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Comparison of the pharmacokinetics of lansoprazole 15- and 30-mg sachets for suspension versus intact capsules
CLINICAL THERAPEUTICs®/VoL.2 6 , N o . 12, 2 0 0 4
Comparison of the Pharmacokinetics of Lansoprazole 15- and 30-mg Sachets for Suspension Versus Intact Capsules Fouad Amer, MD, MPH, 1 Michael D. Karol, PhD, 2 Wei-Jian Pan, PhD, 2 Janice S. Griffin, RN, BSN, 1 Nancy L. Lukasik, RN, BSN, 1 Charles S. Locke, PhD, 2 and Yi-Lin Chiu, P h D 2 ~TAP Pharmaceutical Products Inc., Lake Forest, and 2Abbott Laboratories, Abbott Park, Illinois
ABSTRACT
Objective: The pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension were compared with those of corresponding doses of lansoprazole oral capsules. Methods: Healthy adult male and female subjects were randomized (1:1 ratio) into 2 Phase I, open-label, singledose, 2-sequence, 2-period complete crossover studies. In the first study, each subject received 1 lansoprazole 15-rag sachet mixed with water and 1 lansoprazole 15-rag oral capsule; in the second study, each subject received 1 lansoprazole 30-rag sachet mixed with water and 1 lansoprazole 30-rag oral capsule. Administration of the 2 formulations was separated by a washout period of ___7days. Blood samples were collected before and after each administration to assess the pharmacokinetic parameters of lansoprazole and bioequivalence between suspension and capsule. Results: Thirty-six subjects (19 males, 17 females) with a mean (SD) age of 32.0 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg received lansoprazole 15 rag. Thirty-six subjects (22 males, 14 females) with a mean (SD) age of 38.0 (8.3) years and mean (SD) body weight of 75.1 (9.7) kg received lansoprazole 30 rag. The pharmacokinetic parameters of the 15- and 30-rag lansoprazole sachets for suspension were similar to those of the corresponding doses of the oral capsules. The mean (SD) values for Cmax and AUC from time 0 to infinity (AUCo_~) for the lansoprazole 15-rag sachet (591.9 [242.3] ng/mL and 1614 [2065] ng.h/mL, respectively) did not differ significantly from those for the lansoprazole 15-rag capsules (578.6 [275.2] ng/mL and 1620 [2290] ng.h/mL, respectively). These parameters also did not differ significantly between the lansoprazole 30-rag sachet and 30-rag capsule: mean (SD) Cmax, 1103 (428.3) and 1077 (465.6) ng/mL, respectively; mean (SD) AUCo_~, 2655 (1338) and 2669 (1311) ng.h/mL, respectively. The 90% CIs for Cm~x and AUCo_~ ratios were contained within the 0.80 to 1.25 equivalence range, supporting bioequivalence. Conclusions: These findings suggest that the 15- and 30-rag lansoprazole sachets for suspension are bioequivalent to the corresponding doses of oral capsules. The sachet for suspension may provide an alternative route of administration to patients who have difficulty swallowing solid oral formulations. (Clin Ther. 2004;26: 2076-2083) Copyright © 2004 Excerpta Medica, Inc. Key words: pharmacokinetics, proton pump inhibitor, lansoprazole capsule, lansoprazole sachet for suspension, alternative dosage formulations. AcceptedJor publication September 13, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
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Copyright © 2004 Excerpta Nedica, Inc.
F. A m e r et al.
INTRODUCTION
Proton pump inhibitors (PPIs) are widely used in the treatment of various acid-related disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal anti-inflammatory drug-induced gastropathy. 1-, Because these agents are inactivated by exposure to gastric juice, they are administered orally as delayed-release capsules that contain enteric-coated granules (eg, lansoprazole, omeprazole, esomeprazole) or as delayed-release enteric-coated tablets (eg, rabeprazole, pantoprazole) that should not be chewed or crushed. 5 Alternative methods of delivering the enteric-coated granules contained in the lansoprazole and omeprazole capsules have been evaluated for use in the treatment of patients who have difficulty swallowing solid oral dosage formulations. 6-16 These alternative modes of administration involve opening the capsules and sprinkling their contents over a small amount (1 tablespoon) of soft foods (eg, applesauce, pudding, yogurt, cottage cheese) and swallowing the mixture without chewing or crushing the granules. In addition, the granules can be mixed into a small amount of acidic fruit juice (eg, apple, cranberry, grape, orange, pineapple, prune, tomato) or liquid dietary supplement before drinking or mixed with 40 mL of apple juice and administered through a nasogastric or gastrostomy tube. Finally, lansoprazole is also approved as an IV formulation and as an orally disintegrating tablet. 17 Lansoprazole is the only PPI approved by the US Food and Drug Administration (FDA) that is commercially available as a 15- and 30-mg strawberryflavored sachet for suspension. 18 The strawberryflavored lansoprazole sachet contains enteric-coated granules that are designed to be suspended in water before oral administration. A recent, single taste-test study performed in children (aged 5-11 years) by Tolia et a119 found that the strawberry-flavored lansoprazole suspension was well liked by 95% of the 110 children who tasted it. The goal of the current study was to compare the pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension with those of the corresponding doses of lansoprazole oral capsules.
