Esophageal transit and in vivo disintegration of branded risedronate sodium tablets and two generic formulations of alendronic acid tablets: a single-center, single-blind, six-period crossover study in healthy female subjects.
BACKGROUND
Delayed esophageal transit or disintegration of oral bisphosphonate tablets before they enter the stomach may be of concern with respect to iatrogenic complications among patients receiving longterm treatment. Different formulations of generic bisphosphonate tablets meeting regulatory requirements may have substantial differences in pharmaceutical attributes from the branded product that may result in different characteristics during esophageal transit.


OBJECTIVE
The primary objective of this study was to evaluate and compare esophageal transit times and in vivo disintegration of 3 bisphosphonate formulations, one branded and the others generic, that are commercially available in Canada and the United Kingdom.


METHODS
This was a single-center, randomized, singleblind, 6-period crossover study in healthy postmenopausal women aged >50 years. Each subject received a single oral dose of a branded risedronate sodium 35-mg tablet and 2 generic formulations of alendronic acid 70-mg tablets (Novopharm Limited, Toronto, Canada, and Teva UK Limited, Morley, United Kingdom) in both the erect and semisupine (45 degrees ) positions. Although the products are labeled to be taken in the erect position, the semisupine position was included to simulate dosing in bedridden patients. Subjects took tablets with 30 mL of water in the morning after an overnight fast. The tablets were radiolabeled with technetium-99m ion-exchange resins to enable visualization and measurement of esophageal transit time and disintegration using a gamma camera. Dynamic scintigraphic images were obtained for a total of 10 minutes: 2 images per second for the first 30 seconds and 1 image every 15 seconds for 9.5 minutes. This was a mechanistic study and tolerability was not assessed.


RESULTS
The study was conducted in 20 healthy white female subjects with a mean age of 62 years (range, 51-77 years). The effect of body position was statistically significant (P = 0.043), with the estimated hazard ratio (HR) of 0.74 indicating longer transit time in the semisupine position relative to the erect position. There was a statistically significant difference in transit time among the 3 types of tablets (P = 0.007), with the Novopharm tablet (HR = 0.59; P < 0.001) and Teva tablet (HR = 0.71; P = 0.042) having longer transit times compared with the risedronate tablet. In 4 instances, the Novopharm tablet disintegrated and dispersed in the esophagus, once in the erect position and 3 times in the semisupine position.


CONCLUSIONS
In these healthy female subjects, esophageal transit was delayed when the tablets were given in the semisupine position. The branded risedronate tablet had a significantly faster transit time than the 2 generic formulations of alendronate tested.
Perkins
Alan C
AC
Academic Medical Physics and Wolfson Digestive Diseases Centre, University Hospital, Nottingham, United Kingdom. alan.perkins@nottingham.ac.uk
Blackshaw
P Elaine
PE
Hay
Peter D
PD
Lawes
Simon C
SC
Atherton
Clare T
CT
Dansereau
Richard J
RJ
Wagner
Leigh K
LK
Schnell
Dan J
DJ
Spiller
Robin C
RC
D000368:Aged; D019386:Alendronate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004947:Esophagus / Q000000981:diagnostic imaging / Q000502:physiology*; D012968:Etidronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005772:Gastrointestinal Transit; D006801:Humans; D008875:Middle Aged; D011187:Posture; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D000068296:Risedronic Acid; D016037:Single-Blind Method; D013670:Sodium Pertechnetate Tc 99m; D013607:Tablets
D050071:Bone Density Conservation Agents; D016568:Drugs, Generic; D019275:Radiopharmaceuticals; D013607:Tablets; D013670:Sodium Pertechnetate Tc 99m; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate