DRUG EVALUATION
`
`Drugs 1996 Mar: 51 (3): 460-482
`0012~7/96/0003.()46()/$23.00/0
`
`© Adis International limited. All rights reserved.
`
`Pantoprazole
`A Review of its Pharmacological Properties and
`Therapeutic Use in Acid-Related Disorders
`
`Andrew Fitton and Lynda Wiseman
`Adis International Limited, Auckland, New Zealand
`
`Various sections of the manuscript reviewed by:
`G. Brunner, Medizinische Hochschule Hannover, Abt fUr Gastroenterologie und Hepatologie, Hannover,
`Germany; G. Dobrilla, Divisione di Gastroenterologia, Ospedale Generale Regionale, Bolzano, Italy;
`C. Howden, Division of Digestive Diseases and Nutrition, The University of South Carolina, Columbia,
`South Carolina, USA; G. ]udmaier, Clinic of Internal Medicine, Department of Gastroenterology, Innsbruck,
`Austria; U. Klotz, Dr. Margarete Fischer-Bosch-Institut fUr Klinische Pharmakologie, Stuttgart, Germany;
`H. Koop, 4th Department of Medicine, Klinikum Buch, Berlin, Germany; T. Miwa, Department of Internal
`Medicine, Tokai University School of Medicine, Kanagawa, Japan; ]. Mossner, Zentrum fUr Innere Medizin,
`Medizinische Klinik und Poliklinik II, Universitat Leipzig, Leipzig, Germany; EO. Maller, FARMOVS
`Institute for Clinical Pharmacology and Drug Development, Department of Pharmacology, University of the
`Orange Free State, Bloemfontein, South Africa; G. Sachs, Department of Physiology and Medicine,
`Wadsworth VAMC and ACLA Medical Center, Los Angeles, California, USA; B. Simon, Facharzt fUr Innere
`Medizin-Gastroenterologie, Krankenhaus Schwetzingen, Schwetzingen, Germany; C.]. van Rensburg,
`Gastroenterology Unit, Department of Internal Medicine, Tygerberg Hospital, Tygerberg, South Africa.
`
`Contents
`. . . . . . . . . . . .
`Summa~
`1. Pharmacodynamic Properties
`1.1 Mechanism of Action ..
`1.2 Effects on Gastric Secretions
`1.2.1 Gastric Acid
`1.2.2 Gastrin .. . . . . . . .
`1.2.3 Pepsin. . . . . . . . . .
`1.3 Effects on Gastric Mucosal Morphology .
`1.4 Effects on Experimental Mucosal Ulceration
`1.5 Effects on Helicobacter pylori.
`1.6 Other Effects ................. .
`2. Pharmacokinetic Properties ........... .
`2.1 Absorption, Distribution, Metabolism and Elimination
`2.2 Drug Interactions
`3. Therapeutic Use ............ .
`3.1 Gastric Ulcer. . . . . . . . . . . . .
`3.1.1 Comparison with Ranitidlne
`3.1.2 Comparison with Omeprazole
`3.2 Duodenal Ulcer . . . . . . . . . . . . .
`3.2.1 Comparisons with Ranitidine and Famotidine .
`3.2.2 Comparisons with Omeprazole . . . . . . . . .
`3.3 Treatment of Ulcers Resistant to H2 Receptor Antagonists.
`3.4 Gastro-Oesophageal Reflux Disease ......... .
`3.4.1 Comparisons with Ranitidine and Famotidine . . . .
`
`461
`465
`465
`466
`466
`468
`469
`469
`469
`469
`470
`470
`470
`471
`472
`473
`473
`473
`473
`473
`475
`475
`475
`475
`
`

