HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Dmochowski, R. Articles by Gupta, S. Search for Related Content PubMed PubMed Citation Articles by Dmochowski, R. Articles by Gupta, S. Social Bookmarking                   What's this?

Effect of the Proton Pump Inhibitor Omeprazole on the Pharmacokinetics of Extended-Release Formulations of Oxybutynin and Tolterodine

From the Department of Urology, Vanderbilt University School of Medicine, Nashville, Tennessee (R. Dmochowski); Ortho-McNeil Pharmaceutical, Inc, Raritan, New Jersey (A. Chen); ALZA Corporation, Department of Clinical Pharmacology, Mountain View, California (G. Sathyan, S. Gidwani, S. Gupta); and Wake Forest University School of Medicine, Department of Urology, Winston-Salem, North Carolina (S. MacDiarmid).

Address for reprints: Roger Dmochowski, MD, Department of Urology, Vanderbilt University School of Medicine, Medical Center North, Room A1302, Nashville, TN 37232-2765.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
This study assessed the effect of the proton pump inhibitor omeprazole on the bioavailability of the extended-release formulations of oxybutynin and tolterodine. Forty-four healthy volunteers received each of 4 treatments in a 4-period crossover design. The treatments consisted of osmotically controlled extended-release oxybutynin chloride tablets at 10 mg/d or extended-release tolterodine tartrate capules at 4 mg/d, with and without preceding treatment with 20 mg omeprazole daily for 4 days. Blood samples collected predose and at scheduled time points for 36 hours postdose were analyzed for oxybutynin and its active metabolite, N-desethyloxybutynin, or tolterodine and its active 5-hydroxymethyl metabolite, as appropriate. The AUC ratios for oxybutynin and its metabolite with and without prior omeprazole fell within the 80% to 125% range (accepted as the criterion for bioequivalence), as did those for tolterodine and its active moiety. The peak concentration ratios for oxybutynin and metabolite also conformed to this range; those for tolterodine did not. Increasing gastric pH with omeprazole does not substantially alter the pharmacokinetic properties of extended-release oxybutynin but may alter those of extended-release tolterodine.

Key Words: Extended-release oxybutynin • extended-release tolterodine • omeprazole • pharmacokinetics • bioequivalence

The in vivo and in vitro characteristics of extended-release formulations are frequently affected by food or other factors that alter gastrointestinal pH.^10-12 Food ingestion does not significantly alter the pharmacokinetics of the oxybutynin extended-release tablet.¹³ One study showed increased serum tolterodine concentrations after immediate-release tolterodine in the presence of food, although no clinically relevant effects on exposure to the active moiety were apparent.¹⁴ However, another study indicated that there was no significant effect of food ingestion on the bioavailability of tolterodine extended-release capsules.¹⁵ Immediate-release tolterodine, administered at twice the recommended therapeutic dosage, did not significantly alter the disposition of omeprazole.¹⁶

A study evaluating the effects of coadministration of the extended-release formulations of either tolterodine or oxybutynin and antacid in healthy human volunteers showed elevated peak concentrations for tolterodine and its active 5-hydroxymethyl metabolite (likely due to an increase in gastric pH by coadministration of antacid). Accelerated drug release from an extended-release formulation, commonly referred to as dose dumping, can affect efficacy because these formulations are no longer able to provide prolonged release with stable concentration of the drug. The oxybutynin extended-release tablet formulation was not affected by the presence of antacid.^17,18

The available data suggest that drug release from the osmotically controlled system employed in the extended-release formulation of oxybutynin is essentially insensitive to external factors, such as pH, GI motility, and food.^5,7,18 The impact of other drugs that increase gastric pH, such as a proton pump inhibitor, on the bioavailability of extended-release formulations of oxybutynin and tolterodine has not been described previously. Accordingly, this study was designed to evaluate the effects of the proton pump inhibitor omeprazole on the pharmacokinetics of extended-release formulations of oxybutynin and tolterodine.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Overview
This was a single-site, open-label, randomized, single-dose, 4-treatment, 4-period crossover study. Each participant received 4 treatments, in 1 of 4 sequences, with a washout period of 5 to 7 days between treatments. The treatments consisted of OROS-based extended-release oxybutynin chloride tablets 10 mg/d or extended-release tolterodine tartrate capsules 4 mg/d, with and without antecedent treatment with omeprazole 20 mg/d, for 4 days. The study took place at MDS Pharma Services (Phoenix, Ariz).

