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    © All Rights Reserved
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    67 views18 pages

    Pompa Proton Inhibitor

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    Yenny Yenyen
    farmakokinetik klinik

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    © All Rights Reserved
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    Eur J Clin Pharmacol (2008) 64:935-951 DOT 10,1007SCRDIS-ISAIS3 REVIEW ARTICLE Proton pump inhibitors: an update of their clinical use and pharmacokinetics Roocived: 21 Jamury 2008 /Acceptet: 1 July 2008 /Publshod anne: 5 Auzust 2008 (© Springst-Verlags 2008 Abstract Background Proton pump inhibitors (PPIs) represent drugs of first choice for treating peptic uloer, Helicobacter pylori infection, gastrooesophageal reflux disease, nonsteroidal anti-inflammatory drug (NSAID}induced gastrointestinal lesions (complications), and Zollinger Ellison syndrome, Results The available agents (omeprazoleesomeprazol, lan soprazok, pantoprazole, and rabeprazole) differ somewhat in their pharmacokinetic properties (e, time-dosedependant bioavailability; metabolic pattem, interaction potential, genct- ic vatability, For all PPIs, there is a clear relationship between drug exposure (area under the plasma concentration! time curve) and the pharmacodynamic response (inhibition of ‘acid secretion), Furthamore, clinical cutoome (e.g., healing and eradication rates) depends on maintaining intragastric pH ‘values above certain threshold levels. Thus, any changes in clrug disposition will subsoquently be translated directly into clinical efficiency so that extensive metabolizersof CYP2CI9 ‘will demonstrate a higher rate of therapeutic nonresponse. Conclusions This update of pharmacokinetic, phammacotty- namic, and clinical data will provide the necessary guide by S.Shi- U. Koz Dr, Manic Fischer Boschlnsitut fir Klinische Phamakoogic, Ausbachstalle 11, 70576 Stuttzat, Gamany comail:ubichkotaikpstutartde S.Shi-U. Klow. University of Tusbingen, Tucbinan, Gamay Presen aairess: S.Shi Department of Pranvacy of Union Hospital, Toni Medical Colles, Huazhong University of Scimce and Tecinokcey, Wal, People’s Republic of China “hich to select between the various PPIs that diffe-based ‘on pharmacodynamic assessments—in their relative poten cies (c2. higher doses are needed for pantoprazole and lansoprazole compared with rabeprazole) Despite their ‘well-documented clinical efficacy and saty, there is still ‘a certain number of patients who are refractory t treatment ‘with PPIs (nonresponder), which will leave sufficient space for future drug development an clinical research. ‘Keywords Proton pump inhibitors «Pharmacokinetics Pharmacodynamics - Pepticulcer- Reflux disease + Helicobeacier pylori infection Introduction Proton pump inhibitors (PPIs) are the mainstays in treating, acid-related diseases. Since the introduction of cmeprazole in 1989, other PPIs became available, e.g, limsoprazole (1995), pantoprazole (1997), rabeprazole (1999), and the S- enantiomer of omeprazole 2001). PPls inhibit selectively and imeversibly the gastric HK’ ATPase (the proton pump) that accamplishes the final step in acid secretion. All PPIs inhibit both basal and stimulated secretion of gastric acid, independent of the nature of parietal cell stimulation [1]. PPIs underzo extensive hepatic metabolism by the cytochrome P4S0 (CYP) system, and CYP2CI9 polymomhisms have been shown to substantially influence the pharmacoki- netics, phamacodynamics, and clinical outcome of PPIs [2, 3]. In addition, pharmacokinetic and phamacody. namic differences between PPIs are reflected in their influence on both speed and degree of gastric acid suppression, which subsequently may affect their clinical efficacy [4]. D springer 936 EurJ Clin Pharmacol (2008) 64935-951 PPis are drugs of fist choice for peptic ulcers (PU) and their complications (e.g., bleeding). gastroesophageal reflux disease (GERD), nonsteroidal antiinflammatory drug (NSAID)induoed gastrointestinal (GD) lesions, Zol- lingerElison syndrome, dyspepsia, and eradication of Helicobacter pylori (E. pylori) with two antibiotics [5, 6] PPIs have demonstrated an excellent safety profile after approximately two decades of clinical use [7]. There are some unspecific adverse events (AEs) such as headache, nausea, and dianhea, but the main concem is emewing fiom the long-term suppression of acid secretion [8]. During the last few years, much new data have been Published on the pharmacological characteristics and therapeutic efficacy of PPIs. Therefore, it appears appro- priate 10 provide an update on the pharmacokinetics, Pharmacodynamic action, and clinical use of PPIs. Pharmacokinetic properties PPIs are substituted benzimidazole derivatives and mem= brane-permeable, weak bases that aocurnulate in acid spaces of the active parietal cell as prodrugs. Here, they undergo acic-eatalyzed conversion to the active sulfenic acid and sulfonamide derivatives. These bind covalently via disule fide bridges to cysteine residues on the alpha subunit of the 17K ATPase, thus inhibiting acid secretion up © 36 h [1]. Whereas racemic PPI prodrugs possess a chiral center, the identical biological active principle (which is optically inactive) is formed from both enantiomers. The main Pharmacokinetic parameters of all PPIs are compared in Table | [6, 9} ‘Omeprvzole and esomeprazole ‘Omeprazole is administered as a racemic mixture of its two enantiomers, S-omeprazole (esomeprazole) and R-omepra- ole. Both prodrugs are acid labile and usually administered as encapsulated enteric-ccated granules. After oral admin- istration, they are rapidly absorbed [9]. They should be swallowed at least | h before eating, The bicavailablity (F) of esomeprazole was significantly reduced when taken ‘within 15 min before eating a highefat meal compared with fasting conditions [|0} When increasing the dose and after repeated administration of omeprazole or esomeprwole, the maximal plasma concentration (Cag) ad area under the ‘concentrationsime curve (AUC) increased in a nonlinear fashion [11], which is due to decreased