs. 26,27.

a dosage of 40 mglday 26. In a separate study, intravenous administration of single doses of esomeprazole 1 or 2 weeks before and the day after 5 days of oral administration was found to decreaseplasma CL from 22 to 15.5 l/h, and from 17 to 9.2 l/h, with a dosage of 20 and 40 mg esomeprazole, respectively. Correspondingly, the plasma elimination half-life (t& increased from 0.8 to 1.2 h with both drug doses 26. The corresponding CL values after single iv doses of omeprazole racemate (20 and 40 mg) were 28 l/h and 24 l/h, respectively 27. Thus, the CL of esomeprazole is lower than that of omeprazole racemate. In a study involving 38 patients with symptoms of GERD, pharmacokinetic variables were evaluated after 5 days oral dosing with esomeprazole (20 and 40 mg) and omeprazole (20 mg). AUC following dosing with esomeprazole 20 mg was approximately 80% higher than with omeprazole 20 mg. This led to maximum plasma esomeprazole concentrations (C,,,) much higher (almost twofold) than those reached with the same dose of omeprazole racemate (2.42 vs 1.41 umol/l) l9 (Fig. 4). This suggests that the increased AUC of esomeprazole relative to omeprazole is attributable to an advantageous metabolism (i.e., lower first-pass elimination) probably due to inhibition of CYP2C19 activity, which is responsible for approximately two-thirds of the total esomeprazole metabolism, and a lower systemic CL for esomeprazole 2126. The higher esomeprazole bioavailability provides the rationale for an improvement of clinical efficacy of the drug compared with omeprazole, since the control of gastric acid secretion

Fig. 4. In patients with GERD,the area under the plasma concentra- 1 tion-time curve fAUC1 for esomeprazole 20 mg/day was 80% 1 greater than that of omeprazole20 mg/day, after 5 days of treat- 1 ment. With esomeprazole 40 mg/day, the AUC was five times 1 greater than that of omeprazole(adaptedfrom ref. 191 1

(i.e., the maintenance of intragastric pH above 4) is correlated to the AUC 28and mucosal healing 20.This means that esomeprazolemay exert a greater control on intragastric pH over the 24-hour period compared with omeprazole, which may translate into improved symptom control of GERD and other acid-related disorders 19.Furthermore, the effect of esomeprazole is more predictable, since inter-subject variability in AUC was lower with the S-isomer than with omeprazole 1929(Fig. 5). Patients with severe liver function deficit had a lower rate of metabolism, as would be expected, compared with GERD patients with no liver dysfunction, where-

Fig. 5. Variability in the inhibitionof pentagastrin-stimulatedacid secretion following esomeprazole f20 mg/dayl or omeprazole f20 mg/dayl treatment for 5 days in healthyvolunteers. Note that the interindividual variability with esomeprazoleis lower than that with omeprazole[adaptedfrom ref. 291.

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as those with mild or moderate liver diseaseexhibited no relevant alteration in the pharmacokinetics of esomeprazole 3o. In this respect, it is unlikely that impairment of renal function may alter esomeprazoledisposition. A slight sex difference was observed in the pharmacokinetics of esomeprazole,since the AUC and C,, were slightly (not significantly) higher in females than in males 2629. The elderly may exhibit altered drug (including PPIs) disposition as a result of a reduced metabolic capacity of cytochrome P450 isoforms 3132.However, differencesin PPI metabolism in the elderly are not clinically relevant, and thus dose adjustment is not required simply on the basis of patient age. A study aimed at evaluating the pharmacokinetic profile of esomeprazole (40 mg once daily) in elderly volunteers revealed that AUC and Cmax values of the drug were not significantly different from those obtained in a group of middle-aged patients with GERD. This means that esomeprazole, which has a wide therapeutic window, do not require dose adjustment in the elderly like all other PPIs 33. Altered absorption of drugs with pH-sensitive absorption and/or altered metabolism are the main events leading to potential drug interactions with PPIs. Since esomeprazolemay interact with CYP2C 19, drug interaction studies were conducted with diazepam, phenytoin and (R)-warfar...