SUBJECTS AND METHODS Two Phase I, randomized (1:1 ratio according to a schedule generated before study initiation), open-label,
single-dose, 2-sequence, 2-period complete crossover studies were designed. The studies were performed at 1 center (Parkway Research Center, Miami, Florida), with one study evaluating lansoprazole 15 mg and the other study evaluating lansoprazole 30 mg. Study protocols were reviewed and approved by the investigational siteg institutional review board. All subjects provided written informed consent before the performance of any study-specific procedures. The procedures followed were in accordance with FDA regulations and Good Clinical Practice guidelines governing clinical study conduct. 2° Healthy male and nonpregnant, nonlactating female volunteers between the ages of 19 and 53 years with body weight within 10% of height, sex, and body frame guidelines21 and who had abstained from nicotine products for _>6 months before study initiation were eligible. Medical history and physical examinations, 12-lead electrocardiogram, vital sign measurements, routine evaluations of hematology (eg, white and red blood cell counts, hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin concentration, platelet count) and chemistry laboratory values (eg, aspartate and alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, bilirubin, creatinine, total protein, albumin, total cholesterol, triglycerides, lactate dehydrogenase, sodium, potassium, chloride, calcium, phosphorus, glucose, uric acid) and urinalysis (eg, specific gravity, urine pH, glucose, ketones, protein, blood, urobilinogen, bilirubin, microscopic examination) were not to have yielded any evidence of clinically significant medical disease or conditions in any of the study subjects. Subjects were not to have taken any prescription or nonprescription medications (excluding oral contraceptives or hormone replacement therapy in female subjects) within the 2 weeks before and during the course of the studies. Women of childbearing potential were required to have a negative prestudy urine pregnancy test and agreed to utilize an effective means of birth control (eg, oral contraceptives) from 2 weeks before and throughout the study. Subjects enrolled in each study were assigned in equal numbers to 1 of 2 sequences that contained a single dose of lansoprazole capsule and a single lansoprazole sachet for suspension. The sequences of the treatments were such that each subject received both 2077
CLINICALTHERAPEUTICS®
formulations by the time of study completion. A washout period of >7 days separated the 2 periods of each study, during which the different formulations were administered. Subjects were confined to the clinical research unit and supervised for -28 hours during the first period of the study (from the afternoon of day -1 through the evening of day 1) and -40 hours during the second period of the study (from day -1 through the morning of day 2). The subjects abstained from ingestion of food and beverages except for the scheduled meals provided during the study periods and water to quench thirst. All subjects received the same standardized meals in the same sequence. Grapefruit or grapefruit-containing products, as well as xanthine- and/or caffeinecontaining foods and beverages, were prohibited during the study periods. On each day of treatment administration, 1 of the lansoprazole formulations was administered at - 8 AM, after a >12-hour fast, and no food was served until after collection of the 3-hour blood sample at -11 AM. The lansoprazole 15- or 30-mg oral capsule was administered with 180 mL of water, and a hand-andmouth check was performed to ensure ingestion of the capsule dose. The 15- or 30-mg lansoprazole sachet for suspension was prepared by mixing the granules with 30 mL of tap water and swirling the mixture f o r - 1 minute or until the suspension thickened. Subjects swallowed the suspension immediately, the cup was rinsed with an additional 30 mL of water, and the subject then drank the rinse liquid. If necessary, the cup was rinsed with an additional 30 mL of water and the subject consumed this liquid to ensure that all of the granules from the lansoprazole sachet for suspension were ingested. Subjects were instructed not to chew the granules, and a mouth check was performed after administration of the suspension to ensure its ingestion. Safety profile evaluations were conducted through monitoring of vital signs that included sitting blood pressure, pulse, respiratory rate, oral temperature, and body weight. Subjects were closely monitored by the investigator for evidence of drug intolerance and for the development of clinical or laboratory evidence of an adverse event. All adverse events that occurred during the course of the study were reported in detail on the subjectg chart and followed to a satisfactory resolution. The investigator assessed each adverse event for 2078
severity and possible relationship to the study drug. Severity was defined as follows: mild--transient and easily tolerated; moderate--resulted in subject discomfort and interruption of normal activities; or severe-resulted in considerable interference with normal activities, and may be incapacitating or life-threatening. In addition, relationship to study drug was determined as definite, probable, possible, or not related. Pharmacokinetic Evaluation
Blood samples for the determination of plasma lansoprazole pharmacokinetic parameters were collected from each subject on day 1 of each crossover period. Seven-milliliter blood samples were collected by venipuncture into labeled evacuated heparinized tubes at: hour 0 (immediately before the 8 AM dose administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours after administration. Blood samples were centrifuged within 2 hours of collection. From each sample, plasma was transferred with a new plastic pipette into a labeled polypropylene tube, immediately frozen, and stored at -20°C or lower until analysis to assure stability of lansoprazole. Concentrations of lansoprazole in plasma samples were determined using a validated liquid chromatography method with tandem mass spectrometric detection (MDS Pharma Services, Lincoln, Nebraska). 22 Analyses were conducted in a blinded manner with regard to formulation. Pharmacokinetic parameters of lansoprazole were estimated using noncompartmental pharmacokinetic methods described as follows. Values for Cmax and Tmax were taken directly from the plasma concentrationtime profile for each subject. The value of the terminal elimination rate constant (~) was obtained from the slope of a least-squares linear regression of the logarithms of the plasma concentration-time data from the terminal log-linear phase of the profile. The terminal log-linear phase was identified by visual inspection. A minimum of 3 concentration-time data points were used to determine [~. The terminal elimination T1/2 was calculated as ln(2)/~. The AUC from time 0 to the time of the last measurable concentration (AUC T) was calculated by using the linear trapezoidal method. The AUC was extrapolated to infinity (AUCext) by dividing the last measurable plasma concentration by ~. The AUC from time 0 to infinity (AUCo_~) was the sum of AUC T and AUCext. The per-
F. Amer et al.
centage of the contribution of AUCext to the overall AUCo_~ was calculated by dividing the AUCext by the AUCo_~ and multiplying the quotient by 100. The total apparent oral plasma clearance value (CUE, where F is the bioavailability) was calculated by dividing the administered dose by the AUCo_~. Statistical Analysis
Each study was designed to enroll 36 subjects such that if >32 subjects (>16 in each sequence group) completed the stud>> it would provide -80% power for achieving the equivalence claim with respect to Cm~x and AUCo_~ if the central values differed by 5%. Analysis of variance (ANOVA) was performed for Tmax, [~, and the logarithms of Cmax and AUCo_~ to determine the effects of sequence, subject nested within sequence, period, and regimen. All statistical tests used in the analysis of data were 2-tailed and compared at a significance level of P < 0.05. The bioavailability of the lansoprazole sachet for suspension regimen relative to the same dose administered as the intact capsule was assessed by two 1-sided tests with 90% CIs obtained from the analyses of the natural logarithms of Cm~x and AUCo_~. The CIs were obtained by exponentiation of the end points of CIs for the difference of mean logarithms obtained within the framework of the ANOVA model. For the sample size calculations, the variance for the logarithm of AUCo~ and the logarithm of Cm~x were assumed to be 0.0297 and 0.0697, respectively, using data from previous studies (studies M95-393, M97-764, and M97-393, TAP Pharmaceuticals, Inc., Lake Forest, Illinois). RESULTS
Thirty-six healthy individuals were enrolled in each study. An approximately equal number of males and females were enrolled in each study (53% males [19/36] and 47% females [17/36] in the lansoprazole 15-mg study and 61% males [22/36] and 39% females [14/36] in the lansoprazole 30-mg study). Subjects enrolled in the lansoprazole 15-mg study had a mean (SD) age of 32 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg. Those enrolled in the lansoprazole 30-mg study had a mean (SD) age of 38 (8.3) years and a mean (SD) body weight of 75.1 (9.7) kg. In both studies, subjects were predominantly Hispanic (83% and 72% in the lansoprazole 15and 30-mg studies, respectively).
