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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Aim:

To compare the 24-h intragastric pH effects of simplified lansoprazole suspension, 30 mg, administered nasogastrically, with pantoprazole, 40 mg, administered intravenously.

Methods:

Thirty-six healthy adults were enrolled and given simplified lansoprazole suspension, 30 mg (nasogastrically), or pantoprazole, 40 mg (intravenously), once daily for five consecutive days in a cross-over fashion. Intragastric pH was monitored at baseline and on Days 1 and 5 of each treatment period. The pharmacokinetic parameters of lansoprazole and pantoprazole were also determined on Days 1 and 5.

Results:

No statistically significant changes in pharmacokinetic parameters occurred between Days 1 and 5 with either regimen, except for pantoprazole Cmax. On Days 1 and 5, significantly higher mean 24-h intragastric pH values were observed with 30 mg simplified lansoprazole suspension compared with 40 mg intravenous pantoprazole (Day 1, 3.13 vs. 2.67; Day 5, 3.95 vs. 3.61, respectively; P < 0.05). Additionally, 30 mg simplified lansoprazole suspension produced significantly (P < 0.05) higher percentages of time intragastric pH was above 3, 4, 5 or 6 as compared with 40 mg intravenous pantoprazole throughout Days 1 and 5.

Conclusions:

A 30 mg dose of simplified lansoprazole suspension administered nasogastrically was consistently more effective at controlling intragastric pH than pantoprazole, 40 mg, administered intravenously.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The healing of duodenal and gastric ulcers and erosive oesophagitis, and the relief of reflux-related symptoms, are directly related to the effective control of intragastric pH.1–4 A highly significant predictable relationship between ulcer healing, and the degree and duration of intragastric pH suppression, and the length of treatment was observed by Jones et al.1 In addition, the effective control of intragastric pH has also been highly correlated with a reduced incidence of recurrent gastro-oesophageal reflux disease and mucosal damage.4

It is well established that proton pump inhibitors effectively suppress gastric acid secretion and are superior to histamine-2 receptor antagonists in this regard.5–12 Lansoprazole and omeprazole, two widely used proton pump inhibitors, are available as capsule formulations that may be difficult to administer in those who are unable to, or have difficulty in, swallowing. To provide treatment to these individuals, several investigators have confirmed that the bioavailability and effects on intragastric pH of the capsule contents emptied into various liquids and soft foods prior to oral or nasogastric tube administration are comparable to those of the respective orally administered capsule formulation.13–20 In a comparative study of four liquid formulations of lansoprazole and omeprazole, the duration of time the lansoprazole suspension maintained the intragastric pH above 3 and 4 was greater than that observed with omeprazole.19 Pantoprazole, a recently launched proton pump inhibitor in the USA, is available as a 40 mg enteric-coated tablet. Pantoprazole is also available in the USA as a 40 mg/vial freeze-dried powder for reconstitution prior to parenteral administration. Intravenous pantoprazole has shown a rapid dose-dependent suppression of gastric acid output, with pharmacodynamic efficacy being comparable following equivalent intravenous and oral doses.21, 22

The purpose of this cross-over study was to compare the acid inhibitory efficacy (as determined by 24-h intragastric pH monitoring) of lansoprazole, 30 mg, prepared as an 8.4% sodium bicarbonate-based suspension and administered via a nasogastric tube, with a 40 mg intravenous dose of pantoprazole, each given once daily for five consecutive days.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Subjects and study design

Healthy male and non-pregnant, non-lactating female volunteers between the ages of 18 and 45 years (inclusive) were eligible for participation in this Phase I, randomized, open-label, two-way cross-over, single-centre study. Eligible subjects were non-smokers (abstained from all tobacco use during the 6 months prior to the study), weighing within ± 10% of the acceptable range according to the 1983 Metropolitan Life Table for Height and Weight. Eligible subjects had no evidence of a clinically significant medical condition based on medical history and physical examinations, 12-lead resting electrocardiogram, routine laboratory evaluations (haematology, chemistry and urinalysis) and urine screen for drugs of abuse. Subjects were not to have taken any prescription or over-the-counter medication within the 4 weeks prior to study drug administration and had no known allergy to lansoprazole, omeprazole, rabeprazole or pantoprazole. Each volunteer signed an informed consent form prior to study participation. This study was conducted at Charterhouse Clinical Research Unit Ltd, The Stamford Hospital, Ravenscourt Park, London, UK, between November 3 and December 20, 1999. Approval of the study protocol was obtained from the local ethics committee prior to initiation of the trial.

