Pantoprazole

Am J Health Syst Pharm. 2001;58(11)

Pharmacokinetics

Understanding the pharmacodynamics of the PPIs is more relevant than knowing their pharmacokinetic parameters, since the duration of action depends on the rate of de novo proton-pump regeneration, not the duration of drug circulating in the body. Although the mean plasma half-life (t _1/2) after a single 40-mg intravenous dose of pantoprazole is 1.0 hour (range, 0.8 to 1.3 hours),^[4] a steady state of acid secretion does not occur until after approximately three days of once-daily dosing because a balance develops between synthesis of new enzyme and drug inhibition of existing ATPase.^[5] Pantoprazole is acid unstable and is thus prepared as an enteric-coated tablet, which should not be crushed. Its absorption is rapid, and the maximum concentration occurs approximately 2.5 hours after single or multiple oral 40- mg doses. Pantoprazole is well absorbed, undergoes limited first-pass metabolism, and has an absolute bio-availability of approximately 77%. The drug may be taken without regard to meals or antacids. Its apparent volume of distribution (V) is approximately 11.0 to 23.6 L, and the serum protein binding is ~98%. Pantoprazole is extensively metabolized in the liver through the cytochrome P-450 system, predominantly by CYP2C19 demethylation with subsequent sulfation and has a serum elimination half-life of about 1.1 hours. Pantoprazole does not accumulate, and its pharmacokinetics are not altered by multiple daily dosing. No dose adjustments are recommended in geriatric patients or those with renal failure or mild to moderate hepatic failure. In patients with severe liver cirrhosis, the half-life is somewhat prolonged to seven to nine hours.^[6] Pharmacokinetic data for individuals under 18 are not available.^[1]

A pharmacokinetic trial evaluating single intravenous doses in healthy volunteers found that 20- mg, 40-mg, and 80-mg doses exhibited a linear relationship in regard to the primary pharmacokinetic characteristics of area under the curve and maximum concentration. The t _1/2, clearance, and V were consistently not influenced by different doses and were similar to the pharmacokinetic parameters noted earlier for oral administration.^[4]

A clinical trial in healthy volunteers found equipotent inhibition of gastric acid secretion by equal doses of oral or intravenous pantoprazole. The primary parameter for the equivalence analysis was the percentage of time at which the intragastric pH was at least 4 or higher. The secondary parameter was the percentage of time at which the intragastric pH was at least 3 or higher.^[5] Clinical efficacy and pharmacodynamic equivalence of oral and intravenous 40-mg doses of pantoprazole have also been demonstrated in patients with erosive esophagitis.^[7,8,9]

