Pharmacokinetics of teduglutide in subjects with renal impairment.

PURPOSE: Teduglutide is a recombinant analogue of human glucagon-like peptide-2 that has recently been approved for the treatment of short bowel syndrome in adults. This study was designed to study the influence of renal function and age on teduglutide pharmacokinetics. METHODS: This was an open-label study with six parallel groups (6 subjects each). Three groups with renal impairment (moderate, severe and end-stage renal disease) were compared to healthy subjects with normal renal function, which were matched to the renal-impaired subjects with respect to demographics. At least two elderly subjects (≥65 years) were enrolled per group. A single dose of 10 mg teduglutide was subcutaneously administered to each subject. Teduglutide plasma concentrations were measured using a validated liquid chromatography method with tandem mass spectrometric detection, and the primary pharmacokinetic variables (AUCinf and Cmax) were calculated. RESULTS: Area under the concentration versus time curve extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of teduglutide in subjects with end-stage renal disease were approximately 2.59- and 2.08-fold higher, respectively, than those of healthy subjects. The AUCinf and Cmax were also slightly higher in subjects with moderate and severe renal impairment. Comparison of healthy subjects aged <65 years with healthy elderly subjects revealed very similar pharmacokinetics in both subgroups. CONCLUSIONS: In our study population, the primary pharmacokinetic parameters of teduglutide increased with increased severity of renal impairment. These results suggest that the daily dose of teduglutide should be reduced by 50 % in patients with moderate and severe renal impairment and end-stage disease. We found no effect of age on the pharmacokinetics of teduglutide in healthy subjects. The treatment was well tolerated, and there were no safety concerns.

Efficacy and safety of pantoprazole 20 mg once daily treatment in patients with ulcer-like functional dyspepsia.

OBJECTIVE: To investigate the efficacy of pantoprazole 20 mg once daily (o.d.) in relieving epigastric pain associated with ulcer-like functional dyspepsia. RESEARCH DESIGN AND METHODS: In this double-blind, placebo-controlled, multicentre study, patients experiencing ulcer-like functional dyspepsia, with epigastric pain as the predominant symptom, were randomised to receive pantoprazole 20 mg or placebo o.d. for 28 days. Primary endpoint was the complete relief (i.e. absence) from epigastric pain after 28 days' treatment. The odds ratio (OR) for pantoprazole/placebo and its 95% confidence intervals (CIs) were determined. Significant superiority of pantoprazole was concluded if the value 1.0 was above this interval. RESULTS: Of 419 patients (intention-to-treat [ITT]) randomised to treatment, 207 received pantoprazole and 212 received placebo. Epigastric pain relief was achieved after 28 days' treatment in 55% of pantoprazole recipients and 45% of placebo recipients (per-protocol [PP]: 58% and 47%, respectively). Pantoprazole demonstrated statistically significant superiority compared with placebo in the ITT (OR: 0.68; 95% CI: 0.46-0.99) and PP populations (OR: 0.64; 95% CI: 0.42-0.98). Pantoprazole was more efficacious than placebo in relieving heartburn and acid regurgitation after 7, 14 and 28 days of treatment. The sum score of gastrointestinal symptoms after 28 days was statistically significantly lower in the pantoprazole than placebo group. Fewer patients receiving concomitant psychotropic medication experienced relief from epigastric pain than those not receiving such medication. Adverse events did not significantly differ between pantoprazole and placebo. CONCLUSIONS: Results of this study suggest that pantoprazole 20 mg is more efficacious than placebo, and is a well-tolerated treatment for relieving epigastric pain in patients with ulcer-like functional dyspepsia. Further research is needed to confirm these findings.

Determination of ReQuest-based symptom thresholds to define symptom relief in GERD clinical studies.

BACKGROUND/AIMS: The growing importance of symptom assessment is evident from the numerous clinical studies on gastroesophageal reflux disease (GERD) assessing treatment-induced symptom relief. However, to date, the a priori selection of criteria defining symptom relief has been arbitrary. The present study was designed to prospectively identify GERD symptom thresholds for the broad spectrum of GERD-related symptoms assessed by the validated reflux questionnaire (ReQuest) and its subscales, ReQuest-GI (gastrointestinal symptoms) and ReQuest-WSO (general well-being, sleep disturbances, other complaints), in individuals without evidence of GERD. METHODS: In this 4-day evaluation in Germany, 385 individuals without evidence of GERD were included. On the first day, participants completed the ReQuest, the Gastrointestinal Symptom Rating Scale, and the Psychological General Well-Being scale. On the other days, participants filled in the ReQuest only. GERD symptom thresholds were calculated for ReQuest and its subscales, based on the respective 90th percentiles. RESULTS: GERD symptom thresholds were 3.37 for ReQuest, 0.95 for ReQuest-GI, and 2.46 for ReQuest-WSO. CONCLUSION: Even individuals without evidence of GERD may experience some mild symptoms that are commonly ascribed to GERD. GERD symptom thresholds derived in this study can be used to define the global symptom relief in patients with GERD.

Look--but also listen! ReQuest: an essay on a new validated scale to assess the outcome of GERD treatment.