Eligible subjects were randomly assigned in equal numbers to one of the two sequence groups. The sequences of treatment were such that each subject received both regimens upon completion of the study. A washout period of at least 2 weeks separated the two dosing regimens. Subjects were confined to the study site during the screening period for baseline intragastric pH recording, and during each period from the evening prior to the Day 1 24-h intragastric pH measurement through to 24 h following the Day 5 pH measurement. Standardized meals were served at approximately the same times (breakfast at 09.00 h, lunch at 12.00 h and dinner at 17.00 h) and in the same sequence during the confinement phase of each cross-over period. On Days 1 and 5, water was restricted 1 h prior to and 1 h after dosing, and regulated and recorded thereafter, allowing subjects a maximum of 50 mL of water per hour. Grapefruit or grapefruit-containing products and xanthine- and/or caffeine-containing foods and beverages were prohibited during the study periods. Meals were consumed within the same number of minutes relative to dosing in order to minimize response variability.

During each cross-over period, one box of study medication, containing either seven lansoprazole 30 mg capsules in a blister strip (Zoton, Takeda Chemical Industries Limited, Osaka, Japan) or 10 vials containing 40 mg of pantoprazole powder (Protium IV, Byk Gulden Pharmaceuticals, Konstanz, Germany), was dispensed on Day 1. During the lansoprazole study period, a #8 French nasogastric tube was inserted through the subject’s nares for simplified lansoprazole suspension (SLS) administration. The nasogastric tube was inserted and removed on a daily basis. One hour before dosing, the granules from one 30 mg lansoprazole capsule were transferred into a 30-mL syringe (with a 20-gauge needle in place). Ten millilitres of 8.4% sodium bicarbonate solution (Abbott Laboratories, North Chicago, IL, USA) was drawn into the syringe and the contents mixed thoroughly for at least 5 min. The resulting mixture (3 mg lansoprazole/mL) was injected into the nasogastric tube and 30 mL of water was used to flush the syringe and the nasogastric tube to ensure complete administration of lansoprazole. During the intravenous pantoprazole study period, a cannula was inserted intravenously into the subject’s forearm prior to drug administration. A physiological saline solution (0.9% NaCl) drip was started to ensure proper placement of the cannula. Within 3 h prior to dosing, two vials of 40 mg pantoprazole powder were separately reconstituted with 10 mL of the physiological saline solution. From these two vials, all 20 mL of the mixed solution (4 mg pantoprazole/mL) was drawn into a 50/60 mL graduated syringe. Approximately 2–3 mL of the solution was used to fill the syringe extension tubing. Ten millilitres of the drug solution was infused intravenously (over 15 min) into the subject via the saline drip line using a syringe pump. The remaining 7–8 mL of solution was not delivered to the subject. During both treatment periods, each dose was administered once daily to the subjects at 08.00 h (1 h before breakfast) for five consecutive days.

Safety evaluations were conducted through daily monitoring of vital signs that included sitting blood pressure, pulse, respiratory rate, oral temperature and weight. Subjects were closely monitored for any adverse event that was assessed by the investigator for severity and possible relationship to the study drug. Severity was defined as: mild, transient and easily tolerated; moderate, resulted in subject discomfort and interruption of normal activities; or severe, resulted in considerable interference with normal activities, may be incapacitating or life-threatening. In addition, the relationship to the study drug was determined as definite, probable, possible or no relationship.

Pharmacokinetic and statistical analyses

Blood samples for the determination of lansoprazole or pantoprazole pharmacokinetic parameters were collected from each subject on Days 1 and 5 of each cross-over period. The 7.5-mL blood samples were collected in heparinized tubes at: hour 0 (immediately prior to 08.00 h dose) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 24 h after study drug administration. During the intravenous pantoprazole period, all sampling times were relative to the start of the infusion. Plasma was isolated by centrifugation at approximately 5 °C within 30 min of blood collection, transferred to appropriately labelled plastic tubes, frozen immediately at a maximum temperature of – 20 °C in a non-cycling freezer and shipped to MDS Pharma Services (Lincoln, NE, USA) for analysis at the completion of the study.