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Table 1. Placebo-Controlled Studies of Pantoprazole for Erosive Esophagitis Associated with GERD a
Reference	Study Design (n = Patients in Efficacy Analysis) No. Patients	No. Patients	Results	Baseline Condition
Koop et al.^[10]	R, DB, P, MC. Study duration: 8 wk. PAZ 40 mg once a day (n = 149) versus RAN 150 mg b.i.d. (n = 69). Unbalanced ratio, 2:1	Enrolled: 249. Excluded: 31 (17 in PAZ group, 14 in RAN group)	PAZ was better than RAN in terms of healing rates at 4 wk (69% vs. 57%, p = 0.054). Statistical significance was reached after 8 wk (82% vs. 67%, p < 0.01). At 4 wk, PAZ provided significantly superior relief of the three key symptoms of heartburn, acid regurgitation, and odynophagia, when compared with RAN. Overall, PAZ patients experienced a higher rate of complete symptom resolution (72% vs. 52%, p < 0.01)	Patients had endoscopy-proven acute reflux esophagitis grade II or grade III (Savary and Miller classification)
Bochenek ^[11]	R, PC. Study duration: 8 wk. PAZ 10 mg once a day (n = 149), PAZ 20 mg once a day (n = 149), PAZ 40 mg once a day (n = 149), NIZ 150 mg b.i.d. (n = 69), or placebo	Not available	Endoscopic healing rates at 4 wk of therapy in the five groups were 42%, 57%, 70%, 21%, and 14%, respectively. The respective healing rates at 8 wk were 59%, 76%, 83%, 37%, and 32%. PAZ-treated patients had significantly fewer GERD symptoms by the end of both wk 4 and 8 (p < 0.01). At 4 and 8 wk, patients being treated with any dose of PAZ demonstrated superior EE healing compared with either NIZ or placebo (p < 0.001, Fisher's exact test)	Patients had endoscopically documented EE grade, 2 (Hetzel-Dent scale)
Corinaldesi et al.^[12]	R, DB, Par, MC. Study duration: 8 wk. PAZ 40 mg once a day (n = 103), OMZ 20 mg once a day (n = 105)	Enrolled: 241. Excluded: 33 (17 in PAZ group, 16 in OMZ group)	Healing rates for PAZ and OMZ were 78.6% vs. 79%, respectively, after 4 wk, and 94.2% and 91.4%, respectively, after 8 wk of therapy (p > 0.05 at 4 and 8 wk). Both groups experienced a similar time course of relief of the key symptoms -- heartburn, acid regurgitation, and pain on swallowing -- after 2 and 4 wk (p > 0.05). There were no significant differences between the treatment groups in primary efficacy variables or in key symptom data	Patients had grade II or III reflux esophagitis (Savary-Miller scale)
Mössner et al.^[13]	R, DB, Par, MC. Study duration: 8 wk. PAZ 40 mg once a day (n = 170), OMZ 20 mg once a day (n = 86). Unbalanced ratio, 2:1	Enrolled: 286. Excluded: 30 (21 in PAZ group, 9 in OMZ group)	The 4-wk healing rates for PAZ compared with OMZ were 74% vs. 78%, respectively (p = 0.57). Cumulative healing rates after 8 wk were 90% vs. 94%, respectively (p = 0.34). After 4 wk, 83% of the PAZ group and 86% of the OMZ group were completely free of symptoms (p = 0.72). There were no significant differences between the treatment groups in healing rates or symptom relief

a GERD = gastroesophageal reflux disease, PAZ = pantoprazole, RAN = ranitidine, R = randomized, DB = double-blind, P = prospective, MC = multicenter, NIZ = nizatidine, EE = erosive esophagitis, OMZ = omeprazole, Par = parallel group, C = crossover.

Table 2. Placebo-Controlled Studies of Pantoprazole for Duodenal Ulcers a
Reference	Study Design (n = Patients in Efficacy Analysis)	No. Patients	Results	Baseline Condition
Cremer et al.^[20]	R, DB, Par, MC. Study duration: 4 wk. PAZ 40 mg once a day (n = 124), RAN 300 mg h.s. (n = 126)	Enrolled: 276. Excluded: 26	PAZ was superior to RAN in endoscopically confirmed healing at 2 wk (73% vs. 45%, p < 0.001) and in symptom improvement at 2 wk (84% vs. 72%, p < 0.05). Healing rates at 4 wk were not significantly different in the two treatment groups, with cumulative healing rates of 92% and 84% (p = 0.073)	Patients had endoscopy-diagnosed duodenal ulcers
Chen et al.^[21]	R, DB, SC, Par. Study duration: 4 wk. PAZ 40 mg once a day before breakfast (n = 73), RAN 300 mg h.s. (n = 65)	Enrolled: 160. Excluded: 22	There was a trend toward better healing rates in the PAZ group at 2 wk (61% vs. 51%), which reached significance at 4 wk (97% vs. 77%, p < 0.01). The rate of pain-free ulcer incidents was higher in the PAZ group than in the RAN group at 2 wk (84% vs. 60%, p < 0.01).	Patients had endoscopy-diagnosed duodenal ulcers
Rehner et al.^[22]	R, DB, MC, Par. Study duration: 4 wk. PAZ 40 mg once a day (n = 185), OMZ 20 mg once a day (n = 91)	Enrolled: 286. Excluded: 10	Ulcer healing rates for PAZ and OMZ were 71% vs. 74% (p > 0.05) at 2 wk and 96% vs. 91% (p > 0.05) at 4 wk, respectively. Symptom relief at 2 wk was 85% vs. 86%, respectively (p > 0.05).	Patients had endoscopy-diagnosed duodenal ulcers
Beker et al.^[23]	R, DB, MC, Par. Study duration: 4 wk. PAZ 40 mg once a day (n = 124), OMZ 20 mg once a day (n = 131)	Enrolled: 270. Excluded: 15	Per protocol analysis, ulcer healing rates for PAZ and OMZ were 71% vs. 65% at 2 wk (p = 0.31) and 95% vs. 89%, respectively, at 4 wk (p = 0.09). Pain relief at 2 wk was 81% vs. 82%, respectively (p = 0.87).	Patients had endoscopy-diagnosed duodenal ulcers

a PAZ = pantoprazole, RAN = ranitidine, R = randomized, DB = double-blind, Par = parallel group, MC = multicenter, SC = single center, OMZ = omeprazole.