Study Population
This study was conducted in 44 healthy adult men and women, aged 18 to 45 years. The participants had no clinically relevant abnormalities as determined by medical history, physical examination, blood chemistry, hematology, and urinalysis. Women were required to use a medically appropriate method of contraception throughout participation in the study. The protocol and consent form were approved by the MDS Pharma Services Institutional Review Board (Lincoln, Neb). The protocol and associated risks of participation were explained in detail to the participants orally and in writing, and their written informed consent was obtained prior to enrollment in the study.

Protocol
Each participant completed the 4 treatments in 1 of 4 computer-generated treatment sequences. The treatments were (1) oxybutynin extended-release tablet, 10 mg, for 4 days; (2) omeprazole, 20 mg/d for 4 days, followed by oxybutynin extended-release tablet, 10 mg, 1.5 hours after the last dose of omeprazole; (3) tolterodine extended-release capsule, 4 mg, for 4 days; and (4) omeprazole, 20 mg/d for 4 days, followed by tolterodine extended-release capsule, 4 mg, 1.5 hours after the last dose of omeprazole.

On each study day, blood samples were collected before the dose of oxybutynin or tolterodine at roughly 0745. The study medication was given at 0800, and blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose. For the treatments involving pretreatment with omeprazole, the dose of omeprazole was administered at roughly 0630 for 4 days. On the fourth day, the study medication was administered roughly 1.5 hours after the last omeprazole dose.

Analysis
Samples were analyzed for oxybutynin and its active metabolite, N-desethyloxybutynin, or tolterodine and its active 5-hydroxymethyl metabolite (5-HM), as appropriate, using validated high-performance liquid chromatography (HPLC) combined with a tandem mass spectrometry (LC/MS/MS) method. The method to quantitate tolterodine and 5-HM was validated in the range of 0.1 to 50 ng/mL for both analytes. The lower limit of quantitation (LLOQ) for both analytes was 0.1 ng/mL. The samples for tolterodine and 5-HM were spiked with their corresponding deuterated internal standards (D-14 labeled), and the extraction procedure was fully automated and used the Cohesive Aria online turbulent flow chromatography system coupled to a Sciex API3000 mass spectrometer (Table I).¹⁹ The method to quantitate oxybutynin (MDS Pharma Services, Montreal, Québec) was validated in the range of 0.1 to 50 ng/mL, and its active metabolite was validated in the range of 1.0 to 500 ng/mL. The LLOQ for oxybutynin and N-desethyloxybutynin was 0.1 ng/mL and 1.0 ng/mL, respectively. The samples for oxybutynin and N-desethyloxybutynin were spiked with deuterated internal standards (D10-oxybutynin), and a liquid-liquid procedure was used for extraction. The extracted samples were injected into an HPLC system coupled with a Sciex API 150 mass spectrometer (Table II).

Acceptance for analytical batches was assessed based on performance of calibration standards and quality control (QC) samples. During the analysis of samples from this study, the mean concentrations of the standards ranged from 96.3% to 103.6% of the nominal values for oxybutynin and 90.2% to 106.0% for N-desethyloxybutynin. Coefficients of variation between runs for oxybutynin QC samples from acceptable analytical runs ranged from 4.1% to 11.4% for the 4 concentrations of QC samples. Coefficients of variation between runs for N-desethyloxybutynin QC samples from acceptable analytical runs ranged from to 2.9% to 12.3% for the 4 concentrations of QC samples assessed.

