Intragastric pH Research Articles

Pharmacodynamics of 2 dosages of orally administered esomeprazole in client-owned, healthy dogs: A prospective, crossover study.

Esomeprazole use is increasing in dogs, but the gastrointestinal adverse events associated with q12h dosing necessitate pharmacodynamic evaluation of a reduced dose and frequency of administration. To compare the efficacy of 2 doses of (q24h) esomeprazole in raising intragastric pH in dogs. Nine healthy, client-owned dogs, >20 kg. Prospective, randomized, double blinded, crossover study. Esomeprazole (0.5 or 1 mg/kg q24h) was orally administered for up to 5 days per treatment arm, and the mean percentage time intragastric pH was ≥3 (MPT3) and ≥4 (MPT4) for 24 hours periods were compared to pretreatment pH using a continuous pH monitoring system. Dogs failing to reach pH goals (MPT3 ≥75%, MPT4 ≥66%) with once daily dosing received esomeprazole 1 mg/kg PO q12h to determine if a higher dose would improve acid suppression. No significant difference in the MPT3 or MPT4 was identified between treatments for any time point (P > .05). Both doses increased the MPT pH ≥3 and 4 median [range] (0.5 mg/kg, 1 mg/kg) on days 1 (MPT3: 76.8% [44-100], 69.2% [28.2-100]; MPT4: 65.6% [16.7-99.3], 54.9% [14.9-93.3]; P = .0009) and 2 (MPT3:77.2% [27.4-100], 75.4% [49.4-89.5]; MPT4: 66.3% [15.5-100], 59.7% [33.8-81.2]; P = .0005) of PPI treatment compared to pretreatment (MPT3: 58.3% [0.02-93.9], 52.6% [6.1-94.7]; MPT4: 25.2% [0-86.8], 32.4% [1.8-89.3]). Six dogs (66%, [0.36, 0.97]) reached pH goals established in humans with q24h dosing. Both q24h PO esomeprazole doses were effective in raising intragastric pH, despite high intersubject variability, but 33% of dogs required q12h dosing to reach pH goals.

Comparative Efficacy of Dexlansoprazole, Pantoprazole, Esomeprazole, and Rabeprazole in Achieving Optimal 24-Hour Intragastric pH Control: A Randomized Crossover Study Using Ambulatory pH Monitoring.

Proton pump inhibitors (PPIs) regulate gastric acid reflux. Dexlansoprazole's efficacy in prolonging acid suppression compared to conventional PPIs and placebo requires evaluation. A prospective, randomized, placebo-controlled, five-way crossover pilot study was conducted on healthy volunteers comparing the potency of dexlansoprazole to conventional PPIs in which five patients were randomized into five treatment cohorts, including dexlansoprazole 60 mg, pantoprazole 40 mg, esomeprazole 40 mg, rabeprazole 20 mg, and placebo, assessing 24-hour intragastric pH using Z/pH Recorder (ZepHr®, Diversatek, Inc., Milwaukee, WI) and analyzing statistical differences via paired t-test. Dexlansoprazole showed significantly longer durations with pH > 4.0 compared to placebo(P < 0.001) and all other PPIs (P < 0.05) over 24 hours. Although not significant in the first 0-12-hour period, dexlansoprazole maintained significantly higher pH levels in the last 12-24-hour period compared to pantoprazole (P = 0.001) and esomeprazole (P = 0.044) but not with rabeprazole (P = 0.075). Additionally, during the 24-hour pH monitoring measured at 30-minute intervals, dexlansoprazole (mean pH = 3.98 ± 0.11) consistently showed higher values than pantoprazole (mean pH = 3.48 ± 0.12), rabeprazole (mean pH = 3.66 ± 0.05), esomeprazole (mean pH = 3.66 ± 0.05), and placebo (mean pH = 2.52 ± 0.12), indicating its superior potency. Dexlansoprazole's dual-delayed release mechanism demonstrates superior acid suppression compared to traditional PPIs and placebo in this pilot study. Larger studies are needed to further evaluate its long-term efficacy and safety.

