High Gastric pH Research Articles

Abstract CT064: Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study

Abstract Debio 0123 (D0123), an oral, brain-penetrant, highly selective WEE1 inhibitor, is currently in clinical development, both in combination and as monotherapy, for the treatment of patients with solid tumors. Food and gastric acid-reducing agents e.g. proton pump inhibitors (PPIs) may modify the solubility, bioavailability, safety and efficacy of oral cancer drugs. Polymedication in cancer patients is common and food restrictions can impact patient compliance and wellbeing. In order to adequately inform drug dosing in clinical trials, effects of food and high gastric pH on D0123 bioavailability were studied over three cycles in patients treated in the dose escalation of a Phase 1 study of D0123 in combination with Carboplatin (CTID NCT03968653).D0123 was given on Days 1-3 and 8-10 of each 21-day cycle in combination with carboplatin on Day 1. Current standard administration of D0123 is in fasted conditions and PPIs are prohibited. Dose-limiting toxicities were evaluated in cycle 1. The effect of food and high-gastric pH were assessed in cycles 2 and 3, respectively. In cycle 2 on Day 10, patients were receiving a high-fat meal and in cycle 3, the PPI lanzoprazole 30 mg BID was administered from Day 7 to 11. PK parameters (area under the curve (AUC), maximum concentration (Cmax)) were determined post-Day 10 dose and compared between cycle 1 (fasted) and cycle 2 (fed) or 3 (high gastric pH). Preliminary data from 3 cohorts, 3 dose levels (n=10) resulted in about 5 pairwise comparisons for food and for high gastric pH effects. Absence of D0123 accumulation between cycles was confirmed, allowing for inter-cycle comparison. Oral bioavailability of D0123 appears pH-dependent, suggesting that co-medication with PPIs should be avoided. In contrast, food intake has a limited impact on drug absorption, at all doses tested. Furthermore, D0123 administration with food may increase treatment convenience and tolerability, leading to its implementation in other D0123 trials. TABLE 1. NAND Mean change [ min ; max ] Effect of food (cycle 2 versus cycle 1) Effect of high gastric pH (cycle 3 versus cycle 1) AUC24 -3% [ -17% ; +8% ] -31% [ -39%; -23% ] Cmax -10% [ -26% ; 0% ] -33% [ -41% ; -20% ] Citation Format: Anne Bellon, Omar Saavedra, Ingrid M. Desar, Mathilde Jalving, Jourik A. Gietema, Carla van Herpen, Stefan van Ravensteijn, Esteban Rodrigo Imedio, Sylvia van Haren, Melanie Wirth, Sandrine Micallef, Vito Dozio, Rikke Frederiksen Franzen, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Hans Gelderblom. Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT064.

Abstract CT140: A phase 1 study of the IAP inhibitor xevinapant (Debio 1143) to evaluate food effect and drug-drug interactions with a proton pump inhibitor in healthy volunteers

Abstract INTRODUCTION: Xevinapant is an oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity to apoptosis, thereby enhancing the efficacy of chemoradiotherapy (CRT) and radiotherapy (RT). Xevinapant 200 mg/d (d1-14, Q3W) + CRT showed clinical benefit vs placebo + CRT in a phase 2 study of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN; NCT02022098). Two phase 3 studies are currently ongoing evaluating xevinapant in combination with CRT (TrilynX; NCT04459715) or RT (XRay Vision; NCT05386550) in patients with LA SCCHN, with dosing under fasting conditions or without regard to food, respectively. METHODS: A 2-stage study (Debio 1143-107) was conducted to assess the effect of food on 2 different formulations of xevinapant and the effect of co-administration with the proton pump inhibitor pantoprazole to evaluate the effect of high gastric pH on bioavailability of xevinapant. Stage 1 was an open-label, randomized, 4-arm, crossover study with 26 healthy volunteers (HV) treated with a single oral dose of xevinapant 200 mg in fasted or fed (high-fat diet) conditions with 2 different formulations. Stage 2 was a randomized, 2-way crossover study with 12 HV treated with a single oral dose of xevinapant 200 mg with or without pantoprazole. Pharmacokinetics (PK) and pharmacodynamics (PD) samples (Ciap1 levels in peripheral blood mononuclear cells [PBMCs]) were collected over 72 h post dose. The utilization of HV to address clinical pharmacology aspects of xevinapant was justified by holistic assessment of the toxicology, safety, and pharmacology profiles. RESULTS: Following a single dose of xevinapant 200 mg, exposures in HV under fasted conditions were consistent with those observed previously in cancer patients. Xevinapant formulations were bioequivalent and were considered safe and well tolerated in both fasted and fed conditions. Food delayed Tmax and decreased xevinapant Cmax by 39% but did not meaningfully alter the extent of absorption of xevinapant, as evidenced by no change in AUC, which is the most relevant exposure metric for efficacy based on xevinapant’s mechanism of action. Stage 2 data indicated that the PK of xevinapant was not affected by treatment with pantoprazole. Ciap1 levels in PBMCs decreased at least 4-fold compared to the baseline for all treatments and were reduced up to 72 h post single dose. No relevant differences in PD were observed across treatments. PK simulations indicated no relevant change in AUC and no impact on target engagement at steady state with food. CONCLUSION: These data indicate that xevinapant can be administered without regard to food or gastric acid reducing agents, which would be advantageous for patient convenience and compliance. Citation Format: Valérie Nicolas-Métral, Elisabeth Rouits, Camille Riff, Dany Spaggiari, Norbert Wiedemann, Pierre Colin, Eleanor Harrison-Moench, Rafael Crabbé, Heidi Nauwelaerts, Andreas Schroeder, Carolina Haefliger, Yulia Vugmeyster. A phase 1 study of the IAP inhibitor xevinapant (Debio 1143) to evaluate food effect and drug-drug interactions with a proton pump inhibitor in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT140.