Similar criteria were used to access run acceptance for tolterodine and the 5-HM metabolite.

During the analysis of samples from this study, the mean concentrations of the standards ranged from 97.7% to 104% of the nominal values for tolterodine and 98.3% to 102.0% for the 5-HM metabolite. Coefficients of variation between runs for tolterodine QC samples from acceptable analytical runs ranged from 9.3% to 13.9% for the 4 concentrations of QC samples. Coefficients of variation between runs for 5-HM metabolite for QC samples from acceptable analytical runs ranged from 11.0% to 14.4% for the 4 concentrations of QC samples assessed.

The tolterodine active moiety concentration profile was calculated as the sum of unbound tolterodine plus the 5-HM metabolite.¹⁵ Tolterodine is predominantly metabolized by cytochrome P-450 (CYP) 2D6 to 5-HM, which is pharmacologically active and has equivalent antimuscarinic potency to tolterodine.^20-23

The area under the curve (AUC), C_max, and time to C_max (t_max) of each drug and its active metabolite were determined for the conditions with and without prior omeprazole treatment. The area under the concentration-time curve (AUC_t) from hour 0 (baseline) to the last detectable concentration at time t was calculated using the linear trapezoidal rule. The AUC from time 0 to infinity (AUC) was calculated as the sum of AUC_t and the area extrapolated to infinity, calculated by the concentration at the last time t (C_t) divided by k, where k is the apparent elimination rate constant. C_max and t_max were derived directly from the original data.

Sample Size
From previous studies, the within-subject root mean square errors of C_max for oxybutynin and tolterodine were 0.33 and 0.52, respectively. The larger value (0.52) was used in the sample size calculation to ensure adequate power for the analyses of both study drugs. Based on an estimated coefficient of variation of 0.56,²⁴ a total of 38 participants were estimated to provide 80% power to detect a 30% difference.

Statistical Analysis
To compare treatment with oxybutynin extended-release tablets and tolterodine extended-release capsules with and without omeprazole pretreatment, a mixed-effects analysis of variance (ANOVA) model—including treatment, sequence, treatment-sequence interaction (fixed factors), and subject within sequence (random effect)—was used. For oxybutynin extended-release tablets, the parameters tested were log-transformed oxybutynin and N-desethyloxybutynin AUC_t, AUC, and C_max. For tolterodine extended-release capsules, the variables tested were log-transformed tolterodine, the 5-HM metabolite, and the active moiety AUC_t, AUC, and C_max. The ratio of the least squares estimate of the mean parameters for the oxybutynin extended-release tablet and tolterodine extended-release capsule treatments with and without omeprazole pretreatment and the 90% confidence intervals were also estimated and compared.²⁵ A standard criterion based on Food and Drug Administration (FDA) guidelines was used to determine bioequivalence. Treatments were said to be bioequivalent when the 90% confidence interval of the ratio of means for the indicated kinetic parameter fell within the range of 80% to 125%.²⁶

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Baseline Characteristics
Forty-four participants were randomized to the 4 treatment sequences; the intent-to-treat (ITT) population was 43 (17 men, 26 women). The mean (± SD) age of these participants was 28.5 ± 7.6 (for the ITT population). The ethnic/racial distribution of the participants was 34.9% white, 4.7% African American, and 60.5% other. The mean height and weight of the participants were 166.8 ± 8.7 cm and 65.6 ± 8.8 kg, respectively. Thirty-nine participants completed the study. Reasons for premature discontinuation were subject choice (n = 1), pregnancy (n = 1), and other (n = 3).