`

`Pantoprazole: A Review
`
`3.4.2 Comparisons with Omeprazole
`3.5 Eradication of H. pylori.
`4. Tolerability .................. .
`5. Dosage and Administration. . . . . . . . .
`6. Place of Pantoprazole in the Management of Acid-Related Disorders .
`
`461
`
`476
`476
`476
`477
`478
`
`Summary
`-~--~
`Synopsis
`
`Pharmacodynamic
`Properties
`
`Pantoprazole is an irreversible proton pump inhibitor which. at the therapeutic
`dose of 40mg, effectively reduces gastric acid secretion.
`In controlled clinical trials, pantoprazole (40mg once daily) has proved su(cid:173)
`perior to ranitidine (300mg once daily or 150mg twice daily) and equivalent to
`omeprazole (20mg once daily) in the short term (::;8 weeks) treatment of acute
`peptic ulcer and reflux oesophagitis. Gastric and duodenal ulcer healing pro(cid:173)
`ceeded significantlyfaster with pantoprazole than with ranitidine, and at similar
`rates with pantoprazole and omeprazole. The time course of gastric ulcer pain
`relief was similar with pantoprazole, ranitidine and omeprazole, whereas duo(cid:173)
`denal ulcer pain was alleviated more rapidly with pantoprazole than ranitidine.
`Pantoprazole (40mg once daily) showed superior efficacy to famotidine (40mg
`once daily) in ulcer healing and pain relief after 2 weeks in patients with duodenal
`ulcer in a large multicentre nonblinded study.
`In mild to moderate acute reflux oesophagitis, significantly greater healing
`was obtained with pantoprazole than with ranitidine and famotidine, whereas
`similar healing rates were seen with pantoprazole and omeprazole. Pantoprazole
`showed a significant advantage over ranitidine in relieving symptoms of heart(cid:173)
`burn and acid regurgitation. Reflux symptoms were similarly alleviated by
`pantoprazole and omeprazole.
`Preliminary results indicate that triple therapy with pantoprazole, clar(cid:173)
`ithromycin and either metronidazole or tinidazole is effective in the treatment of
`Helicobacter pylori-associated disease; however, these findings require confir(cid:173)
`mation in large well-controlled studies.
`Pantoprazole appears to be well tolerated during short term oral administra(cid:173)
`tion, with diarrhoea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%)
`and skin rash (0.4%) representing the most frequent adverse events. The drug has
`lower affinity than omeprazole or lansoprazole for hepatic cytochrome P450 and
`shows no clinically relevant pharmacokinetic or pharmacodynamic interactions
`at therapeutic doses with a wide range of drug substrates for this isoenzyme
`system.
`In conclusion, pantoprazole is superior to ranitidine and as effective as om(cid:173)
`eprazole in the short term treatment of peptic ulcer and reflux oesophagitis, has
`shown efficacy when combined with antibacterial agents in H. pylori eradication,
`is apparently well tolerated and offers the potential advantage of minimal risk of
`drug interaction.
`Pantoprazole causes irreversible inhibition of proton pump (H+,K+-ATPase) func(cid:173)
`tion. It is chemically more stable than omeprazole or lansoprazole under neutral
`to mildly acidic conditions, but is rapidly activated under strongly acidic condi(cid:173)
`tions. This pH-dependent activation profile underlies the improved in vitro selec(cid:173)
`tivity of pantoprazole against parietal H+,K+-ATPase compared with omeprazole.
`Oral pantoprazole (20 to 60mg once daily for 5 to 7 days) produces dose-related
`
`© Adis International limited. All rights reserved.
`
`Drugs 1996 Mar: 51 (3)
`
`

`

`462
`
`Fitton & Wiseman
`
`inhibition of basal, nocturnal and 24-hour gastric acid secretion in healthy vol(cid:173)
`unteers, with minimal additional inhibition at higher doses (80 and 120mg). An
`intragastric pH >3 was sustained for 8 and 14 hours with pantoprazole 40 and
`60mg, respectively, in healthy volunteers. Steady-state gastric acid inhibition was
`significantly more pronounced when pantoprazole (40mg) was given in the morn(cid:173)
`ing rather than the evening. In patients with duodenal ulcer and Helicobacter
`pylori infection, an intragastric pH >3 was sustained for 19 hours with
`pantoprazole 40mg.
`Oral pantoprazole 40mg appears to be more effective than omeprazole 20mg
`and as effective as omeprazole 40mg in inhibiting gastric acid secretion in healthy
`volunteers. Once daily administration of pantoprazole 40mg to healthy volunteers
`was significantly more effective than omeprazole 20mg in elevating daytime and
`24-hour intragastric pH, and marginally more effective than omeprazole 40mg in
`inhibiting nocturnal acid secretion. Pantoprazole was significantly superior to
`ranitidine 300mg once daily in increasing median daytime and 24-hour intra(cid:173)
`gastric pH.
`Pentagastrin-stimulated acid secretion in healthy volunteers is inhibited in a
`potent and long-lasting (> 24hours) manner after oral (20 to 40mg once daily) or
`intravenous (:5;80mg single dose; 15 to 30mg once daily) administration of
`pantoprazole.
`In patients with peptic ulcer, a marginally greater elevation in median fasting
`serum gastrin level was seen after 2 to 4 weeks' treatment with pantoprazole 40mg
`once daily «60%) than with ranitidine 300mg once daily (",30%), whereas sim(cid:173)
`ilar increases (:5;40%) were seen with pantoprazole 40mg and omeprazole 20mg
`(both once daily).
`Serum pepsinogen I levels are elevated following oral pantoprazole adminis(cid:173)
`tration, the effect being more exaggerated in patients with H. pylori infection
`(:5;150% increase).
`Toxicity studies in mice have shown gastric mucosal and submucosal glandu(cid:173)
`lar hyperplasia, but no evidence of gastric tumours, on prolonged exposure to
`high dose pantoprazole. In humans, long term (36 months) therapy with
`pantoprazole (40 to 80mg daily) has not been associated with any significant
`increase in enterochromaffin-like cell density.
`Pantoprazole does not appear to influence endocrine function on short term
`administration. No significant changes in adrenocorticotrophic hormone (ACTH)(cid:173)
`stimulated plasma testosterone or cortisol levels, or basal plasma thyroid hor(cid:173)
`mone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone,
`luteotrophic hormone, prolactin or somatotrophic hormone levels were observed.
`
`PantoprazoIc is rapidly absorbed after oral administration, with peak plasma con(cid:173)
`centrations of 1.1 to 3.1 mg/L occurring 2 to 4 hours after ingestion of an enteric(cid:173)
`coated 40mg tablet. The drug is subject to low first-pass hepatic extraction,
`displaying an estimated absolute oral bioavailability of 77%. Concomitant food
`intake does not affect bioavailability. Pantoprazole has a short mean plasma ter(cid:173)
`minal elimination half-life (tl/2~; 0.9 to 1.9 hours); however, inhibition of acid
`secretion, once accomplished, persists long after the drug has been cleared from
`the circulation. On repeated oral administration, the pharmacokinetics of
`pantoprazole (20 and 40 mg once daily) are similar to those after single dose
`administration.
`In accordance with its high degree of plasma protein binding ('" 98%),
`
`Pharmacokinetic
`Properties
`
`© Adis Interna~onal Limited. All rights reserved.
`
`Drugs 1996 Mar; 51 (3)
`
`