Mathematical model of the relationship between pH holding time and erosive esophagitis healing rates.

Effective suppression of gastric acid secretion promotes healing of erosive esophagitis. Treatment guidelines recommend proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs). Emerging evidence also supports potassium-competitive acid blockers (P-CABs). The aim was to construct a mathematical model to examine the relationship between pH holding time ratios (HTRs) and erosive esophagitis healing rates with H2RAs, PPIs and P-CABs. By literature search, we identified studies of H2RAs, PPIs or P-CABs that reported mean pH >4 HTRs at steady state (days 5-8) and erosive esophagitis healing rates after 4 and/or 8 weeks. We aggregated treatments by drug class and developed a non-linear, mixed-effects model to explore the relationship between pH >4 HTRs and healing rates. The pH dataset included 82 studies (4297 participants; 201 dosage arms); healing rate data came from 103 studies (43,417 patients; 196 treatment arms). P-CABs achieved the longest periods with intragastric pH >4, and the highest healing rates after 4 and 8 weeks. The predicted probabilities of achieving ≥90% healing rates at 8 weeks were 74.1% for P-CABs, 17.3% for PPIs and 0% for H2RAs. P-CABs provide the longest duration with intragastric pH >4 and, accordingly, the highest healing rates of erosive esophagitis.

Intragastric restructuring dictates the digestive kinetics of heat-set milk protein gels of contrasting textures

The gelation of milk proteins can be achieved by various means, enabling the development of diverse products. In this study, heat-set milk protein gels (15 % protein) of diverse textures were made by pH modulation and two gels were selected for dynamic in vitro gastric digestion: a spoonable soft gel (SG, pH 6.55′ Gʹ of ∼100 Pa) and a sliceable firm gel (FG, pH 5.65; Gʹ of ∼7000 Pa). The two gels displayed markedly different structural changes and digestion kinetics during gastric digestion. The SG underwent substantial structural compaction during the first 120 min of gastric digestion into a denser and firmer gastric chyme (26.3 % crude protein, G* of ∼8500 Pa) than the chyme of the FG (15.7 % crude protein, G* of ∼3000 Pa). These contrasting intragastric structural changes of the gels reversed their original textural differences, which led to slower digestion and gastric emptying of proteins from the SG compared with the FG. The different intragastric pH profiles during the digestion of the two gels likely played a key role by modulating the proteolytic activity and specificity (to κ-casein) of pepsin. Preferential early cleavage of κ-casein in SG stimulated coagulation and compaction of solid chyme, whereas rapid hydrolysis of αS- and β-caseins in the FG weakened coagulation. This study provided new insights into controlling the structural development of dairy-based foods during gastric digestion and modulating digestion kinetics.

Optimizing Gastroesophageal Reflux Disease treatment: A call to shift from omeprazole.

Gastroesophageal reflux disease (GERD) is a disorder of the upper respiratory tract, which develops due to the regurgitation of acid from the stomach into the oesophagus. If left untreated, GERD may cause serious complications such as Barrett's oesophagus, oesophageal strictures, and oesophageal adenocarcinoma. According to a study published by Nirwan JS et al in 2020, individuals suffering from Gastroesophageal reflux disease globally is 1.03 billion.[1] Proton pump inhibitors (PPIs) are frequently used drugs for the treatment of GERD. Omeprazole belongs to PPIs class of drugs and it has been a drug of choice for GERD because it is affordable, easily available, and it can be taken along with other medicines. However, Proton pump inhibitors are not completely risk-free, chronic use of Proton Pump inhibitors has been associated with decreased calcium and magnesium absorption increasing the risk of osteoporosis and electrolyte disturbances respectively. It also increases the risk of community-acquired pneumonia [2] However, Esomeprazole the s-isomer of omeprazole yields much better results than omeprazole. It is more effective and safe in the treatment of GERD, not only does it decrease the symptoms of the disease rapidly ie. heartburn [4] but also it reduces the relapse of the symptoms twice that of omeprazole. Maintenance of intragastric pH &gt; 4 is an effective measure for the management of gastroesophageal reflux disease, esomeprazole has demonstrated improved acid inhibition over omeprazole with a high mean percentage of 24-hour intragastric pH &gt; 4. The healing rate for reflux esophagitis and relapse was also higher for esomeprazole than that of omeprazole.[3] According to a study, the number of individuals with GERD in the South Asia region is around 8000 per 100000 [4]. Knowing the extent of Gastroesophageal patients present in Pakistan and how rapidly this number can escalate due to poor lifestyle modifications. Omeprazole which is the most frequent drug prescribed for the treatment of GERD [5] should be discouraged and Esomeprazole being more beneficial in terms of healing time and relapse of symptoms should be promoted to prevent chronic use adverse effects of Proton pump inhibitors. Overall, such a measure will improve the quality of life of a person suffering from gastroesophageal reflux disease which otherwise may lead to more severe implications.