All enrolled subjects in each study received both formulations of the specified dose of lansoprazole. The mean plasma concentration-time profiles after administration of the lansoprazole 15-mg sachet for suspension and the 15-mg intact capsules are presented in Figure 1. The mean plasma concentrationtime profiles after administration of the lansoprazole 30-mg sachet for suspension and the 30-mg intact capsules are given in Figure 2. The mean (SD) pharmacokinetic values for lansoprazole 15 and 30 mg after administration as the sachet for suspension formulation and as the intact capsules are summarized in Table I. No statistically significant differences were observed in any pharmacokinetic parameters between lansoprazole 15-mg sachet for suspension and 15-mg oral capsules or between lansoprazole 30-mg sachet for suspension and 30-mg oral capsules. Lansoprazole 15- and 30-mg sachets for suspension displayed Cmax and AUCo_~ values that were similar to those observed with the respective doses administered as the intact capsules. The 90% CIs for evaluating bioequivalence and the corresponding point estimates of relative bioavailability are summarized in Table II. The 90% CIs for the ratio of the sachet for suspension and oral capsule formulations were 0.949 to 1.179 and 0.930 to 1.188 for the Cmax of lansoprazole 15 and 30 mg, respectively, and 0.959 to 1.128 and 0.914 to 1.109 for the AUCo_~ of lansoprazole 15 and 30 mg, respectively. The 90% CIs for the ratios of regimen geometric means for Cm~x and AUCo_~ were contained entirely within the 0.80 to 1.25 range required for bioequivalence, supporting that the lansoprazole sachet for suspensions are bioequivalent to the intact oral capsule formulations. 2~ Mild dizziness (in 2 patients after administration of lansoprazole 15-mg sachet for suspension), mild headache (in 1 patient after administration of lansoprazole 15-mg sachet for suspension, and in 1 patient before dosing of the lansoprazole 30-mg capsule), and mild nausea (1 patient after administration of the lansoprazole 30-mg capsule) were the only adverse events reported during the study. None of the reported cases of mild dizziness, headache, or nausea were considered by the investigator to be related to studydrug administration. No clinically significant changes from screening were observed for any laboratory or vital sign parameters. 2079
CLINICAL THERAPEUTICS ®
- ~ - Suspension, 15 mg -O-Capsule, 15 mg 450 O.
400 E v
b
350 300 250 -
g
200 -
(0
150-
t~
E
100 -
O_ 50-
0
I
I
I
I
I
I
2
4
6
8
10
12
Time After Dose (h)
Figure I. Mean plasma c o n c e n t r a t i o n - t i m e profiles f o r l a n s o p r a z o l e 15-mg sachet f o r suspension and 15-mg oral capsule.
DISCUSSION
The current studies found that lansoprazole sachets for suspension, prepared in 30 mL of tap water and swirled for -1 minute before administration, displayed similar concentration-time curves and nearly identical pharmacokinetic characteristics compared with those of the respective intact 15- and 30-mg cap-
sules. The suspension formulation was well tolerated, although the open-label study design may have partially introduced some reporting bias for safety measures that were sensitive to subjectivity (eg, dizziness). Although the pharmacokinetic results observed in these studies may be limited by the subject demographics (enrollment of subjects with body weight - D - Suspension,30 mg - 0 - Capsule, 30 mg
900 800 E 700 v
b
g c O
(0 t~
E
600 500 400 300 200 -
O_ 100 0
i
i
i
i
1"
2
4
6
8
I0
12
Time After Dose (h) Figure 2. Mean plasma c o n c e n t r a t i o n - t i m e profiles f o r l a n s o p r a z o l e 3 0 - m g sachet f o r suspension and 3 0 - m g oral capsule.
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F. Amer et al.
Table I. Mean (SD) pharmacokinetic values for lansoprazole 15 and 30 mg, grouped according to dose and formulation. Lansoprazole 15 mg
Pharmacokinetic Measure
Tm~×, h Cm~×, ng/mL AUC T, ng'h/mL AUCo~, ng'h/mL TI/2, h*
CUF, Uh
Lansoprazole 30 mg
Sachet for Suspension (n -- 36)
Capsule (n = 36)
Sachet for Suspension (n = 36)
Capsule (n = 36)
1.7 (0.8) 591.9 (242.3) 1439 (I 398) 1614 (2065) 1.05 (0.34) 14.5 (6.2)
1.7 (0.8) 578.6 (275.2) 1451 (1582) 1620 (2290) 1.03 (0.33) 15.6 (8.5)
2.0 (0.7) 1103 (428.3) 2624 (I 306) 2655 (1338) I. 15 (0.32) 14.4 (7.6)
1.8 (0.8) 1077 (465.6) 2641 (1293) 2669 (131 I) 1.15 (0.32) 15.0 (9.9)
AUC T = AUC from time 0 to the time of the las-Lmeasurable concentration; A U C o ~ = AUC from time 0 to infinity; CUF = apparent oral plasma clearance. eHarmonic mean (pseudo SD, based on the jackknife variance).23
within 10% of ranges based on height, sex, and body frame; predominantly Hispanic), the parameters observed in the present work were similar to those seen in previous pharmacokinetic studies of lansoprazole capsule granules. <7,13 Chun et al 6 administered the contents of a 30-mg lansoprazole capsule mixed with a tablespoonful of applesauce and the intact capsule to healthy volunteers, finding no statistically significant differences in mean values for Tmax (1.8 vs 1.7 hours), Cmax (696 VS 800 ng/mL), Tu2 (1.21 vs 1.23 hours), or AUCo_~ (1909 vs 2021 ng.h/mL). In a subsequent crossover study in healthy volunteers, Chun et al r found comparable bioavailability and pharmacokinetic parameters after administration of intact lansoprazole 30-mg capsules and the capsule contents when emptied into apple juice and administered through a nasogastric tube.