`

`Pantoprazole: A Review
`
`463
`
`pantoprazole has a relatively low apparent volume of distribution (mean 0.16
`Llkg at steady-state). Following an initial distribution phase, plasma pantoprazole
`concentrations decline in a monophasic manner, with an apparent mean t'/2P of
`0.9 to 1.9 hours.
`Pantoprazole undergoes extensive hepatic metabolism via cytochrome P450-
`mediated oxidation followed by sulphate conjugation. Elimination is predomi(cid:173)
`nantly renal, with ",80% of an oral or intravenous dose being excreted as urinary
`metabolites; the remainder is excreted in the faeces and originates primarily from
`biliary secretion.
`The pharmacokinetics of pantoprazole do not appear to be modified to any
`clinically relevant extent by renal impairment or haemodialysis. Although meta(cid:173)
`bolism and elimination of pantoprazole are impaired in patients with hepatic
`dysfunction, Cmax is only marginally elevated, indicating that pantoprazole may
`be administered to patients with hepatic impairment without dosage adjustment.
`In the elderly, the pharmacokinetics of pantoprazole are comparable to those in
`the young.
`Pantoprazole has lower affinity than omeprazole or lansoprazole for the he(cid:173)
`patic cytochrome P450 (CYP) enzyme system and does not appear to induce CYP
`activity. In healthy human volunteers, pantoprazole shows no clinically relevant
`interaction at therapeutic doses with phenazone (antipyrine), diazepam, digoxin,
`theophylline, carbamazapine, diclofenac, phenprocoumon, phenytoin, warfarin,
`nifedipine, caffeine, metoprolol or ethanol. In addition, it does not appear to
`compromise hormonal contraceptive efficacy as no interaction with a low dose
`combined oral contraceptive was shown. Conversely, the pharmacokinetics of
`pantoprazole are not modified to any clinically relevant extent by coadministered
`antacids, phenazone, phenytoin, digoxin or theophylline.
`
`In clinical trials investigating the efficacy of pantoprazole therapy in patients with
`peptic ulcer or reflux oesophagitis, pantoprazole (40mg), omeprazole (20mg) and
`famotidine (40mg) were administered once daily, and ranitidine (300mg) was
`administered as a single daily dose (peptic ulcer) or in 2 divided doses (reflux
`oesophagitis).
`Healing of acute gastric ulcer proceeded significantly faster with pantoprazole
`than with ranitidine [cumulative ulcer healing rates after 2, 4 and 8 weeks' treat(cid:173)
`ment of37, 87 and 97% (pantoprazole) and 19,58 and 80% (ranitidine)]. How(cid:173)
`ever, pain relief was similar with the 2 treatments (72% of pantoprazole and 68%
`of ranitidine recipients were completely pain-free after 2 weeks).
`In comparison with omeprazo\e, the gastric ulcer healing rate was initially
`(after 4 weeks) significantly higher with pantoprazole (88 vs 77%); however, after
`8 weeks, cumulative ulcer healing rates with the 2 drugs were similar (97 vs 96%).
`Both drugs rapidly alleviated gastric pain (79% of pantoprazole and 68% of
`omeprazole recipients were pain-free after 2 weeks), nausea, vomiting, retching,
`heartburn and acid regurgitation.
`Pantoprazole has performed significantly better than ranitidine in healing un(cid:173)
`complicated acute duodenal ulcer and in alleviating ulcer pain. Ulcer healing rates
`were invariably higher with pantoprazole than with ranitidine (61 to 81 % vs 35
`to 53% at 2 weeks; 82 to 100% vs 70 to 86% at 4 weeks). This advantage generally
`translated into a significant superiority for pantoprazole in relief of ulcer pain (77
`to 84% vs 58 to 72% of patients pain-free) and other gastrointestinal symptoms
`(79 to 87 vs 64 to 71 % of patients symptom-free) after 2 weeks' therapy.
`
`Therapeutic Use
`
`© Adis International Limited. All rights reserved.
`
`Drugs 1996 Mar; 51 (3)
`
`