Impact of obesity and roux-en-Y gastric bypass on the pharmacokinetics of (R)- and (S)-omeprazole and intragastric pH.

This study employed physiologically-based pharmacokinetic-pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on the pharmacokinetics and intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched the observed data from non-obese, morbidly obese, and post-gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]/[omeprazole] and [5-hydroxy-omeprazole]/[omeprazole]. The morbidly obese model accounted for the down-regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (S)-omeprazole, while hepatic CYP2C19 affected both (R)- and (S)-omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism-based PD model to assess the effect of omeprazole on intragastric pH. Following 40 mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non-obese, obese, and post-gastric bypass populations, and the daily time with pH >4 was 14.7, 16.4, and 24 h. Our PBPK/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post-RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population.

Intelligent Magnetic Microrobots with Fluorescent Internal Memory for Monitoring Intragastric Acidity

AbstractThis study investigates the dynamic fluctuations of pH caused by gastric acid secretion, a process of both biological and clinical significance, with microrobots. Abnormal patterns of acidity often indicate gastrointestinal diseases, underlying the importance of precise intragastric pH monitoring. Traditional methods using fluorescent probes face challenges due to their faint solid‐state fluorescence, limited target specificity, and accuracy. To overcome these obstacles, pH‐responsive fluorescent organic microparticles decorated with magnetite (Fe3O4) nanoparticles are engineered. These microrobots exhibit a unique fluorescence switching capability at a critical pH, enabling the monitoring of gastric acidity. The magnetic part of these microrobots ensures magnetic maneuverability to enable targeted navigation. The microrobots’ fluorescence switching mechanism is elucidated through comprehensive spectroscopy, microscopy, and X‐ray diffraction analyses, revealing molecular‐level structural transformations upon interaction with gastric acid and antacids. These transformations, specifically protonation and deprotonation of the microrobots’ fluorescent components, prompt a distinct fluorescence response correlating with pH shifts. In vitro and ex vivo experiments, simulating stomach conditions, confirm the microrobots’ efficacy in pH‐responsive imaging. The results showcase the promising diagnostic potential of microrobots for gastrointestinal tract diseases, marking a significant advancement in imaging‐based medical diagnostics at targeted locations.

Dual acid-pump blocking as novel therapeutic approach to treatment of acid-related diseases

Proton-pump inhibitors are highly efficient in the treatment of acid-related disease; however, their efficacy in treating reflux symptoms, healing esophageal erosions and peptic ulcers and eradicating Helicobacter pylori is sometimes suboptimal. Potassium-competitive acid blockers have a different mechanism of action, resulting in higher and longer-lasting increases in intragastric pH, which is neither non-inferior or superior to those of proton-pump inhibitors. The pharmacology, metabolism and mechanism of action of these drugs are different, therefore, it is hypothesised, that their combined use might be of clinical benefit through increased intragastric pH. This hypothesis is supported by pharmacological, physiological and microbiological data. The combined administration of proton-pump inhibitors and potassium-competitive acid blockers should be investigated in short-term therapy (4–8 weeks); if their complementary or additive effect is proven, dual acid pump blocking can be of further benefit in managing gastroesophageal reflux disease, peptic ulcers and eradicating Helicobacter pylori infection, in cases refractory to current therapies. For safety reasons, long-term administration of this combination as maintenance treatment should be avoided.