The administration of acid-inhibitory therapy is problematic among patients who are unable to swallow solid oral formulations. Several previous studies have found that the enteric-coated, delayed-release granule contents of the commercially manufactured lansoprazole or omeprazole capsules can be sprinkled onto a small amount of soft food or mixed with acidic fruit juices or liquid dietary supplements before oral administration without compromising the drug's bioavailability, pharmacokinetics, or clinical effects as compared with the intact capsules. 6-16 The availability of a strawberry-flavored sachet for suspension containing 15 or 30 mg of lansoprazole enteric-coated, delayed-release granules may be beneficial in the treatment of adults with swallowing difficulties as well as in children. Although not investigated in the present work, it is anticipated that the sachet suspen-
Table II. Point estimates and 90% CIs for ratio of geometric means for bioequivalence assessment of lansoprazole sachets for suspension and lansoprazole capsules. Sachet vs Capsule
No. of Subjects
Point Estimate of Ratio
90% CI of Ratio
15 mg Cma×, ng/mL AUC0~, ng'h/mL
36 36
1.058 1.040
0.949 I. 179 0.959 1.128
30 mg Cmax, ng/mL AUCo~, ng'h/mL
36 36
1.051 1.007
0.930 I. 188 0.914 1.109
A U C 0 ~ = AUC from time 0 to infinit~z
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CLINICALTHERAPEUTICS®
sion would produce the same gastric-acid antisecretory effects (ie, pharmacodynamics and effectiveness) as other formulations of lansoprazole. 2~ CONCLUSIONS These findings suggest that the 15- and 30-mg lansoprazole sachets for suspension are bioequivalent to the corresponding doses of the oral capsules. The sachet for suspension may provide an alternative route of acid-inhibitory medication administration to patients who have difficulty swallowing solid oral formulations. ACKNOWLEDGHENTS
This research was supported by a grant from TAP Pharmaceutical Products Inc., Lake Forest, Illinois. The authors gratefully acknowledge the following for their contributions to these studies: Mitchell A. Rosenberg, MD, and colleagues, Parkway Research Center, Miami, Florida; and Karen E. Rynkiewicz, Abbott Laboratories, Abbott Park, Illinois. Editorial support was provided by Susan Ruffalo, PharmD, MedWrite, Inc., Newport Coast, California. REFERENCES
1. Chey WD, Moayyedi P Review article: Unmvestigated dyspepsia and non-ulcer dyspepsia--the use of endoscopy and the roles of Helicobacter pylori eradication and antisecretory therapy Aliment Pharmacol Ther. 2004; 19(Suppl 1): 1-8. 2. Freston JW, Triadafilopoulos G. Review article: Approaches to the long-term management of adults with GERD-proton pump inhibitor therapy, laparoscopic fundoplication or endoscopic therapy7 Aliment Pharmacol Ther. 2004;19(Suppl 1):35-42. 3. Kimmey MB, Lanas A. Review article: Appropriate use of proton pump inhibitors with traditional nonsteroidal anti-inflammatory drugs and COX-2 selective inhibitors. Aliment Pharmacol Ther. 2004; 19(Suppl 1):60-65. 4. Holtmann G, Howden CW Review article: Management of peptic ulcer bleeding--the roles of proton pump inhibitors and Helicobacter pylori eradication. Aliment Pharmacol Ther. 2004;19(Suppl 1):66-70. 5. Welage LS. Pharmacologic properties of proton pump inhibitors. Pharmacotherapy. 2003;23: 74S-80S. 6. Chun AH, Eason CJ, Shi HH, Cavanaugh JH. Lansoprazole: An alternative method of administration of a capsule dosage formulation. Clin Ther. 1995;17:441-447.
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7. Chun AH, Shi HH, Achari R, et al. Lansoprazole: Administration of the contents of a capsule dosage formulation through a nasogastric tube. Clin Ther. 1996;18: 833-842. 8. Sharma VK, Ugheoke EA, Vasudeva R, Howden CW The pharmacodynamics of lansoprazole administered via gastrostomy as intact, non-encapsulated granules. Aliment Pharmacol Ther. 1998; 12:1171-1174. 9. Zimmermann A, Wakers JK, Katona B, Souney P Alternative methods of proton pump inhibitor administration. Consult Pharm. 1997;9:990-998. 10. SharmaVK. Comparison of 24-hour intragastric pH using four liquid formulations of lansoprazole and omeprazole. Am J Health 5yst Pharm. 1999;56(Suppl 4):$18-$21. 11. Sharma VK, Vasudeva R, Howden CW Simplified lansoprazole suspension--a liquid formulation of lansoprazole--effectively suppresses intragastric acidity when administered through a gastrostomy Am J Gastroenterol. 1999;94:1813-1817. 12. Freston J, Chiu YL, Pan WJ, et al. Effects on 24-hour intragastric pH: A comparison of lansoprazole administered nasogastrically in apple juice and pantoprazole administered intravenously Am J Gastroenterol. 2001; 96:2058-2065. 13. Doan TT, Wang Q, GriffinJS, et al. Comparative pharmacokmetics and pharmacodynamics of lansoprazole oral capsules and suspension in healthy subjects. AmJ Health 5yst Pharm. 2001;58:1512-1519. 14. Gunasekaran TS, Hassall EG. Efficacy and safety of omeprazole for severe gastroesophageal reflux in children. J Pediatr. 1993;123:148-154. 15. Mohiuddm MA, Pursnani KG, Katzka DA, et al. Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules. Dig Dis 5ci. 1997;42:715-719. 16. Taubel JJ, Sharma VK, Chiu YL, et al. A comparison of simplified lansoprazole suspension administered nasogastrically and pantoprazole administered intravenously: Effects on 24-h intragastric pH. Aliment Pharmacol Ther. 2001;15:1807-1817. 17. US Dept of Health and Human Services Web site. Available at: http:llwwwfdag°v/cder/f°ilappletter/ 2002/21428,20406s052,2128 ls0071tr.pdf. Accessed November 15, 2004. 18. Prevacid [package insert]. Lake Forest, Ill: TAP Pharmaceutical Products Inc; 2004. 19. Tolia V,Johnston G, Stolle J, Lee C. Flavor and taste of lansoprazole strawberry-flavored delayed-release oral
F. A m e r et al.
suspension preferred over ranitidine peppermintflavored oral syrup m children aged between 5-11 years. Paediatr Drugs. 2004;6:127-131. 20. Guidance for industry: E6 Good clinical practice: Consolidated guidance. US Dept of Health and Human Services Web site. Available at: http://wwwfda. gov/cder/guidance/959fnl.pdf. Accessed November 15, 2004. 21. 1983 Metropolitan height and weight table for men and women on metric basis. Metropolitan Life Insurance Company Stat Bulletin. 1983;6:2-9.