first-pass elimina- tion and decreased systemic cleazanoe (CL). Furthermore, due to a lower metabolic rate of esomeprazole compared with Re or racemic omeprazole, esomeprazole resulted in higher AUC values [1]. Similarly, in patients with GERD, the Cou and AUC values of esomeprazole inaweased! on day 7 versus day I by 80% and 50%, respectively [12] ‘Omeprazole and esomeprazole are extensively metabo~ lized by CYP2CI9 and CYP3A4, Omeprazole is converted mainly to hydroxyl and S-Odesmethyl metabolites by CYP2CI9 and to the sulfone by CYP3A4 [6]. In vito studies suggest that esomeprazole is predominantly metab- lized by CYP3A4 and consequently is less dependent on CYP2CI9, which recently could be substantiated by a clinical study [13] Approximately 80% of each dose is excreted as metabolites in the urine [6]. CYP2CI9 polymerphisms can significantly influence the metabolism of omeprazole and esomeprazole [3, 14]. ‘Table 1 Pharmacokinetic properties of proton pump inhibitrs (according to Klotz [6)) Parmot Omeprzne Bsomerraale Lansoprale ——Pantopmimle——_—Rabepraole tow 6 1s 1221 m4 35 Fa 25-40 (Turon multiple SO acute dosing) 70-80 80-90) n 2 osina) (hrc desing) Lincar phamacokincics No No Yes Yes Ys fia 0s ons 048 2 08 V tikey 013035, 022-026 oa as - oth) os12 oss 921 0820 614 CL [mtnin) 4004620 330 Gate) 160-250tehwonic) 400-650 0-225 - CLE [min] 20 310 1s wo cea Negligible Negligible Negtiie Negligible Negligible Ent of ae Ab tia oF Clostiae Chet Geta Alta Renal insulceney Cetin F = Ciostat) Geytiz — AiPstioe Hepatic dysfinction Ly tha THF? CLptet Cte? GhuahFe Abtiet Jos tine to mensimal plasra convention, F oral bioavailability, fe faction of dug unbound in plasma, appara volume of diswibaien, f2 clininaton hal i, CL systemic clearance, CL/F apparent oral clearmec, faction excreted in unchanged fom io wine 7 incase, | decraxs, + no significant chang, arrons in purstheses effets are equivocal D springer Eur J Clin Pharmacol (2008) 61:935-951 oar Acconing to metabolic ate (phenotype) individuals can be ‘classified as homozygous extensive metabolizes (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM). The frequencies of these three sub- ‘groups show a wide interethnic variation, The prevalence of PM ranges fiom 1.2% to 3.8% in Caucasian Europeans and, ‘up to 23% in Asian Oceanian populations [15, 16]. PMs exhibit a 3- to 10-fold and hetEMs a 2- to 3-fold higher AUC (drug exposure) compared with homEMs [3, 14]. Ina recent study mean AUC ratios of omeprazole were :2.7-9.0 after a single oral dose of 40. mg and 1:1.7:43 after a single in, dose of 20 mg in six homEMS, eight hetEMs, and six PMs, respectively. Therefore, in PMs, F ‘was higher than that in homEMs andl hetEMs (87% vs. 62% and 41%; P<0.001) [17}. Similariy, in homEMs, hetEMs, ‘and PMs, the relative AUC ratios were 1:2.87.5 and t2 ratios 1:1:1.7 for omeprazole, indicating that disposition of ‘omeprazole is greatly dependent on the C¥P2C19 genotype [18], Similar ratios were reported after repeated doses of ‘omeprazole [9]. Interestingly, the elderly EMs showed a wide variance in their CYP2CI9 activity and were Phenotypically closer to the PMs than the young EMs ‘compared with the young PMs, Thus, in the elderly, the CYP2CI9 genotype may not be as usefil as phenotyping, 20} The most frequently and extensively described variant alleles for PMs are CYP2CI9*2 and CYP2C19*3, which encode for nonfunctional proteins. Recently, the CYP2C19*1 allele has been identified, which is associated with a very rapid metabolism phenotype and has a frequency of 18% both in Swedes and Ethiopians but only 4% in Chines populations [21]. Such subjects need higher doses of emeprazole for acid suppression [22, 23]. ‘The phamacokinetics of omeprazole was compared in 18 healthy adults and in 12 chikiren with GERD (mean age 6.1 years). Oral clearance (CL/F) and apparent volume of distribution (V) in healthy adults (0.62 L/h per kg and 0.76 Likg, respectively) were not significantly clfferent from those in chikiren with GERD (0.51 L/h per kg and 0.66 Likg, respectively). Therefore, dosing on a milligram kilogram basis was recommended, with no farther adjust ‘mats for teating GERD inchildren [24]. tn 27 children with, GERD aged II] years, the pharmacokinetic properties of escmepnizole were both dose (between 5-20 mg) and age pendent, The younger children (1-5 years) showed a mare rapid metabolism compared with older children (6-11 years) [25]. In 28 adolescent patients with GERD aged 12-17 ‘yeas, the mean AUC and Cox Values of esomeprzole were 3.5-fold higher with the 40 mg dose compared with the 20 mg dose with single and repeated-dose administration, ‘confining nonlinear phammacokinetics [26]. Al PPIs cause increases in intragastric pH, which can affect absorption of concamitantly given drugs, such as ketoconazole, vitamin By2, and digaxin [27}. In addition, ‘omeprvole caries the potential for inhibiting the hepatic elimination of a wide ringe of drugs, including carbamaze- Pine, diazepam, mephenytoin, methotrexate, nifedipine, phenytoin, warfarin, meflogpine, pyrimethamine, and sulfa dane [6 27, 28}, Likewise, inhibitors of CYP2CI9 or CYP3A4, eg, fluconazole [29] and fluvoxamine [30], can affect the metabolism of omeprazole, Furthenmore, omepra- 2ole is a substrate and inhibitor of P-elycopretein. So druz interactions could be also partly due to an inhibition of P- elycoprotein-mediated drug transport [31, 32} On the ‘contrary, St John’s wort can induce both pathways in the metabolism of omeprazole and decreased its AUC G84%) ‘aNd Cex (38-50%) [33]- AS with smoking, cmeprizole can dose dependently induce CYPIA2 [6], In general, it can be expected that the interaction potential of esomeprazole is similar to that of racemic omeprazole [27, 34]. “Triple therapy with omeprazole/clarthromycitvamoxicillin is widely used to eradicate #1. pylori. ‘The observed Phammmoodynamic synergism of these drugs is at least partly «due to pharmacokinetic interactions. The AUC of omepra- zole increased almost twofold after concomitant administra tion of claritnomycin [35]. Naproxen and rofecoxib did not interact with esomeprazole and visa