Plasma samples were stored frozen until analysis for lansoprazole or pantoprazole concentrations using validated liquid chromatographic tandem mass spectrometric methods. The lower limits of quantification for lansoprazole and pantoprazole were determined to be 5.0 ng/mL and 20.0 ng/mL, respectively. Concentrations below the limits of quantification were reported as zero. Lansoprazole and pantoprazole were extracted from plasma using ethyl ether–methylene chloride. The respective solvent was dried under nitrogen, and the residue reconstituted with acetonitrile and injected onto a liquid chromatograph/tandem mass spectrometer using a normal phase column. A Perkin Elmer Sciex API 365 and Finnigan TSQ7000, with a turbo ion spray interface, were employed for the assays.

Lansoprazole plasma samples were assayed with nine calibration curves with concentrations ranging from 5.00 to 1200.00 ng/mL. Correlation coefficients for the calibration curves for lansoprazole were greater than 0.9977. Plasma samples with lansoprazole concentrations exceeding that of the highest standard (1200.00 ng/mL) were diluted with drug-free plasma and re-assayed. Pantoprazole plasma samples were assayed with 15 calibration curves with concentrations ranging from 20.00 to 2000.00 ng/mL. Correlation coefficients for the calibration curves for pantoprazole were greater than 0.9989. Plasma samples with pantoprazole concentrations exceeding that of the highest standard (2000.00 ng/mL) were diluted with drug-free plasma and re-assayed.

The pharmacokinetic parameters of lansoprazole and pantoprazole were obtained using non-compartmental pharmacokinetic methods. The maximum observed plasma concentration (Cmax) and the time to the maximum observed concentration (Tmax) were taken directly from the plasma concentration measurements. The area under the plasma concentration–time curve over the 24-h time interval (AUC24) was calculated using the linear trapezoidal rule. The terminal elimination rate constant (β) was obtained from the slope of the least-squares linear regression fit of the logarithms of measurable concentrations vs. time in the log-linear terminal phase of the curve. The terminal half-life (t1/2) was calculated as ln(2)/β. The pharmacokinetic parameters on Days 1 and 5 of lansoprazole or pantoprazole were compared. For each compound, analyses of variance (ANOVAs) were performed for the logarithms of Cmax and AUC24 with the effects of period, subject nested within period, day and period by day included in the model. Within the ANOVA framework, a point estimate and a 95% confidence interval for the ratio of Day 5 to Day 1 were determined for the central values of the logarithms of Cmax and AUC24.

Pharmacodynamic and statistical analyses

Ambulatory 24-h intragastric pH monitoring was performed in all subjects at baseline (between 2 and 7 days prior to the first treatment dose of cross-over period 1) and on Days 1 and 5 of each of the cross-over periods. The intragastric pH was recorded using a single-channel antimony internal reference pH electrode (Zinetics Medical, UT, USA) connected to a Flexilog 2020 ambulatory pH monitoring unit (Oakfield Instruments, Witney, Oxon, UK). The tip of the pH electrode was placed 5–10 cm below the cardiac sphincter, which was confirmed with a pressure sensor. The pH monitoring unit was positioned in the stomach of each subject beginning at approximately 08.00 h (before study drug administration for Days 1 and 5), and intragastric pH was sampled every 6 s during each 24-h recording period. The recorded intragastric pH data were downloaded using Flexisoft II software (Oakfield Instruments). The pH monitoring unit was calibrated with standard buffers (pH 1.0 and pH 7.0) before and after each use.

At each pH monitoring session, intragastric pH was sampled every 6 s during the 24-h period and the medians of these values over 15-min intervals were calculated and used in all intragastric pH data analyses. The effect on intragastric pH was quantified using the average pH over the entire 24-h interval and over the time intervals 0–5 h, 6–10 h, 11–15 h and 16–24 h post-dose (inclusive). The percentage of time that intragastric pH was greater than 3, 4, 5 or 6 was also determined. The effects on mean 24-h intragastric pH (calculated as the average of the 15-min medians), average pH over the specified time intervals and percentages of time pH was above 3, 4, 5 or 6 were compared between regimens using a cross-over model ANOVA which included effects for regimen, period, sequence and subject nested within sequence. The effect of subject was random and all other effects were fixed. All statistical tests were two-tailed and P values of less than or equal to 0.050 were considered to be statistically significant.

A study sample size of 26 subjects would provide approximately 95% power to detect a difference between treatment regimens of 0.7 unit in the mean 24-h intragastric pH (two-sided test, P=0.05). This calculation was based on an ANOVA model with an error term variance of 0.45, which was obtained from previous studies (data on file at Abbott Laboratories, Abbott Park, IL, USA and at TAP Pharmaceutical Products Inc., Lake Forest, IL, USA). A total of 36 subjects were enrolled in the study to allow for a few dropouts. Statistical analyses (ANOVAs) for the lansoprazole and pantoprazole pharmacokinetic and pharmacodynamic parameters were performed using Procedure General Linear Models of SAS Version 6.12 with type III sums of squares.23

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

A total of 36 (27 male and nine female; numbered as subjects 101–136) healthy adult subjects were enrolled in the study: 34 of these completed both study periods. The demographic characteristics, including Helicobacter pylori status, of the enrolled subjects are summarized in Table 1. Subjects 119 and 121 received only the pantoprazole and lansoprazole regimens, respectively. Both of these two subjects withdrew consent and did not participate in cross-over period 2 of the study. Subjects 119 and 121 were included in the pharmacokinetic (but not intragastric pH) calculations and summary statistics. The data from these two dropouts were included in the pharmacokinetic analysis because they did not cause any skewness in the data distribution and, more importantly, no pharmacokinetic data comparison between the two regimens was performed. Inclusion of the data from these two dropouts in intragastric pH analysis also did not cause any skewness in the data distribution. However, as one pH data point was from subject 121 with the lansoprazole regimen and one was from subject 119 with the pantoprazole regimen, these subjects were excluded from intragastric pH comparison between the two regimens.

Table 1.   Demographic characteristics of enrolled subjects Thumbnail image of

The mean lansoprazole and pantoprazole plasma concentration–time profiles, with 30 mg SLS (nasogastrically, NG) and 40 mg intravenous pantoprazole, are shown in Figures 1(A) and 1(B), respectively. On average, the Cmax for lansoprazole on both Day 1 and Day 5 was reached within approximately 0.6 h, which is more than 1 h earlier than with lansoprazole intact capsule administration (approximately 1.7 h, November 2000 Prevacid label). Meanwhile, the Cmax for pantoprazole was achieved at 0.25 h post-dosing. The respective pharmacokinetic parameters of lansoprazole or pantoprazole were similar between Days 1 and 5, with no statistically significant changes occurring in any parameter during the 5-day continuous administration, except for pantoprazole Cmax (Table 2). The results of the point estimates and the 95% confidence intervals for the ratios of Day 5 to Day 1 central values for ln(Cmax) and ln(AUC24) are summarized in Table 3. The point estimates indicated that the differences between the central values for lansoprazole Cmax and AUC24 on Day 5 and Day 1 were less than 7%. The confidence intervals were narrow, with centres for the parameter ratio close to unity (1.00) for AUC24 (1.069) and Cmax (0.954). For pantoprazole, the confidence intervals for both Cmax and AUC24 were narrow, with centres a little deviated from unity. The point estimates indicated that the central values for pantoprazole Cmax and AUC24 were 6.8% and 3.5% lower on Day 5 than on Day 1, respectively.

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Figure 1.  Mean plasma concentration–time profiles for lansoprazole (30 mg simplified lansoprazole suspension (SLS) administered nasogastrically (NG) once daily) (A) and pantoprazole (40 mg intravenous (IV) pantoprazole once daily) (B).

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Table 2.    Pharmacokinetic parameters of nasogastrically (NG) administered lansoprazole (simplified lansoprazole suspension, SLS) and intravenous (IV) pantoprazole on Day 1 and Day 5 (mean ± s.d., n=35) Thumbnail image of
Table 3.   The 95% confidence intervals and the corresponding point estimates for the ratio of Day 5 vs. Day 1 central values for logarithms of lansoprazole and pantoprazole AUC24 and CmaxThumbnail image of

The mean intragastric pH–time profiles for baseline, with 30 mg SLS (NG) and 40 mg intravenous pantoprazole, are shown in Figures 2(A) and (B) for Day 1 and Day 5, respectively. In general, SLS led to better pH control than did intravenous pantoprazole, especially during the first 5 h post-dosing. The three major peaks shown on the baseline pH–time curve were primarily due to the gastric juice dilution effect from food consumption during three scheduled meals. The food effect was also seen on both Day 1 and Day 5 with either lansoprazole or pantoprazole administration.