22. MDS Pharma Services. Validation of an LC/MS/M5
Method for the Quantitation of Lansoprazole in Human Heparinized Plasma. Lincoln, Neb: MDS Pharma Services; 1999. MDS Harris Project 20496_2. 23. I_am FC, Hung CT, Pettier DG. Estimation of variance for harmonic mean half-lives. J Pharm 5ci. 1985;74: 229-231.
24. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products--General Considerations. Rockville, Md: US Food and Drug Administration; 2002.
Address correspondence to: F o u a d Amer, MD, MPH, TAP Pharmaceutical Products Inc., 675 N o r t h Field Drive, Lake Forest, IL 60045. E-mail: f o u a d . a m e r @ t a p . c o m
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Comparison of the Pharmacokinetics of Lansoprazole 15- and 30-mg Sachets for Suspension Versus Intact Capsules Fouad Amer, MD, MPH, 1 Michael D. Karol, PhD, 2 Wei-Jian Pan, PhD, 2 Janice S. Griffin, RN, BSN, 1 Nancy L. Lukasik, RN, BSN, 1 Charles S. Locke, PhD, 2 and Yi-Lin Chiu, P h D 2 ~TAP Pharmaceutical Products Inc., Lake Forest, and 2Abbott Laboratories, Abbott Park, Illinois
ABSTRACT
Objective: The pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension were compared with those of corresponding doses of lansoprazole oral capsules. Methods: Healthy adult male and female subjects were randomized (1:1 ratio) into 2 Phase I, open-label, singledose, 2-sequence, 2-period complete crossover studies. In the first study, each subject received 1 lansoprazole 15-rag sachet mixed with water and 1 lansoprazole 15-rag oral capsule; in the second study, each subject received 1 lansoprazole 30-rag sachet mixed with water and 1 lansoprazole 30-rag oral capsule. Administration of the 2 formulations was separated by a washout period of ___7days. Blood samples were collected before and after each administration to assess the pharmacokinetic parameters of lansoprazole and bioequivalence between suspension and capsule. Results: Thirty-six subjects (19 males, 17 females) with a mean (SD) age of 32.0 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg received lansoprazole 15 rag. Thirty-six subjects (22 males, 14 females) with a mean (SD) age of 38.0 (8.3) years and mean (SD) body weight of 75.1 (9.7) kg received lansoprazole 30 rag. The pharmacokinetic parameters of the 15- and 30-rag lansoprazole sachets for suspension were similar to those of the corresponding doses of the oral capsules. The mean (SD) values for Cmax and AUC from time 0 to infinity (AUCo_~) for the lansoprazole 15-rag sachet (591.9 [242.3] ng/mL and 1614 [2065] ng.h/mL, respectively) did not differ significantly from those for the lansoprazole 15-rag capsules (578.6 [275.2] ng/mL and 1620 [2290] ng.h/mL, respectively). These parameters also did not differ significantly between the lansoprazole 30-rag sachet and 30-rag capsule: mean (SD) Cmax, 1103 (428.3) and 1077 (465.6) ng/mL, respectively; mean (SD) AUCo_~, 2655 (1338) and 2669 (1311) ng.h/mL, respectively. The 90% CIs for Cm~x and AUCo_~ ratios were contained within the 0.80 to 1.25 equivalence range, supporting bioequivalence. Conclusions: These findings suggest that the 15- and 30-rag lansoprazole sachets for suspension are bioequivalent to the corresponding doses of oral capsules. The sachet for suspension may provide an alternative route of administration to patients who have difficulty swallowing solid oral formulations. (Clin Ther. 2004;26: 2076-2083) Copyright © 2004 Excerpta Medica, Inc. Key words: pharmacokinetics, proton pump inhibitor, lansoprazole capsule, lansoprazole sachet for suspension, alternative dosage formulations. AcceptedJor publication September 13, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
2.076
doi:l O. I016/j.clinthera.2004.12.008 0149 2918/04/$19.00
Copyright © 2004 Excerpta Nedica, Inc.
F. A m e r et al.
INTRODUCTION
Proton pump inhibitors (PPIs) are widely used in the treatment of various acid-related disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal anti-inflammatory drug-induced gastropathy. 1-, Because these agents are inactivated by exposure to gastric juice, they are administered orally as delayed-release capsules that contain enteric-coated granules (eg, lansoprazole, omeprazole, esomeprazole) or as delayed-release enteric-coated tablets (eg, rabeprazole, pantoprazole) that should not be chewed or crushed. 5 Alternative methods of delivering the enteric-coated granules contained in the lansoprazole and omeprazole capsules have been evaluated for use in the treatment of patients who have difficulty swallowing solid oral dosage formulations. 6-16 These alternative modes of administration involve opening the capsules and sprinkling their contents over a small amount (1 tablespoon) of soft foods (eg, applesauce, pudding, yogurt, cottage cheese) and swallowing the mixture without chewing or crushing the granules. In addition, the granules can be mixed into a small amount of acidic fruit juice (eg, apple, cranberry, grape, orange, pineapple, prune, tomato) or liquid dietary supplement before drinking or mixed with 40 mL of apple juice and administered through a nasogastric or gastrostomy tube. Finally, lansoprazole is also approved as an IV formulation and as an orally disintegrating tablet. 17 Lansoprazole is the only PPI approved by the US Food and Drug Administration (FDA) that is commercially available as a 15- and 30-mg strawberryflavored sachet for suspension. 18 The strawberryflavored lansoprazole sachet contains enteric-coated granules that are designed to be suspended in water before oral administration. A recent, single taste-test study performed in children (aged 5-11 years) by Tolia et a119 found that the strawberry-flavored lansoprazole suspension was well liked by 95% of the 110 children who tasted it. The goal of the current study was to compare the pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension with those of the corresponding doses of lansoprazole oral capsules.