versa. Apparently, esomeprizole can be used in combination with NSAIDs ‘without the risk of pharmacokinetic interactions [36]. Lansoprazole Lansoprazole is rapidly absorbed and displays a linear increase in plasma concentrations over a dose range of 1S— 60 me [37]. Pharmacokinetics of repeated doses is similar to that of a single dose, Lansoprazole is extensively and mpidly (ty: 1-2 h) metabolized into sulfone and 5- hydroxylated metabolites by CYP3A4 and CYP2CI9. A. sulfide metabolite is also present in smaller amounts [6, 37}. As CYP2CI9 is involved in the metabolism of Jansoprzole, it is not suprising that PMs have a 4.4-fold. higher AUC than homEMSs [3] The pharmacokinetics of lansoprazole (15 mg/day) in children with GERD aged 13— 24 months was comparable to those in older children and adults BS]. Fluvoxamine treatment increased AUC of lansoprazole 3.8efold (P<0.01) in homEMs and 2.5-fold (P<0.05) in hetEMs, whereas in PMS, no difference was found in any Phamacckinetic paramster [39]. A double-blind, random- ized contolled trial (RCT) showed that clarithromycin ‘treatment significantly increased Crna of lansoprazole 147, L.7l+, and 1.52-Old and AUC 1555174, and 1.80-fold_ in homEMs, hetEMs, and PMs, respectively. ‘These very similar effects indicate thatthe drug interactions resulted ffom inhibition of CYP3A4 [40]. Surprisingly, ‘gzapefiuit juice had no significant effect on the phaimiaco- kinetics of lansoprazole [41]. D springer 98 EurJ Clin Pharmacol (2008) 64935-951 Larsopnole did not demonstrate relevant interactions ‘with theophylline, phenytoin, prednisone, warfarin, diazo- pam, oral contraceptives, ivabradine, or methotrexate [37, 42, 43}, In renal tansplant recipients receiving tacrolimus and lansoprazole (30 mg) or rabeprazole (20 mg), elevated blood concentrations of tacrolimus were observed only in the very mare subgroup of subjects who are PM of, CYP2CI9 and bearing also the CYPIAS*H"3 genotype [44], Absorption of atazanavir was significantly reduced ‘when coadministered with lansoprazole, as evidenced by a 94% decline in AUC and by a 96% decrease in Cras [45) Pantoprazole Pantoprazole is rapidly absorbed afier oral administration of enteric-coated tablets, which avoid degradation of the PPL by gastric acid [6]. It harclly undergoes first-pass metabo- lism and has a bioavailability of approximately 77%, independent of dose and food intake. Pantoprazole shows linear pharmacokinetics after both iv. and oral administra tion, It is completely metabolized by CYP2CI9 and CYP3A4. In a major pathways pantoprazole undergoes O- «demethylation followed by sulfate conjugation and sulfone! sulfide formation [46] Pantoprvole has apparently no clinically relevant drug interactions, other than the class effect associated! with elevated intragastric pH. No drug interactions have been demonstrated between pantoprazole and a wide range of drugs, such as theophylline, diazepam, carbamazepine, digoxin, and warfarin [46, 47]. Unlike ‘omeprazole, administration of clarithromycin did not increase panteprazole levels [35]. Rabeprazole In healthy subjects, mean F has been calculated © 52% [4S]. Cyuye and AUC values were linearly related t0 the dose, whereas tras, and ty were dose independent. Rabeprazle’s metabolism is unique because of its reduc- tion to rabeprazole thioether via a nonenzymatic pathway ‘with renal elimination of the metabolites. Both CYP2C19 and CYP3A4 contribute only a small fiaction to the overall metabolism [49 Thus, rabeprazole will be less susceptible to the influence of genetic polymorphisms of either CYP2CI9 or CYP3AA {50}. In healthy Chinese subjects, the pharmacokinetics of rabeprazole was dependent to a ‘certain degree on the CYP2C19 genotype. AUC values for abeprvole differed among the three genotype groups (bomEM, hetEM, PM), with relative ratios of 1.0:1.3:1.8 afier a single dose and of 1.0:1.1:1.7 after repeated doses, respectively. These changes were much smaller than those cbserved for other PPIs [51]. The modest differences in AUC of rabeprzole were also consistent with other studies [I8, 52}. However, in 12 Chinese subjects receiving D springer rabeprazole 20 mg bei, the mean AUC values of abeprizole and rabeprazole thioether were higher (P< 0.001) in PMs than in EMs on day 1. Similar results were observed on day 4, which might be due to the high rabeprazole dose (40 mg/day) used in this study [53]. Pharmacokinetic properties of rabeprazole in children 12-16 years old were similar to adults, and during multiple dosing, only headache and nausea were sometimes reported (4). As the CYP450-mediated pathways are secondary in beprizole metabolism, it has a low potential for dus, interactions involving CYPs, Interaction studies with abeprizole revealed no significant metabolic effect on theophylline, phenytoin, warfarin, or diazepam [27, 49]. ‘Clarithromycin or verapamil did not alter the pharmacoki- netics of rabeprzole, imespective of the CYP2CI9 geno- types [55]- Interestingly, fluvoxamine, an inhibitor of CYPIA2 and CYP2CI9, increased AUC of rabeprazole ‘and rabeprazole thioether 2.8- and 5.1-fold in homEMs and 1.7- and 2.6-fold in hetEMs, respectively, whereas no difference was seen in PMs of CYP2C19 [56} According to in vitro experiments all PPIs showed some inhibition of CYP2C9, 2C19, and 3A4; the inhibitory potency of rabeprazole was relatively lower than that of the other PPIs [57] Pharmacodynamic profile ‘The primary effect of PPIs is suppression of gastric acid secretion, which will determine healing rates in GERD and. PU [58} Intragastric pH monitoring allows direct assess+ ment of acid suppression, and it is a very usefill measure with which to compare antisecretory therapies [59]. ‘Typically, the antisecretory effects of PPIs have been reported as mean or median 24-h intragastric pH or suppression of 24-h intragastric acidity expressed as time above a predefined pH threshold, Intragastric pH value above 3 (PU) and 4 (GERD) have been defined as therapeutic targets [60]. PPIs are regarded to be similarly effective, but their potency differs. Such differences may translate into a slight advantage for a particular PPI in a special clinical