`

`464
`
`Fitton & Wiseman
`
`Pantoprazole achieved duodenal ulcer healing and pain relief in a significantly
`larger proportion of patients than did famotidine after 2 weeks (ulcer healing 82
`vs 68%; pain relief 87 vs 72%); however, ulcer healing rates were similar in the
`2 treatment groups after 4 weeks' treatment (93 vs 88%).
`In contrast, pantoprazole and omeprazole have quantitatively similar effects
`on duodenal ulcer healing and symptoms. Cumulative ulcer healing rates were
`similar with the 2 drugs (65 to 74% at 2 weeks; 89 to 96% at 4 weeks), as was
`relieffrom ulcer pain (81 to 86% pain-free at 2 weeks).
`Recent findings indicate that pantoprazole is effective in the treatment of
`peptic ulcers poorly responsive to standard or high dosages of histamine H2 re(cid:173)
`ceptor antagonists. A healing rate of 96.7% was achieved in patients with ulcers
`refractory to high dose ranitidine following 2 to 8 weeks' treatment with
`pantoprazole 40 to 80 mg/day, and pantoprazole maintenance therapy was effec(cid:173)
`tive in preventing ulcer recurrence for up to 3 years.
`In the treatment of mild to moderate acute reflux oesophagi tis, pantoprazole
`appears to be of equivalent efficacy to standard dose omeprazole but superior to
`standard dose ranitidine or famotidine. Significantly higher healing rates were
`obtained with pantoprazole compared to ranitidine (69 vs 57% at 4 weeks; 82 vs
`67% at 8 weeks) and famotidine (80 vs 57% at 4 weeks; 93 vs 72% at 8 weeks).
`Marked symptomatic improvement occurred with pantoprazole and ranitidine as
`early as week 2 of treatment, with pantoprazole showing a significant advantage
`in relieving heartburn (weeks 2 and 4) and acid regurgitation (week 4). Overall
`relief of the 3 main symptoms of reflux (heartburn, acid regurgitation and
`odynophagia) significantly favoured pantoprazole over ranitidine (72 vs 52% of
`patients with complete resolution at 4 weeks).
`Pantoprazole and omeprazole were equally effective in the endoscopic healing
`and symptomatic relief of reflux oesophagitis, as reflected in similar ulcer healing
`rates (74 to 79% vs 75 to 79% at 4 weeks; 90 to 94% vs 91 to 94% at 8 weeks),
`and rates of resolution of reflux symptoms (59 to 71 % vs 69 to 73% at 2 weeks;
`83 to 85% vs 80 to 86% at 4 weeks).
`One week of triple therapy with pantoprazole (40mg twice daily), clar(cid:173)
`ithromycin (500mg 3 times daily) and metronidazole (500mg 3 times daily) in
`patients with H. pylori-associated duodenal ulcer achieved an eradication rate of
`97% and duodenal ulcer healing in 98% of patients after 4 weeks. Administration
`of pantoprazole (40mg twice daily), clarithromycin (500mg twice daily) and
`metronidazole (500mg twice daily) produced H. pylori eradication in all patients
`with H. pylori associated gastrointestinal disease (n = 25). An eradication rate of
`86% was achieved after 5 weeks using 7- to lO-day triple therapy with the same
`dosage of pantoprazole but lower dosages of clarithromycin (250mg twice daily)
`and either metronidazole (400mg twice daily) or tinidazole (500mg twice daily).
`Pantoprazole has been well tolerated in short term (:5; 8 weeks) and long term
`studies (up to 4 years) when administered at the standard dosage of 40mg once
`daily or higher dosages (up to 120 mg/day) to patients with acid-related disorders.
`On short term administration, the most frequent adverse events with the drug
`included diarrhoea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%)
`and skin rash (0.4%). These were generally of mild or moderate intensity, rarely
`necessitating treatment withdrawal, and were no more frequent with pantoprazole
`than with standard dosages of ranitidine and omeprazole. Clinically relevant al-
`
`Tolerability
`
`© Adis Intemational Limited. All rights reserved.
`
`Drugs 1996 Mar: 51 (3)
`
`

`

`Pantoprazole: A Review
`
`465
`
`terations in routine laboratory parameters have not been noted on short term
`therapy.
`Limited long term (6 months to 4 years) tolerability data in patients with peptic
`ulcer indicated that pantoprazole was without significant adverse effects, apart
`from an episode of peripheral oedema which resolved on drug withdrawal, and
`did not increase enterochromaffin-like (EeL) cell density.
`Pantoprazole is available as a 40mg enteric-coated tablet for once daily oral
`administration. Dosage modification is not required in the elderly or in patients
`with renal or hepatic impairment.
`
`Dosage and
`Administration
`
`1. Pharmacodynamic Properties
`
`Pantoprazole, a substituted benzimidazole de(cid:173)
`rivative (fig. I), is an irreversible proton pump in(cid:173)
`hibitor which has been developed for the treatment
`of acid-related gastrointestinal disorders. In com(cid:173)
`mon with other drugs of its class (e.g. omeprazole,
`lansoprazole), pantoprazole reduces gastric acid
`secretion through inhibition of the proton pump on
`the gastric parietal cell.
`
`1 .1 Mechal"1ism of Action
`
`The involvement of the proton pump (H+,K+(cid:173)
`ATPase) in the regulation of gastric acid secretion
`by the parietal (oxyntic) cell is well established
`(fig. 2).1 1,2]
`Optimally, an acid-activated proton pump inhib(cid:173)
`itor should exhibit chemical stability at neutral pH
`(to exclude targets other than parietal cell H+,K+(cid:173)
`ATPase), a high degree of activation under strongly
`acidic conditions and relative stability under
`mildly acidic conditions (to avoid activation in
`other cellular compartments/organelles).
`As a weak base (pKa = 3.9), pantoprazole is
`highly ionised at low pH and readily accumulates
`in the highly acidic canalicular lumen of the stim(cid:173)
`ulated parietal cellP] In this acidic environment
`pantoprazole is rapidly converted to the active spe(cid:173)
`cies, a cationic cyclic sulphonamide, which binds
`covalently to cysteine residues on the luminal
`(acidic) surface of H+,K+-ATPase to form a mixed
`disulphide, thereby causing irreversible inhibition
`of gastric proton pump functionp-5] As H+,K+(cid:173)
`ATPase represents the final step in the secretory
`process, inhibition of this enzyme suppresses gas-
`
`tric acid secretion regardless of the primary stimu(cid:173)
`lus.
`Acid-induced activation is a feature common to
`the substituted benzimidazole class of proton pump
`inhibitors and provides the basis for their selective
`action against gastric H+,K+-ATPase.l6,7] Although
`these compounds are all rapidly activated under
`
`CC~~-{"10
`
`II~~
`I
`o
`H
`Lansoprazole
`
`Fig. 1. Structural formulae of the proton pump inhibitors
`pantoprazole, lansoprazole and omeprazole.
`
`© Adls International limited. All rights reserved.
`
`Drugs 1996 Mar: 51 (3)
`
`