SUBJECTS AND METHODS Two Phase I, randomized (1:1 ratio according to a schedule generated before study initiation), open-label,
single-dose, 2-sequence, 2-period complete crossover studies were designed. The studies were performed at 1 center (Parkway Research Center, Miami, Florida), with one study evaluating lansoprazole 15 mg and the other study evaluating lansoprazole 30 mg. Study protocols were reviewed and approved by the investigational siteg institutional review board. All subjects provided written informed consent before the performance of any study-specific procedures. The procedures followed were in accordance with FDA regulations and Good Clinical Practice guidelines governing clinical study conduct. 2° Healthy male and nonpregnant, nonlactating female volunteers between the ages of 19 and 53 years with body weight within 10% of height, sex, and body frame guidelines21 and who had abstained from nicotine products for _>6 months before study initiation were eligible. Medical history and physical examinations, 12-lead electrocardiogram, vital sign measurements, routine evaluations of hematology (eg, white and red blood cell counts, hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin concentration, platelet count) and chemistry laboratory values (eg, aspartate and alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, bilirubin, creatinine, total protein, albumin, total cholesterol, triglycerides, lactate dehydrogenase, sodium, potassium, chloride, calcium, phosphorus, glucose, uric acid) and urinalysis (eg, specific gravity, urine pH, glucose, ketones, protein, blood, urobilinogen, bilirubin, microscopic examination) were not to have yielded any evidence of clinically significant medical disease or conditions in any of the study subjects. Subjects were not to have taken any prescription or nonprescription medications (excluding oral contraceptives or hormone replacement therapy in female subjects) within the 2 weeks before and during the course of the studies. Women of childbearing potential were required to have a negative prestudy urine pregnancy test and agreed to utilize an effective means of birth control (eg, oral contraceptives) from 2 weeks before and throughout the study. Subjects enrolled in each study were assigned in equal numbers to 1 of 2 sequences that contained a single dose of lansoprazole capsule and a single lansoprazole sachet for suspension. The sequences of the treatments were such that each subject received both 2077
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formulations by the time of study completion. A washout period of >7 days separated the 2 periods of each study, during which the different formulations were administered. Subjects were confined to the clinical research unit and supervised for -28 hours during the first period of the study (from the afternoon of day -1 through the evening of day 1) and -40 hours during the second period of the study (from day -1 through the morning of day 2). The subjects abstained from ingestion of food and beverages except for the scheduled meals provided during the study periods and water to quench thirst. All subjects received the same standardized meals in the same sequence. Grapefruit or grapefruit-containing products, as well as xanthine- and/or caffeinecontaining foods and beverages, were prohibited during the study periods. On each day of treatment administration, 1 of the lansoprazole formulations was administered at - 8 AM, after a >12-hour fast, and no food was served until after collection of the 3-hour blood sample at -11 AM. The lansoprazole 15- or 30-mg oral capsule was administered with 180 mL of water, and a hand-andmouth check was performed to ensure ingestion of the capsule dose. The 15- or 30-mg lansoprazole sachet for suspension was prepared by mixing the granules with 30 mL of tap water and swirling the mixture f o r - 1 minute or until the suspension thickened. Subjects swallowed the suspension immediately, the cup was rinsed with an additional 30 mL of water, and the subject then drank the rinse liquid. If necessary, the cup was rinsed with an additional 30 mL of water and the subject consumed this liquid to ensure that all of the granules from the lansoprazole sachet for suspension were ingested. Subjects were instructed not to chew the granules, and a mouth check was performed after administration of the suspension to ensure its ingestion. Safety profile evaluations were conducted through monitoring of vital signs that included sitting blood pressure, pulse, respiratory rate, oral temperature, and body weight. Subjects were closely monitored by the investigator for evidence of drug intolerance and for the development of clinical or laboratory evidence of an adverse event. All adverse events that occurred during the course of the study were reported in detail on the subjectg chart and followed to a satisfactory resolution. The investigator assessed each adverse event for 2078
severity and possible relationship to the study drug. Severity was defined as follows: mild--transient and easily tolerated; moderate--resulted in subject discomfort and interruption of normal activities; or severe-resulted in considerable interference with normal activities, and may be incapacitating or life-threatening. In addition, relationship to study drug was determined as definite, probable, possible, or not related. Pharmacokinetic Evaluation
Blood samples for the determination of plasma lansoprazole pharmacokinetic parameters were collected from each subject on day 1 of each crossover period. Seven-milliliter blood samples were collected by venipuncture into labeled evacuated heparinized tubes at: hour 0 (immediately before the 8 AM dose administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours after administration. Blood samples were centrifuged within 2 hours of collection. From each sample, plasma was transferred with a new plastic pipette into a labeled polypropylene tube, immediately frozen, and stored at -20°C or lower until analysis to assure stability of lansoprazole. Concentrations of lansoprazole in plasma samples were determined using a validated liquid chromatography method with tandem mass spectrometric detection (MDS Pharma Services, Lincoln, Nebraska). 22 Analyses were conducted in a blinded manner with regard to formulation. Pharmacokinetic parameters of lansoprazole were estimated using noncompartmental pharmacokinetic methods described as follows. Values for Cmax and Tmax were taken directly from the plasma concentrationtime profile for each subject. The value of the terminal elimination rate constant (~) was obtained from the slope of a least-squares linear regression of the logarithms of the plasma concentration-time data from the terminal log-linear phase of the profile. The terminal log-linear phase was identified by visual inspection. A minimum of 3 concentration-time data points were used to determine [~. The terminal elimination T1/2 was calculated as ln(2)/~. The AUC from time 0 to the time of the last measurable concentration (AUC T) was calculated by using the linear trapezoidal method. The AUC was extrapolated to infinity (AUCext) by dividing the last measurable plasma concentration by ~. The AUC from time 0 to infinity (AUCo_~) was the sum of AUC T and AUCext. The per-