situation [61 Onset and degree of acid suppression AL PPI prodrugs undergo accumulation and acid activation in the parietal cell, which relies on their pK, values. Based ‘nin vitro experiments and pK, considerations, it can be estimated that rabeprazole will show the highest accumu- lation and faster conversion to the active form of the PPIs LL]. This might affect the speed of acid suppression by PPIs, Apparently an earlier sustained inhibition of acid Eur J Clin Pharmacol (2008) 61:935-951 79 secretion was seen with rabeprazole than with other PPIs, [62], Comparing the antisecretory efftots on the first day of dosing, rabeprazole achieved better acid control because the invagastric pH (34) and the time of pH >4 during the 24ch postdose were significantly (PS0.04) greater with rabeprazole than with lansoprazole, pantoprazole, or two formulations of omeprazole [63]. In contrast, in 72 healthy ‘volunteers, mean 24h pH and percentage of time for pk>4 ‘were not significantly different between lansoprazole 30 mz and rabeprazole 20 mg, Lansoprazole resulted in greater acid suppression during hous 0-5 on days I and 5, ‘whereas rabeprazole had greater suppression during: hours 11-24 on day 5 [64]. ‘In patients with heartbum, the intragastric pH profiles of all five PPIs were compared afier giving once daily esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg [65, 66]. ‘The results of day 5 sugaest that intragastric pH control with esomeprazole 40 mg/day was superior to other PPIs [65], Similarly, with the same dosing schedule, esomeprar zole maintained intragastric pH >4 for a longer time ‘compared with all other PPIs on days 1 and 5 [66] In seven healthy homEMSs, the median intragastric pH ‘and percent time pl1>4 for 24h increased! dose dependently ‘with omeprazole 10, 20, and 40 mg daily for 7 days, and 10 and 20 mg bid. were comparable with once-daily 20 and 40 mg. Conceming percent time pH>4 at nighttime, ‘omeprazole 20 mg bid. was superior (P<0.085) to 40: mg caily [67]. ‘Three RCTs indicated thata single dose of esomeprazole @O mg i.x) was superior to omeprazole (40 mg ix.) in reducing stimulated acid secretion, However, contol of intragastric pH was similar for escmeprazole and omeprazole at ahigh dose of 80 mg (over 30 min) + 8 mah (for 23.5 h) [68]. Esomeprazole 40 mg iv. resulted in 11.8 h with an intragasiic pl>4 compared with 51 h (P<0.0001) and 7.2 h (P<0001) for pantoprazole 40 mg ix. as infusion or bolus injection, respectively, suggesting that esomeprazole ‘was more potent than panteprazole [69]. Likewise, oral acministation of esomeprazole 40 mg b.id. provided better and more consistent inttagastric acid control than pantopra- ole 40 mebi.d. [70]. In patients with GERD, esomeprazole 0 meg daily oF bai) was compared with lansoprazole (30 mg daily or bid} Mean time pH>4 and mean 24h pH ‘ware highest for esomeprazole 40 mg bic, 5 followed by lnsopraole 30 mg bid, , esomeprazole 40 mg once daly, and lansoprazole 30 mg once daily [71]. Based on three pooled open studies in 80 subjects, single doses of abeprazole (20 mg) and esomeprazole (40 mg) were equivalent in their effects on 244h inwagastric pH. Afier 5 dys’ dosing, rabeprazole (20 mg) maintained pH>4 longer than 20 mg escmeprazole (62% vs 56%; P=0.046), whereas the lower dose (10 mg) of rebeprazole was slightly less effective (48%; P=0.035) [72]. These results were consistent with two other RCTS [73, 74]- ‘Ona milligram basis, acid inhibition by rabeprazole was significantly superior to omeprazole. Afier the initial dose, rabeprazole (20 mg) inhibited acid secretion by 72% after 11h and by 64% after 23 h compared with omeprazole 20 mg (4% and 38% P<0.03), This advantage was maintained for 8 days of treatment [75]. In addition, single and multiple doses of rabeprazole 20 mg produced greater acid suppression than oral or iv. pantoprazole 40 mg [76, 77). Furthermore, a reduced dose of rabeprazoe (10 me: bie <, ) was comparable with the higher dosages of rabeprazole 20 mg b.id. }, to lansoprazole (30 mg b.id. ), and to ‘omeprazole (20 mg b.id. ) for acid-suppressive efficacy [78,9 ‘Overall, pharmacodynamic and clinical data indicated that on a milligram basis, rabeprazole can provide the greatest degree of acid suppression among the available PPIs, It also may provide a faster onset toward a maximal antisceretory effect than other drugs of this class. This can be of therapeutic relevance, as clinical outcome depends on extent and duration of secretory inhibition, Impact of CYP2C19 polymorphism on acid suppression PPI-induced inhibition of acid secretion is closely related to AUC values [3, 14]. As EMs of CYP2CI9 have smaller AUC values than PMs, the genotype-dependent difference in pharmacokinetics will translate directly into. a less pronounced acid suppression in EMs (about 70% of ‘Caucasian patients) compared with PMs (see Teble 2 0 that EMs (and caniers of the CYP2CI9*17 allele) will emonstrate a higher rate of therapeutic nonresponse. This topic has been extensively investigated [80, 81]. Incight healthy EMS, rabeprazole (10 mg/day) showed a faster onset of rising intragastric pH and a stronger inhibition of gastric acid secretion than did lansoprazole GO mg/day) cr omeprazole (20 melday) [82]. In nine healthy, F pylor-negative homEMSs treated with rabepra- ole, omeprazole and lansoprazole once daily at reduced ‘Table 2. Influnce of CYP2C19 genorype on intragastric #1 (accom ing to Klotz (3) Median pH over 24 PPL PM xEM —homEM 57-66 5462 8-40 4a5S 3550 46-50 M4 34S 3848 ‘Omeprazale 20 mg for 738 days) Lansoprazole (30 mg for 8 days) Rabeprazale 20 mg for 8 days) PPL paoeon pump inhibiter, PV poor metabolers fet hetero e0, ‘exensive metabolzers, hom hamazygous exensive meeols D springer 40 EurJ Clin Pharmacol (2008) 64935-951 and standard doses for 7 days; the median values of the 2h peroent of time at pH>4 was dose dependent but did not exceed 65% under any of the regimens tested. Thus, to achieve effective acid suppression for the inital therapy of GERD, higher doses were needed in homEMSs [83]. “The efficacy of omeprazole (10 or 20 mg for 7 days) has been shown to be significantly stranger