An all-in-one therapeutic platform for the treatment of resistant Helicobacter pylori infection

Helicobacter pylori (H. pylori) infection is a major cause of gastric diseases. Currently, bismuth-based quadruple therapy is widely adopted for eradicating H. pylori infection. However, this first-line strategy faces several challenges such as drug resistance, intestinal dysbacteriosis, and patients’ poor compliance. To overcome these problems, an all-in-one therapeutic platform (CLA-Bi-ZnO2@Lipo) that composed of liposomes loading clarithromycin (CLA), Bi, and ZnO2 hybrid nanoparticles was developed for eradicating multidrug-resistant (MDR) H. pylori. The in vitro and in vivo results showed that CLA-Bi-ZnO2@Lipo could target the infection-induced inflammatory mucosa through liposome mediated nanoparticle-tissue surface charge interaction and quickly respond to the gastric acid environment to release CLA, Bi3+, Zn2+, and H2O2. By oral administration per day, the acid triggered decomposition of CLA-Bi-ZnO2@Lipo could significantly increase intragastric pH to 6 within 30 min; The released CLA, Zn2+, and H2O2 further exerted synergistical anti-bacterial effects in which a ∼2 order higher efficacy in reducing MDR H. pylori burden was achieved in comparison with standard quadruple therapy (p < 0.05); The released Zn2+ and Bi3+ could also alleviate mucosal inflammation. Most importantly, the CLA-Bi-ZnO2@Lipo exhibited superior biosafety and nearly no side effects on intestinal flora. Overall, this study developed a highly integrated and safe anti-MDR H. pylori agent which had great potential to be used as an alternative treatment for MDR H. pylori eradication.

Expert Opinion on the Prescription Practice of Rabeprazole and Other Common Proton Pump Inhibitors for Patients with Gastroesophageal Reflux Disease

Objective: The current survey-based study aims to provide further insights on expert opinion regarding the commonly prescribed PPIs in clinical practice, with a specific focus on the use of oral rabeprazole 20 mg as a treatment for gastroesophageal reflux disease (GERD) maintenance therapy in Indian settings.&#x0D; Methodology: The questionnaire-based survey involving 25 questions collected perspectives of experts across various regions of India regarding the prescription practice of rabeprazole 20 mg and other proton-pump inhibitors (PPIs) for treating GERD symptoms.&#x0D; Results: Out of 512 study participants, 44% reported obesity as the common comorbid condition observed in GERD patients, while 28% noted co-morbid diabetes mellitus. According to 68% of the respondents, rabeprazole demonstrated superiority over other PPIs in terms of quicker onset of action, maintaining intragastric pH &gt;4 over 24 hours’ post-dose, and reduced nighttime heartburn. For GERD patients with functional dyspepsia and gastroparesis, 52% of responders favored the addition of domperidone as a prokinetic drug to the PPI treatment. Moreover, the majority of participants (61.91%) observed that rabeprazole 20 mg did not cause a delay in stomach emptying, nor did it raise somatostatin levels or alter baseline motilin levels in GERD patients. These findings underscore the effectiveness of rabeprazole 20 mg in comparison to omeprazole and lansoprazole.&#x0D; Conclusion: Experts recommended rabeprazole 20 mg as the preferred treatment option over omeprazole and lansoprazole for GERD patients with coexisting obesity and diabetes mellitus conditions. Additionally, over half of the respondents reported using a combination of domperidone and other PPIs for GERD patients with functional dyspepsia and gastroparesis.

Gastric pH and serum gastrin concentration in age-matched healthy dogs and dogs with chronic kidney disease.