F. Amer et al.
centage of the contribution of AUCext to the overall AUCo_~ was calculated by dividing the AUCext by the AUCo_~ and multiplying the quotient by 100. The total apparent oral plasma clearance value (CUE, where F is the bioavailability) was calculated by dividing the administered dose by the AUCo_~. Statistical Analysis
Each study was designed to enroll 36 subjects such that if >32 subjects (>16 in each sequence group) completed the stud>> it would provide -80% power for achieving the equivalence claim with respect to Cm~x and AUCo_~ if the central values differed by 5%. Analysis of variance (ANOVA) was performed for Tmax, [~, and the logarithms of Cmax and AUCo_~ to determine the effects of sequence, subject nested within sequence, period, and regimen. All statistical tests used in the analysis of data were 2-tailed and compared at a significance level of P < 0.05. The bioavailability of the lansoprazole sachet for suspension regimen relative to the same dose administered as the intact capsule was assessed by two 1-sided tests with 90% CIs obtained from the analyses of the natural logarithms of Cm~x and AUCo_~. The CIs were obtained by exponentiation of the end points of CIs for the difference of mean logarithms obtained within the framework of the ANOVA model. For the sample size calculations, the variance for the logarithm of AUCo~ and the logarithm of Cm~x were assumed to be 0.0297 and 0.0697, respectively, using data from previous studies (studies M95-393, M97-764, and M97-393, TAP Pharmaceuticals, Inc., Lake Forest, Illinois). RESULTS
Thirty-six healthy individuals were enrolled in each study. An approximately equal number of males and females were enrolled in each study (53% males [19/36] and 47% females [17/36] in the lansoprazole 15-mg study and 61% males [22/36] and 39% females [14/36] in the lansoprazole 30-mg study). Subjects enrolled in the lansoprazole 15-mg study had a mean (SD) age of 32 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg. Those enrolled in the lansoprazole 30-mg study had a mean (SD) age of 38 (8.3) years and a mean (SD) body weight of 75.1 (9.7) kg. In both studies, subjects were predominantly Hispanic (83% and 72% in the lansoprazole 15and 30-mg studies, respectively).
All enrolled subjects in each study received both formulations of the specified dose of lansoprazole. The mean plasma concentration-time profiles after administration of the lansoprazole 15-mg sachet for suspension and the 15-mg intact capsules are presented in Figure 1. The mean plasma concentrationtime profiles after administration of the lansoprazole 30-mg sachet for suspension and the 30-mg intact capsules are given in Figure 2. The mean (SD) pharmacokinetic values for lansoprazole 15 and 30 mg after administration as the sachet for suspension formulation and as the intact capsules are summarized in Table I. No statistically significant differences were observed in any pharmacokinetic parameters between lansoprazole 15-mg sachet for suspension and 15-mg oral capsules or between lansoprazole 30-mg sachet for suspension and 30-mg oral capsules. Lansoprazole 15- and 30-mg sachets for suspension displayed Cmax and AUCo_~ values that were similar to those observed with the respective doses administered as the intact capsules. The 90% CIs for evaluating bioequivalence and the corresponding point estimates of relative bioavailability are summarized in Table II. The 90% CIs for the ratio of the sachet for suspension and oral capsule formulations were 0.949 to 1.179 and 0.930 to 1.188 for the Cmax of lansoprazole 15 and 30 mg, respectively, and 0.959 to 1.128 and 0.914 to 1.109 for the AUCo_~ of lansoprazole 15 and 30 mg, respectively. The 90% CIs for the ratios of regimen geometric means for Cm~x and AUCo_~ were contained entirely within the 0.80 to 1.25 range required for bioequivalence, supporting that the lansoprazole sachet for suspensions are bioequivalent to the intact oral capsule formulations. 2~ Mild dizziness (in 2 patients after administration of lansoprazole 15-mg sachet for suspension), mild headache (in 1 patient after administration of lansoprazole 15-mg sachet for suspension, and in 1 patient before dosing of the lansoprazole 30-mg capsule), and mild nausea (1 patient after administration of the lansoprazole 30-mg capsule) were the only adverse events reported during the study. None of the reported cases of mild dizziness, headache, or nausea were considered by the investigator to be related to studydrug administration. No clinically significant changes from screening were observed for any laboratory or vital sign parameters. 2079
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- ~ - Suspension, 15 mg -O-Capsule, 15 mg 450 O.
400 E v
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Figure I. Mean plasma c o n c e n t r a t i o n - t i m e profiles f o r l a n s o p r a z o l e 15-mg sachet f o r suspension and 15-mg oral capsule.
DISCUSSION
The current studies found that lansoprazole sachets for suspension, prepared in 30 mL of tap water and swirled for -1 minute before administration, displayed similar concentration-time curves and nearly identical pharmacokinetic characteristics compared with those of the respective intact 15- and 30-mg cap-
sules. The suspension formulation was well tolerated, although the open-label study design may have partially introduced some reporting bias for safety measures that were sensitive to subjectivity (eg, dizziness). Although the pharmacokinetic results observed in these studies may be limited by the subject demographics (enrollment of subjects with body weight - D - Suspension,30 mg - 0 - Capsule, 30 mg
900 800 E 700 v
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i
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Time After Dose (h) Figure 2. Mean plasma c o n c e n t r a t i o n - t i m e profiles f o r l a n s o p r a z o l e 3 0 - m g sachet f o r suspension and 3 0 - m g oral capsule.
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Table I. Mean (SD) pharmacokinetic values for lansoprazole 15 and 30 mg, grouped according to dose and formulation. Lansoprazole 15 mg
Pharmacokinetic Measure
Tm~×, h Cm~×, ng/mL AUC T, ng'h/mL AUCo~, ng'h/mL TI/2, h*
CUF, Uh
Lansoprazole 30 mg
Sachet for Suspension (n -- 36)
Capsule (n = 36)
Sachet for Suspension (n = 36)
Capsule (n = 36)
1.7 (0.8) 591.9 (242.3) 1439 (I 398) 1614 (2065) 1.05 (0.34) 14.5 (6.2)
1.7 (0.8) 578.6 (275.2) 1451 (1582) 1620 (2290) 1.03 (0.33) 15.6 (8.5)
2.0 (0.7) 1103 (428.3) 2624 (I 306) 2655 (1338) I. 15 (0.32) 14.4 (7.6)
1.8 (0.8) 1077 (465.6) 2641 (1293) 2669 (131 I) 1.15 (0.32) 15.0 (9.9)
AUC T = AUC from time 0 to the time of the las-Lmeasurable concentration; A U C o ~ = AUC from time 0 to infinity; CUF = apparent oral plasma clearance. eHarmonic mean (pseudo SD, based on the jackknife variance).23
within 10% of ranges based on height, sex, and body frame; predominantly Hispanic), the parameters observed in the present work were similar to those seen in previous pharmacokinetic studies of lansoprazole capsule granules. <7,13 Chun et al 6 administered the contents of a 30-mg lansoprazole capsule mixed with a tablespoonful of applesauce and the intact capsule to healthy volunteers, finding no statistically significant differences in mean values for Tmax (1.8 vs 1.7 hours), Cmax (696 VS 800 ng/mL), Tu2 (1.21 vs 1.23 hours), or AUCo_~ (1909 vs 2021 ng.h/mL). In a subsequent crossover study in healthy volunteers, Chun et al r found comparable bioavailability and pharmacokinetic parameters after administration of intact lansoprazole 30-mg capsules and the capsule contents when emptied into apple juice and administered through a nasogastric tube.