UNLABELLED: The ReQuest (Reflux Questionnaire) is a new instrument: a diary developed specifically to allow patients to measure the totality of their gastroesophageal reflux disease (GERD) symptoms and to track changes each day during treatment, an increasingly important need in clinical trials. This paper reviews the background, development, testing, and validation of the instrument and shows how its flexibility allows it to be used in new ways to assess different aspects of GERD. DEVELOPMENT: There were four key steps. (1) A full symptom spectrum was gathered from experts, literature and, crucially, from GERD patients, and comprised 67 symptom descriptions. (2) By expert consensus, these symptom descriptions were empirically condensed into six easier-to-handle 'dimensions' (acid complaints, upper abdominal/stomach complaints, lower abdominal/digestive complaints, nausea, sleep disturbances, other complaints), to which the seventh, general well-being, was added, a key feature of the instrument. The symptom burden of each dimension is measured as frequency x intensity (general well-being: intensity only). (3) This prototype instrument was tested in PPI clinical trials involving patients with erosive and non-erosive GERD, while the data generated were used to validate the prototype. (4) Finally, the scale was refined by factor analysis, a statistical process. OUTCOME: Detailed statistical testing validating the scale and factor analysis confirmed that empirically condensing the symptom descriptions into dimensions did not affect the measurement properties of the instrument. FURTHER APPLICATION: The structure of ReQuest and its product, which is numerical, makes the instrument highly flexible and allows for its use in other GERD areas. (1) Its subscales, ReQuest-GI and ReQuest-WSO, measure symptoms traditionally associated with reflux and with general well-being, respectively, and permit these to be quantified and tracked independently. (2) Minor degrees of reflux symptoms are common amongst the healthy. The level was determined in a large population without evidence of disease, and a 'GERD symptom threshold' calculated. Reduction below this threshold to 'background levels' is a more realistic end point in clinical trials than the rarely achieved 'complete absence'. (3) ReQuest-GI was re-scaled and integrated with the modified Los Angeles scale used to grade esophageal appearances at endoscopy. The new instrument is a matrix, the ReQuest/LA-classification, which allows both symptoms and endoscopy appearances to be expressed by a single set of numbers in individual patients and in populations. (4) This in turn allows identification of patients who on treatment achieve 'complete remission', i.e. healing and symptom relief. PPI clinical trials confirm that it takes a longer period of treatment to reach this endpoint than healing or symptom relief alone. Thus the conventional 4-8 weeks of PPI therapy may unwittingly result in under-treatment. (5) Studies are in progress to determine the 'minimum clinically important difference' (MCID). This is the minimum change measured on treatment, which is judged as being of clinical benefit, an increasingly important subject. (6) Finally, the ReQuest used in clinical trials has been simplified for application in day-to-day clinical practice. The results obtained with 'ReQuest in Practice', the simplified version, are similar to those observed with the full version, as confirmed in a large-scale study in general practice. The clinical practice version has also been validated. CONCLUSION: (1) The characteristics of ReQuest make it suitable for use as the primary endpoint in clinical trials assessing the outcome of GERD. (2) The subscales allows for closer examination on the nature of GERD and response to treatment. (3) A simplified version has proven suitable for use in daily practice.

Pantoprazole 20 mg on demand is effective in the long-term management of patients with mild gastro-oesophageal reflux disease.

A total of 536 patients with endoscopically confirmed GORD grade 0/I were included in this multicentre study. In the acute phase, patients were treated with pantoprazole 20 mg o.d. for 4 weeks to obtain symptom relief. Symptom-free patients were included in the subsequent long-term phase, and were randomly treated on demand with either pantoprazole 20 mg or placebo for 6 months (antacids as rescue medication). After the 4 weeks acute phase, 439 symptom-free patients entered the long-term phase. The perceived average daily symptom load remained significantly lower during the 6-month on-demand treatment with pantoprazole 20 mg as compared to placebo. Both the rates for unwillingness to continue and number of additional antacids taken were also significantly lower with pantoprazole 20 mg than with placebo. Hence, on-demand treatment with pantoprazole 20 mg is safe and effective in maintaining control of the symptoms heartburn, acid regurgitation and pain on swallowing symptoms in patients with GORD grade 0/I with superiority to placebo.

Determination of ReQuest-based symptom thresholds to define symptom relief in GERD clinical studies.

BACKGROUND/AIMS: The growing importance of symptom assessment is evident from the numerous clinical studies on gastroesophageal reflux disease (GERD) assessing treatment-induced symptom relief. However, to date, the a priori selection of criteria defining symptom relief has been arbitrary. The present study was designed to prospectively identify GERD symptom thresholds for the broad spectrum of GERD-related symptoms assessed by the validated reflux questionnaire (ReQuest) and its subscales, ReQuest-GI (gastrointestinal symptoms) and ReQuest-WSO (general well-being, sleep disturbances, other complaints), in individuals without evidence of GERD. METHODS: In this 4-day evaluation in Germany, 385 individuals without evidence of GERD were included. On the first day, participants completed the ReQuest, the Gastrointestinal Symptom Rating Scale, and the Psychological General Well-Being scale. On the other days, participants filled in the ReQuest only. GERD symptom thresholds were calculated for ReQuest and its subscales, based on the respective 90th percentiles. RESULTS: GERD symptom thresholds were 3.37 for ReQuest, 0.95 for ReQuest-GI, and 2.46 for ReQuest-WSO. CONCLUSION: Even individuals without evidence of GERD may experience some mild symptoms that are commonly ascribed to GERD. GERD symptom thresholds derived in this study can be used to define the global symptom relief in patients with GERD.