Gastric hyperacidity and hypergastrinemia are purported to cause gastric ulceration in dogs with chronic kidney disease (CKD); however, no published studies have evaluated gastric pH with serum gastrin concentrations in dogs with CKD. To compare mean intragastric pH, mean percent pH distribution, and serum gastrin concentrations in dogs with CKD to age-matched, healthy dogs. We hypothesized there would be no difference in mean gastric pH or serum gastrin between groups. Thirteen dogs with CKD; 10 aged-matched healthy dogs. Prospective, case-control study. Serum chemistry, complete blood count, urinalysis, and serum gastrin concentrations were evaluated in all dogs before radiographic-assisted gastric placement of a pH capsule. Forty-eight-hour continuous gastric pH monitoring was performed in all dogs. Serum gastrin concentration, mean pH, and mean percentage time that gastric pH was strongly acidic (pH <1 and pH <2) were compared between groups using a repeated measures mixed-model ANOVA. No significant differences were observed between groups for any pH measurements, including mean ± SD gastric pH (CKD, 2.37 ± 0.87; healthy, 2.39 ± 0.99; P > .05). Serum gastrin concentrations were not significantly different between groups (median [range]: CKD, 10.5 ng/dL [<10-17.1]; healthy, 10.9 ng/dL [<10-15]; P > .05). Our client-owned dogs with CKD did not have lower gastric pH or higher serum gastrin concentrations compared to healthy dogs. Our results suggest that prophylactic gastric acid suppression in dogs with CKD is not warranted unless other clinical indications for use are present.

Keverprazan, a novel potassium-competitive acid blocker: Single ascending dose safety, tolerability, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

BackgroundKeverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. AimsTo evaluate the safety, pharmacokinetics, pharmacodynamics, and food effect of single oral doses of keverprazan in healthy Chinese subjects. MethodsIn the dose-escalated phase Ia trial, the first 8 subjects received keverprazan 5 mg, the others successively entered 10 mg, 20 mg, 40 mg, 60 mg groups and were randomized to receive keverprazan (n = 8), lansoprazole (LSZ) 30 mg (n = 2) or placebo (n = 2) in each dose group. The phase Ib study randomly enrolled subjects to the fasting-fed (n = 7) or fed-fasting (n = 7) groups for evaluating the food effect of keverprazan. ResultsTwenty (35.71%) adverse events (AEs) occurred in phase Ia, including 13 (32.50%), 3 (37.50%), and 4 (50.00%) AEs in the keverprazan, placebo, and LSZ groups, respectively. Four (28.57%) AEs occurred in Phase Ib. The Tmax of keverprazan was 1.25–1.75 h. Cmax and AUC increased with the dose, and the t1/2, CL/F were 6.00–7.17 h, 88.8–198 L/h, respectively. The intragastric pH >5 holding-time ratio (HTR) increased with the dose but reached a ceiling at 20 mg. In the 30 mg LSZ and 5–60 mg keverprazan groups, the intragastric pH >5 HTRs during 24 h were 57.1%±26.4%, 7.9%±8.1%, 26.2%±22.8%, 80.2%±8.8%, 88.1%±8.6%, and 93.0%±1.7%, respectively. The geometric mean ratios (90% CI) of Cmax and AUC0-∞ of keverprazan in plasma under the fed vs. fasting state were 126.8% (109.0%-147.5%) and 134.9% (123.8%-146.9%). ConclusionKeverprazan is tolerable, and provides significant stable and lasting inhibition efficacy of intragastric acidity at 20 mg.

Keverprazan, a novel potassium-competitive acid blocker: Multiple oral doses safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects.