Extended-Release Oxybutynin
The plasma concentration-time profiles of oxybutynin with and without prior omeprazole were similar (Figure 1), as were those of N-desethyloxybutynin with and without omeprazole (data not shown). The corresponding pharmacokinetic characteristics are presented in Table III. The mean AUC_t and C_max values in the omeprazole treatment group were within 20% of the values observed when oxybutynin was administered without omeprazole pretreatment. The 90% confidence intervals (CIs) for the treatment ratios (omeprazole pretreatment/no pretreatment) for log-transformed AUC values for oxybutynin and N-desethyloxybutynin were well within the 80% to 125% range for pharmacokinetic bioequivalence. The geometric means for the oxybutynin and N-desethyloxybutynin AUC ratios were 113.26% (90% CI: 103%-124%) and 103.18% (90% CI: 95%-112%), respectively (Table III). The C_max ratios for the omeprazole pretreatment condition relative to the no-pretreatment condition for the parent drug (113.92; 90% CI: 104%-125%) and metabolite (92.19; 90% CI: 84%-101%) also conformed to the accepted 80% to 125% boundaries (Table III).

View larger version (12K): [in this window] [in a new window]   Figure 1. Mean (±SD) plasma oxybutynin concentration profiles following treatment of extended-release oxybutynin with and without prior omeprazole treatment (n = 39). The plasma profiles of N-desethyloxybutynin were also similar in shape.

Extended-Release Tolterodine
The effect of pretreatment with omeprazole on the plasma concentration-time profile of the tolterodine active moiety compared with no pretreatment is illustrated in Figure 2; the profiles of tolterodine and the 5-HM metabolite with and without prior omeprazole administration were similar in shape (data not shown). Values for the corresponding pharmacokinetic parameters are shown in Table IV. The 90% confidence intervals for AUC ratios for tolterodine, the metabolite, and the active moiety were within the accepted limits of 80% to 125% for pharmacokinetic bioequivalence (Table IV). The C_max ratios for tolterodine, the metabolite, and the active moiety were approximately 40% to 45% greater when extended-release tolterodine capsules were administered following 4 days of omeprazole treatment, compared with the reference (no-pretreatment) condition (P < .001) (Table IV). Thus, the C_max ratio for the active moiety (144.67%; 90% CI: 127%-165%), as well as for the drug and the metabolite, exceeded the 80% to 125% acceptable range for pharmacokinetic bioequivalence.

View larger version (12K): [in this window] [in a new window]   Figure 2. Mean (±SD) active moiety concentration profiles following administration of extended-release tolterodine with and without prior omeprazole treatment (n = 40). The plasma profiles of tolterodine and 5-hydroxymethyl metabolite (5-HM) showed a similar pattern.

The mean t_1/2 values were similar for both extended-release oxybutynin (10.7 ± 5.1 vs 10.8 ± 5.0) and extended-release tolterodine (9.7 ± 4.1 vs 7.9 ± 4.8) with and without omeprazole pretreatment, respectively.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
This study demonstrated that the proton pump inhibitor omeprazole, which increases gastric pH, does not substantially alter the pharmacokinetics of oxybutynin extended-release tablets. This finding is consistent with previous observations^17,18 that the osmotically controlled formulation of oxybutynin is nearly insensitive to the gastrointestinal environment, including the presence of food.

In contrast, the pharmacokinetics of tolterodine extended-release capsules was altered by pretreatment with omeprazole. The C_max values for tolterodine, the 5-HM metabolite, and the calculated active moiety were 40% to 45% greater when the administration of extended-release tolterodine was preceded by omeprazole (P < .001). Furthermore, the 90% confidence intervals for the C_max ratios of the omeprazole pretreatment/no-pretreatment conditions for the active moiety and 5-HM were outside the accepted 80% to 125% boundaries for pharmacokinetic bioequivalence, although the AUC_t and AUC ratios for the 2 conditions were well within the 80% to 125% accepted range. Because only C_max was affected and not the AUC, the observed interaction appears to be the result of faster drug release rather than changes in metabolism. This is consistent with an antacid study in which an increase in gastric pH increased the rate of drug release from tolterodine extended-release capsules.¹⁸ The present data confirm that drug release for extended-release tolterodine is sensitive to pH.