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Figure 2.  Mean intragastric pH–time profiles at baseline, with 30 mg simplified lansoprazole suspension (SLS) administered nasogastrically (NG) once daily and with 40 mg intravenous (IV) pantoprazole once daily on Day 1 (A) and Day 5 (B).

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The 30 mg SLS (NG) regimen was statistically significantly more effective in producing higher mean 24-h intragastric pH values on both Day 1 and Day 5 than 40 mg intravenous pantoprazole (Day 1, 3.13 vs. 2.67, P < 0.001; Day 5, 3.95 vs. 3.61, P < 0.001). On Day 1, 30 mg SLS (NG) produced significantly higher mean pH levels than 40 mg intravenous pantoprazole at time intervals of 0–5 h (3.57 vs. 2.96, P < 0.001), 6–10 h (3.19 vs. 2.82, P < 0.01), 11–15 h (3.35 vs. 2.89, P < 0.05) and 16–24 h (2.73 vs. 2.31, P < 0.01) (Figure 3A). On Day 5, 30 mg SLS (NG) continued to produce significantly higher mean pH levels than 40 mg intravenous pantoprazole at time intervals of 0–5 h (5.04 vs. 4.11, P < 0.001), 6–10 h (4.03 vs. 3.67, P < 0.01) and 11–15 h (3.93 vs. 3.66, P < 0.05) (Figure 3B). On Day 5, the mean pH values with the two regimens were not significantly different during the 16–24 h interval.

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Figure 3.  Comparison between 30 mg simplified lansoprazole suspension (SLS) administered nasogastrically (NG) once daily and 40 mg intravenous (IV) pantoprazole once daily with regard to the mean intragastric pH at several post-dosing time intervals on Day 1 (A) and Day 5 (B) (*P < 0.05, **P < 0.01, ***P < 0.001).

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The 30 mg SLS (NG) regimen also maintained the mean intragastric pH above 3, 4, 5 or 6 significantly longer than did the 40 mg intravenous pantoprazole regimen on both Day 1 and Day 5. The mean percentages of time intragastric pH was above 3, 4, 5 or 6 on Day 1 in those treated with 30 mg SLS (NG) as compared with 40 mg intravenous pantoprazole were 38.08% vs. 26.84% (P < 0.001), 28.28% vs. 18.01% (P < 0.001), 15.63% vs. 9.13% (P < 0.001) and 7.54% vs. 4.50% (P < 0.01), respectively (Figure 4A). On Day 5, the mean percentages of time intragastric pH was above 3, 4, 5 or 6 in those treated with 30 mg SLS (NG) as compared with 40 mg intravenous pantoprazole were approximately 58.92% vs. 49.97% (P < 0.001), 48.07% vs. 39.58% (P < 0.001), 30.02% vs. 23.31% (P < 0.001) and 14.22% vs. 11.95% (P < 0.05), respectively (Figure 4B).

image

Figure 4.  Comparison between 30 mg simplified lansoprazole suspension (SLS) administered nasogastrically (NG) once daily and 40 mg intravenous (IV) pantoprazole once daily with regard to the mean percentage of time the intragastric pH was above 3, 4, 5 or 6 on Day 1 (A) and Day 5 (B) (*P < 0.05, **P < 0.01, ***P < 0.001).

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The incidence of adverse events during the treatment period was similar between the 30 mg SLS (NG) and 40 mg intravenous pantoprazole regimens (26% each). The most frequently reported (two or more subjects in either regimen) treatment-emergent adverse events were headache, dizziness and diarrhoea. The most frequently reported (two or more subjects in either regimen) possibly, probably or definitely treatment-related adverse events were headache, diarrhoea, dizziness and abdominal pain. Possibly, probably or definitely treatment-related asthenia, flatulence, nausea, pharyngitis, rhinitis, pruritus, dysmenorrhoea and menorrhagia were each reported by no more than one subject in each regimen. All adverse events reported during the study were considered to be mild or moderate in severity.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The results of this study conducted in healthy subjects confirm that lansoprazole, suspended in an 8.4% sodium bicarbonate solution, produces effective control of intragastric pH. Our results showed that the acid inhibitory effects of the 30 mg dose of SLS (NG) were greater than those observed with a 40 mg dose of intravenous pantoprazole, and this phenomenon persisted throughout the 5-day clinical trial. The point estimates and the narrow 95% confidence intervals for Cmax and AUC24 between Day 5 and Day 1 of the SLS trial indicate that the delivery of lansoprazole suspension through a nasogastric tube can be consistently conducted in a clinical setting with low and insignificant between-day variability.