Keverprazan, a novel potassium-competitive acid blocker, was approved for treating acid-related diseases. This study aimed to analyze the safety, pharmacokinetics (PKs) and pharmacodynamics (PDs) of multiple doses of keverprazan. This was a randomized, positive-/placebo-controlled, phase Ic trial. Twenty-six healthy adults were randomized to receive 20 mg/day keverprazan (n = 8), 40 mg/day keverprazan (n = 8), placebo (n = 6), or 20 mg/day vonoprazan (n = 4) for 7 days. Safety, PK and PD assessments were conducted. In the keverprazan, vonoprazan, and placebo groups, adverse events (AEs) were reported in nine (56.25%), two (50.00%), and three (50.00%) subjects, respectively. AEs were mild except a moderate abdominal pain leading to withdraw. No serious AEs occurred. The plasma concentration-time profiles of keverprazan showed rapid absorption (median time to maximum plasma concentration of 1.25-3.0 h). The terminal half-life was 6.23 and 7.01 h for keverprazan 20 and 40 mg groups on day 7. The maximum plasma concentration was 43.1 and 93.2 ng/mL, respectively. There was no apparent accumulation of keverprazan and the major metabolite after 7-day administration. The intragastric pH greater than 5 holding time ratios (HTRs) over 24 h postdose increased from 79.1%, 84.4%, and 84.5% on day 1 to 99.0%, 97.4%, and 100.0% on day 7 in the vonoprazan 20 mg and keverprazan 20 and 40 mg groups, respectively. The intragastric pH greater than 5 HTR of keverprazan reached a plateau at 20 mg. Keverprazan is well-tolerable. A steady-state in exposure was generally reached after 7 days of treatment. A dose of 20 mg/day keverprazan can elicit a significant, stable, and long-lasting gastric acid inhibition effect.

Prediction of gastroesophageal reflux episodes by smooth muscle electromyography: A translational study in rats and adolescents

AimsOur aim was to measure the myoelectric modifications during gastric acid secretion along with the gastric pH in a rat model and to detect the gastrointestinal (GI) myoelectric changes in adolescents suffering from gastroesophageal reflux disease (GERD) along with the esophageal pH measurement. Main methodsIn anesthetized rats, gastric acid secretion was initiated with intragastric histamine (50 mg/kg), and gastric pH, GI myoelectric activity and mechanical GI contractions were measured with intragastric pH electrode, subcutaneously implanted smooth muscle electromyography (SMEMG) electrodes and organ implanted strain gauges, respectively. In the clinical study, esophageal pH and GI myoelectric activity were measured in adolescents suffering from GERD with intraesophageal pH electrode and SMEMG electrodes placed on the abdominal surface, respectively. The SMEMG records were analyzed by fast Fourier transformation (FFT) and power spectrum density maximum (PsDmax) values were calculated for the GI segments. Key findingsIn rats, histamine initiated an immediate increase in gastric PsDmax, which preceded the significant reduction in gastric pH by 75 min. The myoelectric change was independent of mechanical GI contractions. In adolescents, the GERD episodes were preceded by a significant increase in gastric PsDmax 45 min earlier. These changes were independent of motion or meals. SignificanceIncreased gastric myoelectric activity during histamine stimulation or GERD might be linked to the enhanced activity of the gastric proton pump, indicating a link between gastric acid secretion and GERD episodes. It is supposed that SMEMG might be a tool for predicting forthcoming reflux episodes in GERD.

Effectiveness of vonoprazan-based regimens compared with proton pump inhibitor-based regimens as first-line Helicobacter pylori agents.

In this study, we compared the success rate of eradicating Helicobacter pylori (H. pylori) in adults and children using vonoprazan (VPZ)-based H. pylori regimens to that of proton pump inhibitors (PPIs). In Japan, the success rate of a VPZ-based regimen as first-line therapy was lower in children than in adults. Compared with adults, children around puberty have higher CYP2C19 and CYP3A4 enzymatic activity to metabolize PPIs and VPZ. Further, children generally have shorter intestinal transit times than adults and may absorb antibiotics to a lesser extent. When comparing success rates of pediatric and adult eradication therapy using VPZ, it is very important to maintain a higher intragastric pH with sufficient gastric acid suppression to maintain H. pylori in a replicating state and amoxicillin and clarithromycin in the intestinal tract for as long as possible by reducing diarrhea as a side effect. Based on the above, it is reasonable that VPZ, which can suppress stomach acids more strongly than PPI, is a more relevant H. pylori eradication therapy.

