Rabeprazole extended-release 50 mg compared with esomeprazole 40 mg and rabeprazole delayed release 20 mg: authors’ reply
Bibliographic record
Abstract
Sirs, We appreciate the comments by Yuan & Hunt.1 Maintenance of gastric pH has been traditionally measured by the percentage of time over 24-h gastric pH is >4.0. This parameter has been widely used in PPI drug development and was well accepted by regulatory agencies. As pointed out in their letter, this parameter has been shown to be positively correlated with clinical outcomes such as healing of erosive oesophagitis (EO).2-4 This was also the parameter used in their recently published article.5 The primary objective of our study6 was to evaluate pharmacodynamic (PD) properties of different prototype formulations; evaluation of pharmacokinetic (PK) parameters was secondary. PK parameters such as Tlast and Clast were estimated as presented, and these parameters were as informative as t1/2 in understanding the relative differences in PD and PK profiles of various prototypes. Furthermore, Clast parameter demonstrated a better correlation with the PD and in vitro dissolution profiles than t1/2. Of note, the t1/2 value from a later study of a 50 mg rabeprazole extended-release formulation was approximately twice (∼4 h) that of rabeprazole delayed-release 20 mg in healthy subjects. Since the study evaluated six prototype formulations and two comparators, a comparison adjusting for multiplicity would not have been practical. Furthermore, data from PK and PD studies are not intended to make any claim of clinical outcomes, but to provide insights on the PK and PD behaviours of prototypes in guiding further clinical development. This was the reason why we only presented P-values for the primary PD endpoint. The choice of different combinations of enteric-coated and pulsatile release tablets that were evaluated in our study were guided by data from other earlier exploratory PK studies, as well as in vitro dissolution profiles. As discussed in our article, the final decision in choosing Group 5 was based on the combination of PK and PD data, as well as other characteristics, such as dissolution profiles and manufacturing feasibility. A direct comparison of the mean percentage of time pH was >4.0 over 24-h period from our study with that in other studies requires caution, due to factors such as the study population. A direct comparison of the mean percentage of time pH was >4.0 during the night-time period from our study with that from their study4 would not be feasible since ‘night-time period’ was defined differently. While mean or median gastric pH is a useful parameter, we believe that averaging the pH value over the 24-h duration is not as valuable as the pH holding time in assessing relative differences in PD profiles of various prototypes. Furthermore, the pH holding time during the night-time period appeared to be the most useful parameter in differentiating between prototypes. The clinical efficacy data from two randomised controlled studies of rabeprazole extended-release 50 mg in moderate to severe EO (baseline Los Angeles Grade C or D) had been published online since November 2010.7 While these data did not demonstrate statistically significant superiority of rabeprazole extended-release 50 mg to esomeprazole 40 mg in healing of moderate and severe EO patients, the data suggest a potential benefit in the most severe patients. The data also support the notion that further prolonged acid suppression may translate into additional benefits in the most severe EO patients. Declaration of personal interests: Drs H. Chen, G. Rossiter, B. Rege, and Y. Lu are employees of Eisai Inc. Declaration of funding interests: The study was funded by Eisai Inc.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.059 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.015 | 0.016 |
| Insufficient payload (model declined to judge) | 0.008 | 0.004 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".