in PMs and hetEMs than in homEMs [84], Likewise, in 31 Korean patients with GERD receiving omeprazole 20 mg daily for 28 days, 24h intragastric pH in PMs (5.3) was higher (P=0.005) than that in homEMs @2.8) and hetEMs (3.6) [85]. In healthy volunteers (six homEMSs, nine hetEMs, five PMs) ‘treated with lansoprazole 30 mg b.id. , the median of 24h intragastric pH in PMs (6.1) was higher (P<0.08) than those in homEMs (4.5) and hetEMs (5.0). In contrast, when lansoprazole 30 mg b.id. was given with famotidine 20 mg, bid. the median intragastric pH was 54, 5.7, and 6.1, respectively. Thus, acid inhibition by lansoprazole was significantly influmced by the C¥P2CI9 genotype, but apparently this genetic influence could be offSet by the concomitant use of the Hereoeptar antagonist famotidine [86). “The impact of the CYP2CI9 genotype on the efficacy of rabeprizole was less consistent, In H, pylorinegative GERD subjects given rabeprazole 10 mgiday for 8 weeks, the intagastric pH elevation was independent of CP2CI9 ‘genotypes [87}, which was consistent with another study [52} In contrast, two studies with rabeprazole 20 or 40 mg, daily for 8 days demonstrated that acid inhibition by rabeprizole was dependent on the CYP2CI9 genotype [88, 89]. In Korean patients, pantoprazole 40 mg daily exhibited a ‘variable acid inhibition that was significantly dependent on the CYP2CI9 genotype [90], Asthere isa significantly positive relationship between the extent and duration of elevated intragastricpH and the clinical efficacy of PPIs, it can be anticipated that the CYP2CI9 ‘genotype will have a significant impact on the therapeutic cutcome of three PPIs (@g., omeprvole, lansoprazole, Pantoprvole) that are predominantly metabolized by this polymorphic enzyme. ‘Therapeutic use Peptic ulcer For the management of PU (healing induction and remission maintenance), both suppression of gastric acid secretion and eradication of # pylori are important mainstays. In general, there is little overall difference in PU bealing rates among PPIs, and reported stall ifer= ences can be explained best by the variable dosage regimens applied [91-93]. H. pylori eradication is accom- plished efficiently (80-90% eradication rates) by standard triple therapy with a PPL, amaxicillin, and clarithromycin or metronidazole [94-96] (Table 3), and there was no significant difference among the PPIs [97-101]. ‘A consensus on the optimal duration (7, 10, or 14 days) of firstline triple therapy is still missing, However, many controlled studies and metaranalyses [102-1C8] indicated that extending this stategy beyond 7 days is very unlikely to be clinically useful, especially if taking antibiotio- induced AES into account [101]. There are even some data suggesting that a rabeprazole-based tiple thempy for 4 «ays will result in eradication rates around 90% [109, 110]. More recently, sequential treatment consisting of 5 days of therapy with a PPI and amexicilin followed by 5 days of PPI + clarithromycin and tinidazole has attracted some favorable attention [11I=1 14]. As already outlined, the genotype of CYP2CI9 affects the pharmacokinetics and phamacodynamics of most PPIs. In a recent metacanalysis of dual and tiple therapies a, marked difference in the 1, pyri eradication rates between, PMshetEMs vs. homEMs was calculated, especially for ‘omeprazole [115]. Therefore, CYP2C19 polymorphism is a major predictor of treatment failure for H. por’ eradication [116 117}, ‘Table 3. Recommendation of Helicahucks pir eradication fonmulated in the Maasticht Consensus Report (adapted fiom Malfrtheiner et a. pay Choise Sateen Fis-choice meament + PPLanonicilln-lariramycin or metronidaole weaument remains dhe recommenda first-choice ueament in populations with less than 15-20% crithrernycin sistance prevalences + In populations with less than 40% mctonidzole resistance prevalence PPlcarithwomycin-metrnidezole is, preferable, + Quecuplethaapies ae allematve firs-chcice treatments. ‘Socondhoice treatment + Bismuh-tasod qusduple therapies remain the best second-choicetrstment + If not avilable, a PPI, amonicilin, or tetacyetine and metronidavole are recommended. “Thirdchoice teatment (esue ‘weatment) + Rescue treatment should be based on ntinicrobial susceptibility testing, D springer Eur J Clin Pharmacol (2008) 61:935-951 on Reflux disease “The objective of weating GERD [18] i to relieve troublesome symptoms (€,, heatbum, regurgitation), to restore quality of life, to heal oesophagitis (if present), and to reduce the risk of ‘complications. Thereby, acid suppression is the mainstay of therapy, and PPIs represent the best choice because they are nore potent than Hteceptor antagonist [11-122]. Depend- jing on the administered dose of the PPI and treatment uration, eg, 4 of 8 weeks, healing in around 50-60% ancl 80-00% of pationts, respectively, has been observed [123+ 126}, Thereby, symptom relief was apparently somewhat faster with mbeprazole than with omeprazole [127, 128]. Healing of GERD can be restored either by maintenance (remission rates about 85%) or, altematively, by on-cemand, treatment [129-132] Several studies have demonstrated the efficacy of pantoprazole (20 mg), esomeprazole (20mg), or abeprizole (10 mg) as on-demand therapy for longterm, management of patients with mild GERD [133, 134). ‘The impact of CYP2CI9 polymorphism on the clinical ‘outcome was also evaluated in patients with GERD. The presence of. variantallele was associated with a significantly lower risk of gastrioacid breakthroughs during PPI therapy [135}, Likewise, in two independent trials, 8-week healing rates of lansoprazole (30 mg) were significantly higher in PMs (85% and 100%) and hetEMs (68% and 95%) compared with homEMs (46% and 77%) [136, 137} Furthermore, during maintenance therapy (15 mg lansopra- ole) remission rates (after 6 months) were 61.5%, 78Y%, andl 100% in homEMs, hetEMs, and PMs, respectively [138]. In contrat, in three studies with esomeprazole, rabeprazle, and omeprazole, healing rates were not significantly affected by the CYP2CI9 genotype [13, 139, 140]. In potients with nonerosive reflux disease (NERD) [118], the response to