Interplay of egg white gel pH and intragastric pH: Impact on breakdown kinetics and mass transport processes

Egg white gels have been utilized as a model system to study protein breakdown kinetics based on physical and biochemical breakdown processes during in vitro gastric digestion. Additionally, the impact of regulating intragastric pH on the breakdown kinetic processes was investigated. The present study evaluated the impact of gel pH (based on the pH of protein dispersion prepared at pH 3, 5 and 7.5) and intragastric pH regulation (with or without adjustment to pH 2 during in vitro gastric digestion) on the effective diffusion of gastric juice components (water and HCl), gel softening kinetics during gastric digestion, microstructural analysis using micro- computed tomography and protein hydrolysis in the liquid and solid fraction of egg white gel digesta. Egg white gels were subjected to 30 s oral digestion and 15, 30, 60, 120, 180 or 240 min gastric digestion in a static in vitro gastric digestion model, with or without gastric pH adjustment to pH 2. The gel pH affected all the properties measured during gastric digestion and each gel pH represented a specific driving mechanism for protein breakdown. A lower gel pH (pH 3) demonstrated a higher diffusion of moisture and acid, resulting in faster softening (p < 0.05). An intermediate pH (pH 5) showed greater protein–protein interactions due to the proximity to the isoelectric point of egg white proteins, resulting in very slow softening during digestion (p < 0.05), and a higher pH (pH 7) resulted in higher acid diffusion, intermediate gel hardness and very slow softening kinetics (p < 0.05). The gastric pH adjustment during digestion of egg protein gels affected (p < 0.05) the equilibrium moisture and acid contents as well as protein hydrolysis. The study confirmed that there is an interplay between initial gel pH and the intragastric pH which affected the breakdown kinetics of egg white gels during the gastric digestion process.

Pharmacokinetic and pharmacodynamic exploration of various combinations of tegoprazan immediate and delayed-release formulations.

The new modified-release formulation of tegoprazan, a novel potassium-competitive acid blocker, is expected to improve the management of acid-related disease, including nocturnal acid breakthrough, by prolonging the duration of acid suppression. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of various combinations of tegoprazan with immediate-release (IR) and delayed-release (DR) formulations. A three-cohort, open-label, randomized, single-dose, three-treatment, six-sequence, three-period crossover study was conducted. Various combinations of tegoprazan IR and DR formulations (50, 75 or 100 mg) were administered orally once per period. The 24-h intragastric pH was monitored before and after each administration. PK blood samples were collected for up to 48 h. PK and PD were compared among treatments. Eighteen healthy Korean subjects completed the study. All treatment groups showed intragastric pH above 4 approximately 1h following tegoprazan administration. Among the various combinations, the IR and DR combination at a 1:1 ratio induced greater gastric acid suppression (%Time pH ≥ 4) than IR alone in each dose group, both for 24 h (50 mg; 59% vs. 52%, P = .2188, 95% confidence interval [CI] -6.92-22.27, 100 mg; 85% vs. 70%, P < .05, 95% CI 8.92-22.19) and at night (50 mg; 27% vs. 16%, P = .1563, 95% CI -11.79-37.71, 100 mg; 77% vs. 49%, P < .05, 95% CI 16.14-42.98), with similar systemic exposure. The combinatorial tegoprazan in the IR and DR 1:1 ratio formulation was found to induce stronger gastric acid suppression throughout the day and at night, compared to the conventional IR formulation.