Table 3. Placebo-Controlled Studies of Pantoprazole for Acute Gastric Ulcers a
Reference	Study Design (n = Patients in Efficacy Analysis)	No. Patients	Results	Baseline Condition
Hotz et al.^[25]	R, DB, MC, Par. Study duration: 4 wk. PAZ 40 mg once a day (n = 147), RAN 300 mg h.s. (n = 74). Unbalanced ratio, 2:1	Enrolled: 248. Excluded 27	Healing rates in the PAZ group were superior to those for the RAN group at the 2-wk (37% vs. 19%, p < 0.01), 4-wk (87% vs. 58%, p < 0.001), and 8-wk (97% vs. 80%, p < 0.001) evaluation periods	Patients had endoscopy-diagnosed gastric ulcers
Witzel et al.^[26]	R, DB, MC. Study duration: 8 wk. PAZ 40 mg once a day (n = 146), OMZ 20 mg once a day (n = 73). Unbalanced ratio, 2:1	Enrolled: 243	Complete ulcer healing was PAZ 88% vs. OMZ 77% (p < 0.05) at 4 wk and 97% vs. 96% at 8 wk (p > 0.05). There was rapid relief from ulcer pain with both PAZ and OMZ, with no significant difference in the incidence of complete pain relief at either 2 or 4 wk. Complete ulcer healing at 4 wk was better in the PAZ group than in the OMZ group. At 8 wk there was no significant difference between treatment groups	Patients had endoscopy-established gastric or intrapyloric ulcers

a PAZ = pantoprazole, RAN = ranitidine, R = randomized, DB = double-blind, MC = multicenter, Par = parallel group, OMZ = omeprazole.

Table 4. Comparison of Pantoprazole and Omeprazole Triple-Therapy Regimens a
Result	OMZ 40	PAZ 40	PAZ 80
Eradication at 4 wk/6 mo (%)	94/92.8	79.7/63.2	93.7/90
Ulcer healing at 4 wk/6 mo (%)	96.4/94	83.5/75.9	96.2/92.5

a OMZ 40 = omeprazole 20 mg twice daily, PAZ 40 = pantoprazole 40 mg once daily, PAZ 80 = pantoprazole 40 mg twice daily.

Table 5. Table 5. Most Frequent Adverse Events Reported as Drug Related in Eight-Week U.S. Trials ^[a]
Study Event	Study 300 -- U.S. (% Incidence)		Study 301 -- U.S. (% Incidence)
Study Event	Pantoprazole (n = 521)	Placebo (n = 82)	Pantoprazole (n = 161)	Nizatidine (n = 82)
Headache	6	6	9	13
Diarrhea	4	1	6	6
Flatulence	2	2	4	0
Abdominal pain	1	2	4	4
Rash	<1	0	2	0
Eructation	1	1	0	0
Insomnia	<1	2	1	1
Hyperglycemia	1	0	<1	0

a Only adverse events with an incidence greater than or equal to the comparators are shown. Adapted from reference 1.

Table 6. Average Wholesale Prices (AWPs) of Proton-Pump Inhibitors Available in the United States ^[a]
Drug	Usual Daily Dose Range	AWP per Tablet, Capsule, or Vial ($)	Cost per Day ($)^[b]	Cost per 30 Days ($)
Pantoprazole (oral)	40 mg q.d.	3.00/40 mg	3.00	90.00
Pantoprazole (intravenous)	40 mg q.d.	20.00/40 mg	20.00	600.00
Lansoprazole	15-30 mg q.d.	3.66/15 mg 3.73/30 mg	3.66-3.73	109.80-111.90
Omeprazole	20 mg q.d.	3.57/10 mg 3.57/10 mg 3.99/20 mg 5.94/40 mg	3.99	119.70
Rabeprazole	20 mg q.d.	3.70/20 mg	3.70	111.00

a	Adapted from reference 44.
b	Based on recommended dosages.

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