standart! doses of PPIs seems to bo—for yet unknown reasons—lower than in patients with GERD [141, 142}, Symproms have been improved by rabepraoke (10 mg), esomeprazole (20 mg}, and lansoprazole (15 mg), and ‘on-cerrand treatment with PPIs appears to be also effective in the longeterm management of NERD [129, 133, 143-146]. NSAID-induced gastrointestinal lesions NSAIDs can cause GI lesions and result in dyspeptic symptoms and ulcerations and lead to increased risk of serious GI complications, Factors associated with an increased risk include intake of low-dose aspirin (ASS), history of ulcer or upper GI bleeding, age > 70 years, and ‘concomitant use of NSAIDs [147, 148]. Therefore, patients at risk should be considered for altematives to NSAID therapy, modifications of risk factors, as well as preventive strategies such as cotherapy with gastroprotective agents (PPIs or misoprostol) or cyclo-oxygenase-2 (COX-2)- selective inhibitors (coxibs) [149]. Importantly, prevention strategies must take into account both GI and cardiovascu- lar (CV) risk factors, as coxibs and probably most traditional NSAIDs increase the incidence of serious CV events [150, 151} Cotherapy with any PPI is an established option for prevention and healing of NSAID-associated GI lesions. All PPIs can provide effective acid suppression and decrease the morbidity anc mortality associated with Gllesions[152, 153]. ‘One meta-analysis of 118 trials (76322 patients) assessed the relative effectiveness and costeffictiveness of five strategies for the prevention of NSAID-induoed GI toxicity, PPIs significantly reduced the risk of symptomatic ulcers [relative risk (RR) 0.09; 95% C1 0.02-0.47 compared with, placebo, and NSAIDs plus PPIs was the most cosi-effective sirategy for avoiding endoscopic ulcers in patients requiring long-term NSAIDs therapy [154]. PPIs will prevent back diffusion of hycrogen ions (the major aggressive factor) into the mucosa In addition, as shown for rabeprazole, the mucosa might be restored by an increase in gastric production of protective mucus an mucin [155, 156}. Recent concem regarding potential CV risks of coxibs vill favor PPI cotherapy with NSAIDs, The minor gastric= sparing effect of coxibs is offset by concomitant use of low= ose ASS, whereas use of some NSAID plus PPI regimens may negate ASS’s antiplatelet benefits. In. addition, NSAIDs plus PPIs is at least as effective as the coxib strategy and may be more cost effective [157]. According, to a meta-analysis of four studies, NSAIDs plus PPIs afforded greater risk reduction for dyspepsia than did ‘coxibs, and NSAIDs plus PPIs vs. NSAIDs alone revealed 12.66% RR rection for PPI cotherapy with an absolute risk reduction of 9% [158]. Consequently, PPI should be ‘considered for the treatment and prevention of NSAIDs induced dyspepsia, It has been found that H. pyiort infection and NSAID use represent independent and synergistic risk factors for PU [159, 160], Ina meta-analysis of 21 studies, uncompli- cated PU was more commen in #. pyloriepositive than H. pylorisnegative NSAID users [odds ratio (OR) 1.81, In six ‘agematched controlled studies, H. pylori infection and NSAIDs use significantly increased the risk of PU COR, 403 and 3.10, respectively). The tisk was 17.5-fold higher ‘when both factors were present [160]. Evidence suegested that H. pylori eradication may prevent NSAID-induced ulcers in NSAID-naive patients, and in patients receiving Jongeterm NSAIDs, PPIs were very effective in preventing ‘ulcer recumence [161, 162} Peptic ulcer bleeding Peptic ulcer bleeding (PUB) represents an important emergency situation that is associated with considerable D springer on EurJ Clin Pharmacol (2008) 64935-951 morbidity, mortality, and healthcare system costs [163]. Several risk factors are involved, and elimination or modification of such etiopathogenetic factors will reduce the frequency of uloer recumences and PUB. Based on clinical and epidemiological data, it is evident that £2. port infection and NSAID intake (including low-dose ASS and ‘coxibs) are the two most important and independent risk factors [164, 165]. In addition, the eldery represent a population of elevated risks [164]. In three recent analyses, RR factors have been estimated (Gee Table 4). All NSAIDs and antiplatele‘anticoagulant agents have a similar poten tial to induce PUB, and if such drugs have to be taken, preventive strategies, incding H. pylori eradication, should be applied [165-168}. ‘Several options for treating PUB and preventing rebleed= ings are available. Epinephrine injection is the most ‘common endoscopic therapy for PUB [169], but following this successfull management, rebleeding will occur in about 20% of patients [170]. Metz-analyses indicate that endo- scopic hemostasis has reciced rebleeding and surgical interventions by >60% and mortality by 45% [I7I} Because profound! acid suppression (intragastric pHI>60) ‘optimizes stability of blood clots overlaying the ulcer and reduces the risk of rebleeding, endoscopic hemostasis is ‘often combined with drug-induced (H-teceptor antago- nists, PPIs) reduction of gastric acidity [172, 173]. Several reviews and meta-analyses of RCTS have been published conceming whether high-dose PPIs (intravenous |y as bolus/infusion and/or orally) affect PUB (see Table 5). Assessed outocmes were most frequently 30-days mortality, bleeding, need for surgerys or endoscopic retreatment. PPIs significantly reduced the risks of rebleeding and the need for surgery. However, mortality was not affected by PPI treatment, Surprisingly, this hard outcome measure was reduced in Asian trials [174-176]. Because most PPIs are Primarily metabolized by the polymorphic CYP2CI9, and Table 4 Relative risk (RR) factors for peptic leer bleeding because PMs are much most frequent (about 20%) in Asians than in Caucasians (about 3%), it could be speculated that in the Asian population, drug exposure by the high standard doses of PP! is more pronounced and thus more effective. Recently it was shown by a randomized prospective study in 129 bleeding peptic ulcer patients that oral ‘treatment with rabeprazole 20 mg bid. ) was oqually