Effect of morning versus night-time administration of proton pump inhibitor (pantoprazole) on thyroid function test in levothyroxine-treated primary hypothyroidism: a prospective cross-over study

BackgroundOne of the common causes of suboptimal control of thyroid stimulating hormone (TSH) in levothyroxine-treated hypothyroidism is coadministration of proton pump inhibitors (PPIs). Morning administration of pantoprazole has been shown to suppress intragastric pH to a greater extent. We therefore aimed to determine the effect of pantoprazole at different time points of the day on thyroid function test (TFT) in levothyroxine-treated overt primary hypothyroidism.MethodsIn this single centre, hospital based, prospective, two arm cross-over study (AB, BA), participants were randomized into 2 groups based on morning (6:00 am – 7:00 am simultaneously with the scheduled levothyroxine tablet) (group M) and evening (30 min before dinner) intake of 40 mg pantoprazole tablet (group N). After the initial 6 weeks (period 1), a washout period of 1 week for pantoprazole was given, and then both the groups crossed over for another 6 weeks (period 2). Patients were instructed to continue the same brand of levothyroxine tablet at empty stomach 1-hour before breakfast. Serum TSH was measured at baseline, week 6, and week 13.ResultsData from 30 patients, who completed the study with 100% compliance, were analysed. Mean TSH values of the study participants were significantly higher both at week 6 and week 13 compared to the baseline. Mean baseline serum TSH concentrations for groups M and N were 2.70 (± 1.36), and 2.20 (± 1.06) µlU/mL, respectively. Mean serum TSH concentrations at the end periods 1 and 2 for group M were 3.78 (± 4.29), and 3.76 (± 2.77) while the levels in group N were 3.30 (± 1.90), and 4.53 (± 4.590) µlU/mL, respectively. There was a significant rise in serum TSH concentration across periods 1 and 2 in both the groups (F2, 58 = 3.87, p = 0.03). Within group changes in TSH across periods 1 and 2 were not statistically significant. Similarly difference in TSH between the groups, either at 6 weeks or at 13 weeks, were also not statistically significant.ConclusionsConcomitant use of pantoprazole, even for 6 weeks, leads to significant elevation in serum TSH in levothyroxine-treated patients who are biochemically euthyroid, irrespective of timing of pantoprazole intake. Early morning and night-time administration of pantoprazole have similar effect on TFT in these patients.

Implementation of CYP2C19 genotyping to guide proton pump inhibitor use at an academic health center.

To describe the implementation of CYP2C19 testing into clinical practice at University of Florida (UF) Health Gainesville hospital to guide proton pump inhibitor (PPI) dosing and the lessons learned from this experience. Different CYP2C19 genotypes are associated with variability in PPI plasma concentrations and intragastric pH, which may contribute to the risk of treatment failure due to subtherapeutic concentrations and adverse effects (eg, infection, bone fracture, renal dysfunction) with sustained supratherapeutic concentrations. Based on evidence available prior to the availability of pertinent Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the UF Health Precision Medicine Program (PMP) developed clinical recommendations, provided through automated alerts at the time of a PPI order, to (1) increase the PPI dose for individuals with genotypes linked to increased CYP2C19 enzyme activity (ie, rapid and ultrarapid metabolizers) to improve the likelihood of drug effectiveness and (2) decrease the dose for individuals with decreased CYP2C19 activity (ie, intermediate and poor metabolizers) to reduce the risk of harm. The CYP2C19-PPI implementation was an iterative process that taught us key implementation lessons. Most notably, physician engagement is essential, problem lists in the medical record are unreliable, and special populations (eg, pediatric patients) need to be considered. Guiding PPI prescribing based on CYP2C19 genotype is a practical approach to potentially improve the benefit-risk ratio with PPI therapy. Physician engagement is key for successful implementation. A CPIC guideline on CYP2C19 genotype-guided PPI dosing is now available, and automated alerts may be instituted to facilitate implementation.

A translational pharmacokinetic/pharmacodynamic approach supports optimal vonoprazan dosing for erosive oesophagitis and Helicobacter pylori infection.

Treatment of acid-related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH >4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium-competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct-link PK/PD models were derived and used to simulate pH HTRs with between-participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non-Asian). Pre-dose, the mean pH >4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. Vonoprazan 20 mg once- and twice-daily dosing demonstrated high, dose-dependent, 24-hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid-related disorders.