The CYP2D6 enzyme is subject to genetic polymorphism. In individuals who lack the enzyme, the 5-HM active metabolite of tolterodine cannot be formed, and the pharmacologic effects are mediated by the unbound drug alone. Serum tolterodine concentrations in these "poor metabolizers" are higher than in those who possess the enzyme.²² In the latter ("extensive metabolizers"), the pharmacologically active moiety is the sum of unbound tolterodine and 5-HM.¹ In the present study, 2 participants had negligible serum 5-HM concentrations of 0.00 at all time points following tolterodine administration. However, a previous investigation presented evidence that exposure to the active moiety (in terms of AUC) in a poor metabolizer was within the range of exposure observed for subjects with the extensive metabolizer genotype.¹⁵ Comparable exposure to the active moiety in extensive and poor metabolizers is also suggested by the 10-fold difference in the extent of tolterodine and 5-HM binding to serum proteins (unbound fractions of 3.7% and 36%).²³ This individual difference among participants is thus unlikely to have influenced our results substantially.

According to the FDA guidance on bioavailability and bioequivalence studies for orally administered drug products, when a test product or experimental condition (such as omeprazole treatment) produces substantially increased plasma levels above the reference condition, the regulatory concern is not therapeutic failure but the adequacy of the safety database pertaining to the test condition or product.²⁵ Accordingly, further clarification of the nature of the interaction between tolterodine extended-release capsules and omeprazole and/or other drugs in this therapeutic class may be appropriate.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Alteration of gastrointestinal pH by pretreatment with the proton pump inhibitor omeprazole did not have a substantial impact on the pharmacokinetic properties of the osmotically controlled formulation of oxybutynin extended-release tablets. The pharmacokinetic parameters C_max, AUC_t, and AUC of oxybutynin and its metabolite, N-desethyloxybutynin, under the omeprazole-pretreated condition relative to administration of oxybutynin without prior omeprazole treatment conformed to the 80% to 125% criterion, which is generally accepted for bioequivalence. In contrast, the C_max ratio for the tolterodine active moiety was significantly elevated, with a 90% confidence interval lower level that exceeded the limit for bioequivalence. Further study of the properties of the tolterodine extended-release capsule to evaluate the safety implications of this finding would be appropriate.

DOI: 10.1177/0091270005278055

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. Clemett D, Jarvis B. Tolterodine: a review of its use in the treatment of overactive bladder. Drugs Aging. 2001;18: 277-304.[Web of Science][Medline] [Order article via Infotrieve]

2. Douchamps J, Derenne F, Stockis A, Gangji D, Juvent M, Herchuelz A. The pharmacokinetics of oxybutynin in man. Eur J Clin Pharmacol. 1988;35: 515-520.[CrossRef][Medline] [Order article via Infotrieve]

3. Drutz HP, Appell RA, Gleason D, Klimberg I, Radomski S. Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct. 1999;10: 283-289.[Medline] [Order article via Infotrieve]

4. Chess-Williams R, Chapple CR, Yamanishi T, Yasuda K, Sellers DJ. The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro. J Auton Pharmacol. 2001;21: 243-248.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Gupta SK, Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol. 1999;39: 289-296.[Abstract]

6. Olsson B, Szamosi J. Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine. Clin Pharmacokinet. 2001;40: 227-235.[CrossRef][Medline] [Order article via Infotrieve]

7. Sathyan G, Chancellor MB, Gupta SK. Effect of OROS® controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride. Br J Clin Pharmacol. 2001;52: 409-417.[CrossRef][Medline] [Order article via Infotrieve]

8. Anderson RU, Mobley D, Blank B, Saltzstein D, Susset J, Brown JS, for the OROS Oxybutynin Study Group. Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. JUrol. 1999;161: 1809-1812.[CrossRef][Medline] [Order article via Infotrieve]

9. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A, on behalf of the Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57: 414-421.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Vashi VI, Meyer MC. Effect of pH on the in vitro dissolution and in vivo absorption of controlled-release theophylline in dogs. J Pharm Sci. 1988;77: 760-764.[Medline] [Order article via Infotrieve]