effective as endoscopic hemoclipping with subsequent iv. administration of Ho-receptor antagonists in tems of hemostasis (93%) and rebleeding: (7%) rates [177] Besides PPIs, (RR: 0433) H-receptor antagonists (RR 0.65) an nitrates (RR: 0.52) can also reduce the risks fOr PUB associated with NSAID intake, low-dose ASS, and. clopidogrel [178]. There is some evidence that iv. PPI therapy is more effective than oral treatment, However, the higher costs involved with i. administration do not justify this preference [179]. In conclusion, the addition of PPIs for endoscopic treatment of PUB is justified only for patients who have a high-risk lesion at endoscopy, as so far; there are no ‘convincing data conceming the reduction of mortality. In ackition, testing for and cure of #4 pyior’ infection should be considered, as this represents an independent risk factor, Zollinger-Ellison syndrome ‘The ZollingerEllison syndrome (ZES; gastrinoma) is characterized by hypersecretion of acid and intestinal ulcerations, Acid output and serum gastrin levels are elevated several fold in these patients. A proportion of subjects (up to 40%) may be cured by resection of the sestrincma, In action, gastrio-acid hypersecretion and the syndrome can be effectively controlled by PPIs [180}. In ‘general, high doses of PPIs (initially often administered intravenously by a short infusion) have been applied and Factor RR factor 5% CD Anmlyzod cases Referee NSAIDs * 37143) 1561 Garcia Rodkigucz & Baneaks Tolost [168] Coxibs* 260936) NSAIDs 5345-62) am Lamas eta. [166] Refecoxib 210.140) Clopidowreticlopidine 280.942) ASS (100 meilay) 27 20-36) Anticoagulans 28 21537) Preexisting peptic ulocr 43 P=008) 2 Fisher etal. [167] Smoking 3.1 (P0023) Use of antiplatelet agents 65 (P=0046) NSAIDs Conis 49 P0060) (CLoanfidence imenal, «NSAIDS wadional nonsterialantnflarmetory dues SDexodcpendent es D springer Eur J Clin Pharmacol (2008) 61:935-951 OB ‘Table 5 Proten pump inhibitor (PPD) therapy fer peptic ulocr bleoding: summary of rent reviews and metaamalyss Asses cuteome (Odds ratio (25% CA) for foc of | Number of tials Rerences (afer 30 dys) hhighelose PPP compl with placcbo (numberof patient)? Morality al als) 101 (140) 24 4373) Leoontiadis etal, [12-176] Mowtality (7 Asian wal) 035 (016-0.74) Robleeding, (049 (037-065) Endoscopic reteatment 022 G05!) Mortality 122-173) 4asi2) Deeward otal. [208] Robleding 81 (61-109) Neal for sursery (0.95 (068-1.35) Mortality all causes) 1@ ©7613) 26 4670) Kho etal [200 leer deaths 058 (035-096) Nomulor deaths 1.60 (105-241) Mortality 18 A855) Bankouc al. 210] Robles Noal for suwery Monaity 11 79-157) 21915) Leontiadis et, 211, 212] Rebleeding (046 (033-064) Noal for sowery 059 (046-076) Mortality and nocd for suery Both rates wore nc different 3 (L085) Anal et al. [213] Robleeding 050 (026-096) SInavencas bolus (40-80 mg) and infsion (at Kast 6-8 meth) ic must be empbusizal that the same tials (patios) have fequently boen analyz ‘control of acid secretion (measurement of acid output; 24-h intragastric pH monitoring) was the primary efficacy endpoint. Doses were generally adjusted (titrated) accord ing to the individual response in lowering basal acid output. In a shorten (7-10 days) open study with 11 male Patients with ZES, omeprazole (20-100 mg/day, mean dose 63 mg), lansoprzole (30-120 mg/day, mean dose 75 mg), and pantoprazole (40-200 mg/day, mean dose 116 mg) demonstrated a comparable antisecretory effect [181]. In 46 ZES patients during long-term (up to 10 years) ‘treatment, the median effective lansoprazole dose to control acid secretion was approximately 80 me/day (range 75-360 mgiday) [182]. Likewise, 49 patients with ZES and eight hypersecretors were treated with a daily median dose of 75 mg lansoprazole (7.5450 meiday) for up to 13 years. Forty-seven patients (70%6) remained symptem and lesion five, and 90% of patients had good 0 excellent clinical ‘outcomes without surgery [183]. In 26 patients with ZES and in nine with idiopathic hypersceretion, control of acid secretion was achieved by individual treatment with pantoprzole at 6 months, with doses of 40mg bid, 24), 80mg bid. (7), andl 120 me bid, (Q)sit filed in two subjects [184] This study was extended to an observation for 3 years 24), With maintenance doses between 40 and 120 mg bide acid output was controlled in all patients [185]. In 20 patients with ZES oF idiopathic hypersecretion, acid output was also contolled by rabepra- zole (60 mg for most patienss) for 2 years. Gastric biopsies showed no enterochromaflinike (ECL) cell dysplasia or neoplasia [186] For these limited clinical data, it can be cancluded that high, individualized doses of PPIs offer a (long-term) treatment option for patients with ZES. Clinical safety and adverse effects PPIs have demonstrated an excellent safety profile after approximately 20 years of clinical use in millions of patients with acid-related diseases, including pregnant ‘women and children [187, 188} PPIs are generally well tolerated, and the incidence of AEs is relatively lows The most frequent AEs, with incidences of 1-3% reported inthe clinical tials, were headache, nausea, diarthea, skin rashes, and constipation [189], Serious AES are inffequent, although rare cases of toxic hepatitis and visual disturbance have bean reparted [189, 190}. An increased risk of community-acquired pneumonia associated with PPI treatment has been found in a large ‘cohort of patients [191 Interestingly, in a population-based ccase-contiol study, the initiation of treatment with PPIs showed a particularly strong association with community: acquired pneumonia (OR 5.0; 95% CI 2.I-11.7), whereas the risk decreased! with treatment (OR 1,3; 95% Cl, 12= 14) [192} Some reports indicated that acute interstitial nephritis (AIN) was associated with PPIs [193, 194) However, a recent systematic review of 6 cases deman- sirated that PPFelated AIN was rare, idiosyncratic, and difficult to predict; there was a low prevalence association [195]. In addition, whether PPIs are a risk factor for D springer ou EurJ Clin Pharmacol (2008) 64935-951 Clostridium difficile-associated disease is. controversial [196, 