Revexepride

Studies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal, >2 hours duration) compared to studies with suboptimal GE test methods.

With an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of 5HT₄ agonists, D₂ receptor antagonist, or ghrelin agonists; trials that measured change in GE (T_1/2) or composite UGI symptoms; trials of patients with functional dyspepsia and gastroparesis; and trials of GE test methods. Standardized mean differences (units expressed as SD) were used to standardize symptom assessments that were not uniform across studies. Random effects model was used to analyze data and meta-regression was used to evaluate the association between change in GE and UGI symptoms.

Of 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T_1/2) in all studies (mean reduction in T_1/2, 16.3 minutes; 95% confidence interval, -22.1 to -10.6 minutes) and in studies that used optimal GE test methods (mean reduction in T_1/2, 23.6 minutes; 95% confidence interval, -32.3 to -14.9 minutes). Promotility agents also significantly reduced UGI symptoms (mean reduction, 0.25 SD; 95% confidence interval, -0.37 to -0.13 SD). Meta-regression found no significant association between change in GE and UGI symptoms. However, when only studies with optimal GE test methods were evaluated, there was a significant positive association between improvement in GE and UGI symptoms (P = .02).

In a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.

Acid-reducing agents (ARAs) may affect drug exposure for orally-administered drugs exhibiting pH-dependent solubility. The aim of this research was to investigate factors predicting the effect of ARAs on drug exposure. Dose (mg)/250 mL/solubility at neutral pH and ratio of solubility at acidic pH to that at neutral pH were investigated as potential factors.

Drug-drug interaction (DDI) study results with ARAs were selected based on PubMed search from 2007 to 2016 and novel drug approvals at the US Food and Drug Administration (FDA) from 2014 to 2016. For the selected drugs, solubility data at acidic and neutral pH were obtained from publications, FDA and European Medicines Agency (EMA) review report, and Japanese interview form.

32 DDI study results with ARAs from 27 drugs having solubility data were obtained. The effect of ARAs on the C_max or AUC ratio% (with/without ARAs) decreased with the increasing values of both factors, but the ratio of solubility showed higher values of squared correlation coefficient R2 (0.75 - 0.78) than the dose (mg)/250 mL/solubility at neutral pH (0.48 - 0.59).

Ratio of solubility at acidic pH to that at neutral pH was a good predictor to estimate the effect of ARAs on drug exposure. Prediction of the effect of ARAs on drug exposure using solubility data would help to consider the necessity and timing for conducting a dedicated DDI study with ARAs and contribute to efficient drug development.
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