The administration of acid-inhibitory therapy is problematic among patients who are unable to swallow solid oral formulations. Several previous studies have found that the enteric-coated, delayed-release granule contents of the commercially manufactured lansoprazole or omeprazole capsules can be sprinkled onto a small amount of soft food or mixed with acidic fruit juices or liquid dietary supplements before oral administration without compromising the drug's bioavailability, pharmacokinetics, or clinical effects as compared with the intact capsules. 6-16 The availability of a strawberry-flavored sachet for suspension containing 15 or 30 mg of lansoprazole enteric-coated, delayed-release granules may be beneficial in the treatment of adults with swallowing difficulties as well as in children. Although not investigated in the present work, it is anticipated that the sachet suspen-
Table II. Point estimates and 90% CIs for ratio of geometric means for bioequivalence assessment of lansoprazole sachets for suspension and lansoprazole capsules. Sachet vs Capsule
No. of Subjects
Point Estimate of Ratio
90% CI of Ratio
15 mg Cma×, ng/mL AUC0~, ng'h/mL
36 36
1.058 1.040
0.949 I. 179 0.959 1.128
30 mg Cmax, ng/mL AUCo~, ng'h/mL
36 36
1.051 1.007
0.930 I. 188 0.914 1.109
A U C 0 ~ = AUC from time 0 to infinit~z
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sion would produce the same gastric-acid antisecretory effects (ie, pharmacodynamics and effectiveness) as other formulations of lansoprazole. 2~ CONCLUSIONS These findings suggest that the 15- and 30-mg lansoprazole sachets for suspension are bioequivalent to the corresponding doses of the oral capsules. The sachet for suspension may provide an alternative route of acid-inhibitory medication administration to patients who have difficulty swallowing solid oral formulations. ACKNOWLEDGHENTS
This research was supported by a grant from TAP Pharmaceutical Products Inc., Lake Forest, Illinois. The authors gratefully acknowledge the following for their contributions to these studies: Mitchell A. Rosenberg, MD, and colleagues, Parkway Research Center, Miami, Florida; and Karen E. Rynkiewicz, Abbott Laboratories, Abbott Park, Illinois. Editorial support was provided by Susan Ruffalo, PharmD, MedWrite, Inc., Newport Coast, California. REFERENCES
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7. Chun AH, Shi HH, Achari R, et al. Lansoprazole: Administration of the contents of a capsule dosage formulation through a nasogastric tube. Clin Ther. 1996;18: 833-842. 8. Sharma VK, Ugheoke EA, Vasudeva R, Howden CW The pharmacodynamics of lansoprazole administered via gastrostomy as intact, non-encapsulated granules. Aliment Pharmacol Ther. 1998; 12:1171-1174. 9. Zimmermann A, Wakers JK, Katona B, Souney P Alternative methods of proton pump inhibitor administration. Consult Pharm. 1997;9:990-998. 10. SharmaVK. Comparison of 24-hour intragastric pH using four liquid formulations of lansoprazole and omeprazole. Am J Health 5yst Pharm. 1999;56(Suppl 4):$18-$21. 11. Sharma VK, Vasudeva R, Howden CW Simplified lansoprazole suspension--a liquid formulation of lansoprazole--effectively suppresses intragastric acidity when administered through a gastrostomy Am J Gastroenterol. 1999;94:1813-1817. 12. Freston J, Chiu YL, Pan WJ, et al. Effects on 24-hour intragastric pH: A comparison of lansoprazole administered nasogastrically in apple juice and pantoprazole administered intravenously Am J Gastroenterol. 2001; 96:2058-2065. 13. Doan TT, Wang Q, GriffinJS, et al. Comparative pharmacokmetics and pharmacodynamics of lansoprazole oral capsules and suspension in healthy subjects. AmJ Health 5yst Pharm. 2001;58:1512-1519. 14. Gunasekaran TS, Hassall EG. Efficacy and safety of omeprazole for severe gastroesophageal reflux in children. J Pediatr. 1993;123:148-154. 15. Mohiuddm MA, Pursnani KG, Katzka DA, et al. Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules. Dig Dis 5ci. 1997;42:715-719. 16. Taubel JJ, Sharma VK, Chiu YL, et al. A comparison of simplified lansoprazole suspension administered nasogastrically and pantoprazole administered intravenously: Effects on 24-h intragastric pH. Aliment Pharmacol Ther. 2001;15:1807-1817. 17. US Dept of Health and Human Services Web site. Available at: http:llwwwfdag°v/cder/f°ilappletter/ 2002/21428,20406s052,2128 ls0071tr.pdf. Accessed November 15, 2004. 18. Prevacid [package insert]. Lake Forest, Ill: TAP Pharmaceutical Products Inc; 2004. 19. Tolia V,Johnston G, Stolle J, Lee C. Flavor and taste of lansoprazole strawberry-flavored delayed-release oral
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suspension preferred over ranitidine peppermintflavored oral syrup m children aged between 5-11 years. Paediatr Drugs. 2004;6:127-131. 20. Guidance for industry: E6 Good clinical practice: Consolidated guidance. US Dept of Health and Human Services Web site. Available at: http://wwwfda. gov/cder/guidance/959fnl.pdf. Accessed November 15, 2004. 21. 1983 Metropolitan height and weight table for men and women on metric basis. Metropolitan Life Insurance Company Stat Bulletin. 1983;6:2-9.
22. MDS Pharma Services. Validation of an LC/MS/M5
Method for the Quantitation of Lansoprazole in Human Heparinized Plasma. Lincoln, Neb: MDS Pharma Services; 1999. MDS Harris Project 20496_2. 23. I_am FC, Hung CT, Pettier DG. Estimation of variance for harmonic mean half-lives. J Pharm 5ci. 1985;74: 229-231.
24. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products--General Considerations. Rockville, Md: US Food and Drug Administration; 2002.
Address correspondence to: F o u a d Amer, MD, MPH, TAP Pharmaceutical Products Inc., 675 N o r t h Field Drive, Lake Forest, IL 60045. E-mail: f o u a d . a m e r @ t a p . c o m
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