11. Rekhi GS, Jambhekar SS. Bioavailability and in-vitro/in-vivo correlation for propranolol hydrochloride extended-release bead products prepared using aqueous polymeric dispersions. J Pharm Pharmacol. 1996;48: 1276-1284.[Medline] [Order article via Infotrieve]

12. Lukkari E, Aranko K, Juhakoski A, Hakonen T, Neuvonen PJ. Effect of time interval between food and drug ingestion on the absorption of oxybutynin from a controlled-release tablet. Pharmacol Toxicol. 1997;81: 31-34.[Medline] [Order article via Infotrieve]

13. Lukkari E, Castrèn-Kortekangas P, Juhakoski A, Löyttyniemi E, Aranko K, Neuvonen PJ. Effect of food on the bioavailability of oxybutynin from a controlled release tablet. Eur J Clin Pharmacol. 1996;50: 221-223.[Medline] [Order article via Infotrieve]

14. Olsson B, Brynne N, Johansson C, Arnberg H. Food increases the bioavailability of tolterodine but not effective exposure. J Clin Pharmacol. 2001;41: 298-304.[Abstract]

15. Olsson B, Szamosi J. Food does not influence the pharmacokinetics of a new extended-release formulation of tolterodine for once daily treatment of patients with overactive bladder. Clin Pharmacokinet. 2001;40: 135-143.[CrossRef][Medline] [Order article via Infotrieve]

16. Brynne N, Böttiger Y, Hallén B, Bertilsson L. Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole. Br J Clin Pharmacol. 1999;47: 145-150.[CrossRef][Medline] [Order article via Infotrieve]

17. Dmochowski R. The effect of pH on drug release from extended-release formulations of oxybutynin and tolterodine. In: 2nd International Consultation on Incontinence of the World Health Organization; July 2001; Paris.

18. Sathyan G, Dmochowski RR, Appell R, Guo C, Gupta SK. Effect of antacid on the pharmacokinetics of extended-release formulations of tolterodine and oxybutynin. Clin Pharmacokinet. 2004;43: 1059-1068.[Medline] [Order article via Infotrieve]

19. Zhou M, Ford L, Niggebrugge A. Applications of automated HTLC-MS/MS in bioanalytical laboratories. In: International Symposium on Pharmaceutical and Biomedical Analysis; September 2003; Orlando, Fla.

20. Nilvebrant L, Andersson K-A, Gillberg P-G, Stahl M, Sparf B. Tolterodine—a new bladder-selective antimuscarinic agent. Eur J Pharmacol. 1997;327: 195-207.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

21. Postlind H, Danielson Å, Lindgren A, Andersson SHG. Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos. 1998;26: 289-293.[Abstract/Free Full Text]

22. Brynne N, Dalén P, Alván G, Bertilsson L, Gabrielsson J. Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of tolterodine. Clin Pharmacol Ther. 1998;63: 529-539.[CrossRef][Medline] [Order article via Infotrieve]

23. Påhlman I, Gozzi P. Serum protein binding of tolterodine and its major metabolites in humans and several animal species. Biopharm Drug Dispos. 1999;20: 91-99.[Medline] [Order article via Infotrieve]

24. Diletti E, Hauschke D, Steinijans VW. Sample size determination: extended tables for the multiplicative model and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43. Int J Clin Pharmacol Ther Toxicol. 1992;30: 287-290.[Medline] [Order article via Infotrieve]

25. US Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products: General Considerations. Accessed August 1, 2003, from www.fda.gov/cder/guidance/index.htm

26. Kimanani E, Stypinski D, Curtis G, et al. A contract research organization's response to the new FDA guidances for bioequivalence/bioavailability studies for orally administered drug products. J Clin Pharmacol. 2000;40: 1102-1108.[Abstract]
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Dmochowski, R. Articles by Gupta, S. Search for Related Content PubMed PubMed Citation Articles by Dmochowski, R. Articles by Gupta, S. Social Bookmarking                   What's this?