`

`466
`
`Fitton & Wiseman
`
`.""..--
`
`-
`
`-
`
`-
`
`Canaliculus
`
`;-JlIb-lh •• ~"",--- pumps
`
`Active
`
`RestIng
`pumps
`
`pantop raZOlel \ t
`
`Acetylcholine
`
`Histamine
`
`Fig. 2. Inhibition of gastric parietal celi W,K+-ATPase activity by pantoprazole. Receptor-mediated stimulation of the parietal celileads
`to activation of the proton pump and exchange of cytoplasmic W for luminal K+ ions. Pantoprazole is concentrated and rapidly
`activated in the acidic lumen of the secretory canaliculus; interaction with H+,K+-ATPase in the canalicular membrane inhibits proton
`pump activity and acid secretion (after Sachs et aIJ1J).
`
`strongly acidic conditions (pH ::;3), pantoprazole is
`chemically more stable than omeprazole or
`lansoprazole under less acidic conditions (pH ",3.5
`to 7.4).[5,8.9] This is reflected in the ",3-fold lower
`inhibitory potency of pantoprazole compared with
`omeprazole against H+,K+ -ATPase under neutral to
`mildly acidic conditions.l5] In in vivo studies in the
`fistula dog, the duration of pantoprazole-induced
`intragastric pH elevation depended on the pre-drug
`acidity of the parietal cell population.l JOI
`The pH-dependent activation profile of
`pantoprazole might be expected to improve its se(cid:173)
`lectivity against parietal cell H+,K+-ATPase and re(cid:173)
`duce the likelihood of inhibitory effects in other
`acidic cell compartments such as lysosomes and
`chromaffin granules. In keeping with this, pantop(cid:173)
`razole is less active in vitro than omeprazole against
`the vacuolar H+-ATPase responsible for lysosomal
`acidification (IC5o = 194 vs 75 IlmoIlL).I5] Whether
`this greater pH selectivity confers an advantage in
`vivo with regard to tolerability has not yet been
`proven.
`Acid-induced activation also facilitated the in
`vitro bactericidal action of pantoprazole (section
`
`1.5), suggesting that this effect is similarly medi(cid:173)
`ated by covalent binding of the active species to a
`membrane-associated target. ATPase activity of a
`type normally associated with eukaryotic cells has
`been identified in the cell membrane of Helicobac(cid:173)
`ter pylori,!J I] and under acidic conditions (pH 4.0)
`this enzyme is strongly inhibited in vitro by
`pantoprazole and other substituted benzimida(cid:173)
`zoles.l l21
`
`1 .2 Effects on Gastric Secretions
`
`1.2. 1 Gastric Acid
`Steady-state gastric acid inhibition after re(cid:173)
`peated once daily oral administration of pan top(cid:173)
`razole to healthy volunteers, is dose-related over
`the range 20 to 60mg,II3,14] with minimal addi(cid:173)
`tional inhibition evident at higher doses (80 and
`120mg) [table 1].1 13,15]
`Oral administration of pantoprazole 40 or 60mg
`once daily for 5 days resulted in significant (vs pla(cid:173)
`cebo) reductions in basal, nocturnal and 24-hour
`intragastric acidity in healthy volunteers, the
`higher pantoprazole dose virtually eliminating
`acidity over a 24-hour period (median 97% reduc-
`
`© Adis International limited. All rights reseNed.
`
`Drugs 1996 Mar: 51 (3)
`
`