The clinical results observed with SLS in this study involving healthy subjects are consistent with those of two recent studies performed in patients that evaluated the intragastric pH effects of liquid formulations of lansoprazole and omeprazole.19, 20 In the lansoprazole study by Sharma et al.,20 six men with an established gastrostomy were given the granule contents of a 30 mg lansoprazole capsule in orange juice, once a day for 7 days, and then, following a 7-day washout period, 30 mg of lansoprazole granules suspended in 10 mL of 8.4% sodium bicarbonate, once a day for 7 days. The percentages of time intragastric pH was above 3, 4 and 5 were 84%, 78% and 66% with the SLS preparation, compared with 78%, 67% and 50% with the orange juice preparation (P > 0.05 for each comparison of lansoprazole suspension vs. lansoprazole in orange juice). Although these percentage values are higher than those observed in the present study, this may be a result of the difference in the populations studied (i.e. Sharma et al.20 performed their study in an older nursing home population with a high prevalence of H. pylori infection). In another comparative study of 30 mg lansoprazole and 20 mg omeprazole liquid preparations, Sharma19 observed a significantly inferior 24-h pH profile with the 20 mg simplified omeprazole suspension compared with 30 mg SLS. Lansoprazole maintained the intragastric pH above 3.0 and 4.0 for 20 and 17 h, respectively, compared with 15 and 12 h, respectively, observed for omeprazole.19 Therefore, the intragastric pH levels for optimal treatment outcomes for duodenal ulcer (intragastric pH > 3 for 16–18 h) and gastro-oesophageal reflux disease (intragastric pH > 4 for 16–18 h) were not achieved with 20 mg simplified omeprazole suspension.

Previous studies have confirmed that the pharmacodynamic effects of intravenous pantoprazole are similar to those of the oral dosage form. Hartmann et al.22 evaluated intragastric pH following 5 days of once-daily 40 mg pantoprazole administered as the oral tablet or intravenous infusion to 20 healthy volunteers. They found that the Day 5 24-h median intragastric pH values following intravenous and oral administration of pantoprazole, 40 mg, were 3.3 and 3.1, respectively.22 In addition, the mean percentages of time during which the pH was above 3 and 4 for the intravenous dosage form were 57% and 42%, respectively, compared with 51% and 38% for the oral dosage form. The values observed for intravenous pantoprazole by Hartmann et al.22 were very similar to those observed on Day 5 in this study.

We are aware of a few studies that have compared the effects of lansoprazole and pantoprazole on intragastric pH. In three comparative studies, greater gastric acid antisecretory effects were observed with orally administered lansoprazole, 30 mg per day, compared with pantoprazole, 40 mg per day.24–26 On Day 1 in all three studies, lansoprazole produced consistently and significantly higher mean percentages of time that the intragastric pH was greater than 4 compared with pantoprazole (44% vs. 24%, P=0.028; 47% vs. 32%, P < 0.001; 50% vs. 31%, P < 0.001).24–26 On Day 5, in two of the studies, lansoprazole continued to produce higher percentages of time that the intragastric pH was above 4 compared to pantoprazole, although the differences narrowed (63% vs. 56%, P < 0.05; 61% vs. 56%, P=N.S.).26 In the study by Florent and Forestier,24 lansoprazole produced a higher mean percentage of time intragastric pH was above 4 on Day 7 compared with pantoprazole (44% vs. 32%, P=0.02).