197} Because longterm antisecretory therapy can affect absorption of calcium, PPIs may increase indirectly the risk of hip fracture, particularly for patients taking more than one dose per day [198, 199]. One nested case-control study showed that the OR for hip fractures increased over time with PPI use: 122, L41, 1.54, and 1.59 for 1, 2,3, and 4 years, respectively [199]. ‘Of major interest is PPI-induced hnypoacidity and hyper+ sgastrinemia. Long-term hypergastrinemia can cause ECL cell hyperplasia, which may predispose to carcinoids and might be important in gastric carcinogenesis [200]. In adkition, PPT therapy affects the pattem and severity of 7% pylori gastritis and accelerates the process of corpus gland, Joss, which is considered a risk factor for the development of gastric cancer [201]. To date, longe-term PPI therapy was not associated with an increased risk of gastric or colorectal cancer [201-203], but apparently it was associated with an ‘up to fourfold increase in the risk of fimdic gland polyps [204], Frequency and size of adenomatous polyps in the ‘colon cases (116) that used PPIs were not different from matched controls (194) in a series of 2,868 consecutive Patients undergoing colonoscopies [205]. ‘Conclusions Since the introduction of PPIs, considerable progress has been achieved in the management of gastric-acid-related disorders (@g., PU, GERD, ZES) and NSAID-induced GI lesions. The sucoess of PPIs is due both to their well documented clinical efficacy and safety. As the active Principles of available PPFprodrugs have the identical mode of action, resulting in elevating intragastric pl, the various PPIs can be used in an interchangeable fashion, ‘Whereas the pharmacodynamic profile of PPISis the same, some pharmacokinetic differences exist among these vahtable ‘agents that can slightly modify their clinical action because there are close relationships between pharmacokinetics, Pharmnoodynamics, and therapeutic cutoome. Systemic drug, exposure (AUC) will determine how fast and how long the intragastric target pH can be maintained above the threshold (Cauzet) level of >3 (PU) or>4 (GERD), which subsequently affects the healing rates of acitelated disorders, including H, pyior’ infections and NSAID-induced Gi lesions, Similar to other drugs, PPIs demonstrate a large interindividual variability in drug. disposition (ee, biom availability, AUC, metabolic pathways, hepatic elimination rates), which is caused by genetic and nongenetic factors. In addition, the interaction potential of PPIs in tems of drug metabolism shows some compound-specific differences. In relation to genetic factors, the influence of poly- morphisms of CYP2CI9 on the clinical outcome of PPIs D springer has beon extensively investigated, As this enzyme is mainly responsible for the metabolism (hepatic elimination rate) of ‘omeprazole, lansoprzole, and pantoprazole, their AUCS ‘and pharmacodynamic responses are much more dependent ‘on the genotypephenotype of CYP2C19 compared with esomeprazole (metabolic contribution by CYP3A4) or rabeprizole (eliminated mainly by a nonenzymatic path- way). It has been well documented by several clinical studies that standard doses of omeprazole and lansoprazole ‘are too low for many EMs (especially carriers of the (CYP2C19*17 mutation), resulting in a lager proportion of nonresponders in this subgroup representing about 70% of ‘Caucasian populations. Thus, geotypeadjusted dosing ‘ould improve the clinical outcome of these PPIs. Likewise, a PPI should be preferred that is less dependent on CYP2CI9 to overcome this genetically controlled variabil- ity 206, As all PPIs dose (AUC)-cependently elevate intragastric pH, solubility and absorption of other drugs given concom- italy might be affected to some extent, as has been exemplified for ketoconazole, vitamin Bs digoxin, atwzana- vin or calcium, In contrast to this “class effect,” druz interactions on the level of hepatic metabolism are more ‘compound specific. With omeprazole, induction of the CYPIA subfamily has been reported, and inhibition of hepatic elimination (mainly via CYP2C19 and CYP3A4) of several crugs must be considered (the latter is seen to some extent with esomeprazole also). The other three PPIs are ‘apparently devoid of this metabolic interaction potential. As the liver represents the major site of elimination for all PPI, Patients with moderate or severe hepatic dysfimetion have a reduced CL, and dose might be reduced for phamacok- netic reasons by factor 2 in such subjects. Due to structural differences affecting the biophysical ‘and biochemical properties ofthe PPIs, different dosages of the various agents are needed for the same pharmacody- namic response, e.g., for control of acid secretion in patients with ZES, relative potency dose ratios can be calculated for omeprazole, lansoprazole, and pantoprazole (1:0.81:0.54). In many cases, PPIs have to be taken Jong term, Under such conditions, hypergastrinemia and ECL cell hyperplasia ‘can develop. However, so far, this has not been associated! with @ significantly inreased risk of gastric cancer. AS experience for almost 20 years is now available, this Potential safety concem regarding all effective antisecretory strategies and conditions should not limit the use of PPIs, For various reasons (¢.2., nonadherence, CYP2CI9¥1 or “17 EM-genotype, resistance), some patients will be refiactory to PPI treatment [207], Such nonresponders might profit fiom an increased dose, a b.id. regimen, the addition of an H-receptor antagonist, or switching to a PPI with higher potency and less impact of genetic poly- Eur J Clin Pharmacol (2008) 61:935-951 ons morphisms, In addition, developing novel PPIs or other antisecretory agents might be an option for the future. In ‘conclusion, based! on long-term experience and extensive clinical data, PPIs still represent digs of first choice for managing PUsinchiding #4. pylori infection, GERD, ZES, and NSAID-induoed GI lesions. They provide a safe and ‘cost-effective treatment, Acknowledgements The socal help of Mrs. U, Hengemithle is, Apyrociatcd. 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