`

`Pantoprazole: A Review
`
`467
`
`tion in H+ ion activity), apart from a 4-hour period
`around midnight.[14] An intragastric pH ~ 3.0 was
`achieved for 33 and 58% of the 24-hour cycle
`(equivalent to 8 and 14 hours) with low- and high(cid:173)
`dose pantoprazole, respectively, compared with
`14.9% of the time with placebo.[14]
`In a separate study, median 24-hour intragastric
`pH was significantly higher with pantoprazole
`40mg (pH 3.8) than with pantoprazole 20mg (pH
`2.9), but no further elevation was obtained with
`pantoprazole 80mg (pH 3.9))13] As confirmation
`of this plateau effect at higher doses after once
`
`daily administration, median 24-hour intragastric
`pH values
`in healthy volunteers receiving
`pantoprazole doses of 40,80 and 120mg were 3.4,
`3.3 and 3.6, respectively, while the median pH ex(cid:173)
`ceeded 4.0 for 33.9, 28.0 and 37.6% of the 24-hour
`cycle)15] Steady-state gastric acid inhibition was
`significantly more pronounced when pantoprazole
`(40mg) was given in the morning rather than in the
`evening, an intragastric pH ~4.0 being recorded for
`a median of 38% (morning administration) and
`31 % (evening administration) of the 24-hour cy(cid:173)
`cle,l23]
`
`Table I. Summary of the effects of short term administration of intravenous and oral pantoprazole (P) on intragastric acidity in healthy human
`volunteers.
`
`Reference
`
`Dose
`(mg)
`
`Median24h Median
`Duration No. of
`(days)
`volunteers intragastric
`daytime
`intragastric
`pH
`pH
`
`Median
`nocturnal
`intragastric
`pH
`
`Mean percentage Mean percentage
`time with
`time with
`intragastric pH
`intragastric pH
`~3.0
`~.O
`
`Intravenous administration
`Brunner et al.1161
`PSO+
`S mg/kg/h
`P40+
`6 mg/kg/h
`
`Fried et al.[171
`
`NS
`
`NS
`
`S
`
`12
`
`4.S
`
`4.5
`
`5.0
`
`99
`
`99
`
`66.S
`
`Oral administration
`Damann et al.[181
`
`Hannan et al,l141
`
`Koop et al,l151
`
`Koop et al.[191
`
`Reill et al.[131
`
`Reill et al.l201
`
`Scholtz et al.[211
`
`Hartmann et al.[221
`
`14
`
`5
`
`7
`
`7
`
`7
`
`7
`
`5
`
`7
`
`12
`
`11
`
`15
`
`7
`
`16
`
`12
`
`1S
`
`16
`
`4.3*
`P40
`1.S
`Placebo
`2.3*
`P40
`3.5*
`P60
`1.4
`Placebo
`3.4t
`P40
`3.3t
`PSO
`3.6t
`P 120
`4.2
`P40
`4.0
`040
`2.9
`P20
`P40
`3.S*
`3.9
`PSO
`4.2**
`P40
`2.7
`R300
`1.6
`Placebo
`3.2
`P40
`3.7
`L30
`2.75
`020
`1.5
`3.S*
`3.15*
`P40
`2.65
`1.4
`2.05
`020
`Abbreviations and symbols: h = hour; L = lansoprazole; NS = not specified; 0 = omeprazole; P = pantoprazole; R = ranitidine; * indicates
`statistically significant difference (p < 0.05) vs placebo; t indicates statistically significant difference (p < 0.05) vs baseline; * indicates
`statistically significant difference (p < 0.05) vs comparator agent or lower dose of pantoprazole.
`
`33*
`5S**
`14.9
`
`2.3*
`1.4
`1.9*
`4.0*
`1.2
`
`3.4
`1.7
`
`3.1*
`3.7*
`1.3
`
`4.3
`4.5
`
`4.4**
`2.0
`1.S
`
`33.9t
`2S.0t
`37.6t
`54.0
`50.0
`
`41.0
`46.0
`35.0
`
`© Adls International Limited. All rights reserved.
`
`Drugs 1996 Mar; 51 (3)
`
`