A recently completed study compared the effects of lansoprazole, 30 mg granules suspended in 40 mL of apple juice and administered via a nasogastric tube, with 40 mg intravenous pantoprazole.27 The study was conducted in 36 healthy male and female subjects and the demographic data were very similar to those of the current study. The findings of this intriguing study by Freston et al.27 were virtually identical to those observed in our study, especially with respect to the Day 1 data. Lansoprazole granules suspended in apple juice and administered via a nasogastric tube were statistically significantly more effective in producing higher mean 24-h intragastric pH values than 40 mg intravenous pantoprazole on both Day 1 (3.07 vs. 2.76, P < 0.001) and Day 5 (3.65 vs. 3.45, P < 0.05). On Day 1, the lansoprazole in apple juice suspension produced significantly higher mean intragastric pH levels at the time intervals of 0–5 h, 6–10 h and 11–15 h and maintained the intragastric pH above 3, 4 and 5 for significantly greater percentages of time compared with 40 mg intravenous pantoprazole. The mean percentages of time intragastric pH was above 3, 4 and 5 on Day 1 in those treated with lansoprazole 30 mg granules in apple juice (NG) were approximately 38%, 27% and 15%, respectively, compared with 28%, 19% and 10%, respectively, in those treated with 40 mg intravenous pantoprazole. Significant differences observed between the lansoprazole (NG) and intravenous pantoprazole regimens on Day 5 included higher mean pH levels at time intervals of 6–10 h (4.00 vs. 3.69, P < 0.01) and 11–15 h (3.82 vs. 3.58, P < 0.05) and a greater percentage of time intragastric pH was above 3 (54% vs. 49%, P < 0.05).

As with the findings of Freston et al.,27 we found it interesting that the acid inhibitory efficacy of SLS given through a nasogastric tube in this study was greater than that of intravenous pantoprazole. Results from the study by Freston et al.27 showed that the time to maximum plasma lansoprazole concentration (Tmax) was virtually identical to that with lansoprazole intact capsule (1.7 h), while, in the present study, Tmax was reduced by approximately 1 h with SLS. The 8.4% sodium bicarbonate solution dissolved the enteric coating and allowed lansoprazole molecules to be absorbed into the small intestine much quicker, and therefore significantly shortened the Tmax value for SLS. This may have led to a faster onset of action of lansoprazole (in SLS) due to the earlier availability of the drug at the target site. The sodium bicarbonate solution caused moderate neutralization of intragastric pH, which, in turn, may have led to proton pump activation and a subsequent increase in the number of target sites for lansoprazole inhibitory activity. The combination of these factors may explain the major difference observed between SLS and lansoprazole suspension in apple juice:27 the much higher mean intragastric pH with the former within 5 h post-dosing (3.57 vs. 2.84 on Day 1 and 5.04 vs. 3.79 on Day 5). These results also confirm the high degree of bioavailability of nasogastrically administered lansoprazole. While intravenous pantoprazole ensures complete delivery of the prescribed dose, nasogastric administration of SLS has to overcome dosing and bioavailability ‘hurdles’. For example, incomplete flushing of the syringe and/or nasogastric tubing may decrease the dose of lansoprazole delivered. In addition, once the dose is administered, it must undergo pharmacokinetic processes, such as gastrointestinal absorption and first-pass metabolism, which may compromise the dosage that is delivered. Despite these unfavourable factors, the pharmacokinetic and pharmacodynamic results noted in our study, as well as in the study by Freston et al.,27 suggest that lansoprazole capsule content emptied and prepared/administered in soft drinks such as apple juice or an 8.4% sodium bicarbonate-based suspension, retain their high degree of bioavailability and maintain their intragastric pH elevating efficacy. In addition, the results from a two-way cross-over clinical trial conducted in healthy subjects have shown that SLS effectively controls intragastric pH, is bioequivalent to the intact lansoprazole capsule and represents an effective therapeutic option in patients who have difficulty in, or are unable to, swallow the capsule formulation of lansoprazole.28

Economic as well as safety benefits are also realized in the administration of therapeutic agents via oral/nasogastric vs. intravenous routes. Overall, patients receiving drugs via a nasogastric tube vs. intravenously are not exposed to the risks of parenterally administered agents (i.e. trauma, infection, pain) or the increased costs of preparing and administering parenteral agents. Further studies to quantify these economic differences are warranted.

In conclusion, the effects on 24-h intragastric pH are significantly greater with the once-daily 30 mg SLS regimen as compared with once-daily 40 mg intravenous pantoprazole. The results of this study also indicate that the clinical efficacy of lansoprazole is maintained when the capsule contents are mixed with a sodium bicarbonate solution and delivered via a nasogastric tube. In patients requiring acid inhibitory therapy, but who are unable to utilize solid oral dosage forms, such as those that are intubated and in intensive care units, significant benefits may be realized through the administration of SLS via a nasogastric tube compared to an intravenous regimen of pantoprazole.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The authors would like to acknowledge Ms Karen E. Rynkiewicz and Mr David L. Bloom for their technical assistance.

This study was supported by an educational grant from TAP Pharmaceutical Products Inc., Lake Forest, IL, USA.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References
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