`

`468
`
`Fitton & Wiseman
`
`Preliminary findings suggest that median 24-
`hour intragastric pH profiles of patients with duo(cid:173)
`denal ulcer and H. pylori infection are higher than
`those in healthy volunteers following treatment
`with proton pump inhibitors; an intragastric pH >
`3 was achieved for 19 hours of a 24-hour cycle with
`pantoprazole 40mg.[24]
`On direct comparison, oral pantoprazole 40mg
`once daily appears to be more effective than omep(cid:173)
`razole 20mg once daily[20,21] and as effective as
`omeprazole 40mg once daily[18] in inhibiting gas(cid:173)
`tric acid secretion in healthy volunteers. Thus, after
`once daily oral administration for 7 days, pantop(cid:173)
`razole 40mg was significantly more effective than
`omeprazole 20mg in elevating daytime and 24-
`hour intragastric pH, the latter value increasing
`from (median) 1.2 (placebo baseline) to 3.15 with
`pantoprazole and
`to 2.05 with omeprazole
`20mgPI] Over an identical period pantoprazole
`was marginally more effective than omeprazole
`40mg in inhibiting nocturnal acid secretion, as re(cid:173)
`flected in the higher nocturnal intragastric pH (3.4
`vs 1.7) and the proportion of the night with an in(cid:173)
`tragastric pH > 4.0 (40 vs 25%).1 18)
`Pantoprazole 40mg and lansoprazole 30mg
`were both more effective than omeprazole 20mg in
`increasing intragastic pH in 18 healthy male volun(cid:173)
`teers,l20] 24-hour median pH values for lansop(cid:173)
`razole, pantoprazole and omeprazole were 3.7, 3.2
`and 2.75, respectively, and the fractions of time
`with intragastric pH >4.0 were 46, 41 and 35%.
`Direct comparison of the effects of oral pan(cid:173)
`toprazole 40mg once daily and ranitidine 300mg
`once daily in healthy volunteers indicated that the
`proton pump inhibitor was significantly superior to
`the histamine H2 antagonist in raising median day(cid:173)
`time intragastric pH (4.4 vs 2.0) and 24-hour pH
`(4.2 vs 2.7). Elevation in nocturnal pH did not dif(cid:173)
`fer significantly between the 2 treatment groups
`(3.1 vs 3.7).1 19)
`Potent and long-lasting inhibition of pentagas(cid:173)
`trin-stimulated acid secretion is seen after oral or
`intravenous administration of pantoprazole to
`healthy volunteers.l25-27) On oral administration of
`pantoprazole 20 or 40mg once daily, acid output,
`
`measured at 2.5 to 3.5 hours and 24.5 to 25.5 hours
`after the first dose (day 1), was reduced by 24 and
`26%, respectively, with pantoprazole 20mg and by
`51 and 52% with pantoprazole 40mg.[25] Corre(cid:173)
`sponding reductions in acid output after the final
`dose (day 7) were 56% and 50% with pantoprazole
`20mg and 85% and 66% with pantoprazole
`40mg,l25]
`
`1.2.2 Gastrin
`As noted with other anti secretory agents, a rise in
`serum gastrin levels accompanies the decreased gas(cid:173)
`tric acidity produced by pantoprazole.[13-15,19,25,261
`A significant elevation in basal and post-prandial
`serum gastrin levels was obtained with oral pan(cid:173)
`toprazole doses of 40mg or higher.l l3,28) Oral ad(cid:173)
`ministration of pantoprazole 40, 80 or 120mg once
`daily for 7 days significantly elevated median 24-
`hour serum gastrin levels from 24 nglL (baseline)
`to 68, 99 and 95 ngIL, respectively, in healthy vol(cid:173)
`unteersP8] This gastrin-elevating effect was most
`pronounced during the day and least during the
`early morning (0300 to 0900 hours), despite the
`low intragastric acidity at the latter time.l l4) Thus,
`in addition to the direct stimulatory effect of low
`intragastric acidity on gastrin release, it appears
`that acid suppression also exaggerates the gastrin
`response to food. I 14) This increase in fasting serum
`gastrin is reversed on discontinuation of pantop(cid:173)
`razole, with gastrin levels recovering to pretreat(cid:173)
`ment values within 7 days of stopping drug in(cid:173)
`take.[25)
`In large-scale randomised clinical trials con(cid:173)
`ducted in patients with peptic ulcer (see section 3),
`a marginally greater elevation in median fasting
`serum gastrin level was seen after 2 to 4 weeks'
`treatment with pantoprazole 40mg once daily
`«60%) than with ranitidine 300mg once daily
`(",,30%),[29-31) whereas similar increases (:5;40%)
`were seen after 2 to 4 weeks of once daily treatment
`with pantoprazole 40mg and omeprazole 20mg.f32,33)
`Pantoprazole caused less stimulation of gastrin
`output than omeprazole in a small study in healthy
`volunteers (n = 7).[18) Although mean 24-hour in(cid:173)
`tegrated plasma gastrin values rose appreciably (3-
`to 4-fold) during once daily administration of
`
`© Adis Intemotlonal Um~ed. All rights reserved.
`
`Drugs 1996 Mar; 51 (3)
`
`

`

`Pantoprazole: A Review
`
`469
`
`pantoprazole 40 to 80mg for periods of 5 to 7
`days,114,IS,191 gastrin output was significantly lower
`with pantoprazole 40mg than with an identical
`dose of omeprazole (1683 vs 3537 ng/L. 24h).l18]
`This finding requires confirmation in a larger
`study. In contrast, gastrin output was greater with
`pantoprazole 40mg than with ranitidine 300mg
`(1781 vs748ng/L.24h).l 191
`Among patients with duodenal ulcer treated
`with pantoprazole 40mg once daily for 5 days, sim(cid:173)
`ilar increases in preprandial and peak prandial se(cid:173)
`rum gastrin levels were noted in H. pylori-positive
`individuals (median 41 and 81 %, respectively) and
`those in whom H. pylori had been eradicated (me(cid:173)
`dian 45 and 69%, respectively),f341 As a conse(cid:173)
`quence of its higher baseline (pretreatment) value
`in infected individuals, the peak prandial serum
`gastrin level during pantoprazole treatment was
`significantly higher in H. pylori-positive patients
`than those in whom H. pylori had been eradicated
`(median 124 vs 76 ng/L).
`
`1.2.3 Pepsin
`As noted with omeprazole,13S,361 serum pep(cid:173)
`sinogen I levels are elevated after pantoprazole
`administration,l34] Patients with duodenal ulcer
`showed significant increases in both fasting and
`preprandial serum pepsinogen I levels following 5
`days' treatment with pantoprazole 40mg daily, the
`effect being more exaggerated in those with H. py(cid:173)
`lori infection,l341 Thus, the median percentage in(cid:173)
`crease in fasting and preprandial serum pepsinogen
`I levels was significantly greater in H. pylori(cid:173)
`positive patients (150% and 114%, respectively)
`than in patients in whom H. pylori had been erad(cid:173)
`icated