PH-dependent drug interactions with acid reducing agents

Gastric acid reducing agents (ARAs) are drugs used for treating peptic ulcer disease. The higher gastric pH caused by ARAs can decrease solubility and absorption of the drugs co-administered with ARAs. The study examines the relationship between solubility and pharmacokinetic (PK) changes of cancer drugs concurrently used with ARAs, and the subsequent dose adjustment of cancer drugs to account for drug interactions. We hypothesize that (1) cancer drugs with pH-dependent solubility are evaluated more for drug interactions with ARAs, as compared to those with pH-independent solubility, (2) a decrease in the area-under-the-concentration curve (AUC) and maximum drug concentration (Cmax), the PK measurements indicative of drug absorption, is observed more in drugs with pH-dependent solubility that sharply decreases at pH 3-5, and (3) dose adjustment is recommended more for drugs with a ≥45% decrease in AUC and Cmax . The results showed no significant difference in the proportions of drugs where drug interactions were evaluated between drugs with pH-dependent solubility versus those with pH-independent solubility. A decrease in AUC and C max was observed more in drugs with pH- dependent solubility that sharply decreased at pH 3-5 than those without such property (50% vs. 0%; p=0.04). Dose adjustment was recommended more for drugs with a ≥45% decrease in AUC and Cmax than for those with a <45% decrease or no change (100% vs. 0%; p=0.002). These findings may help identify drugs with a higher risk of drug interactions with ARAs and assess the need for comprehensive evaluation of drug interactions and dose adjustment.

Australian data on the utilisation and duration on treatment of ibrutinib with a proton pump inhibitor in patients with relapsed or refractory chronic lymphocytic leukaemia.

In Australia, over half of patients with relapsed/refractory chronic lymphocytic leukaemia treated with ibrutinib use concomitant proton pump inhibitors (PPIs). High gastric pH reduces the bioavailability of some Bruton tyrosine kinase inhibitors. There was no difference in duration on ibrutinib with or without concomitant PPI (unadjusted P = 0.61; adjusted hazard ratio: 1.23, 95% confidence interval: 0.75-2.02, P = 0.411). PPI use does not affect ibrutinib treatment persistence.

Cutaneous Sporotrichosis of Face with Verrucous Lesions over Nose, Successfully Treated with a Combination of Itraconazole and Terbinafine: A Case Report.

Dear Editor, A 13-year-old boy presented with nasal erythematous, crusted, confluent papules, and nodules persisting for approximately 35 days [Figure 1]. The patient denied contact with sick cats but mentioned playing in the bushes. The clinical diagnosis was cutaneous sporotrichosis, and he started treatment with itraconazole 100 mg per day, which was administered orally for 10 days and then increased to 200 mg per day. The exudate from the skin lesions was directly examined by a potassium hydroxide test, which was negative for fungal presence. At 25°C, a mycosal media culture of the exudate revealed colonies resembling Sporothrix sp, which appeared membranous, beige, wrinkled, and with a blackened halo [Figure 2]. At 37°C, phenotypic reversal for creamy colonies with beige and colorless verse was observed, thus demonstrating dimorphism. The lactophenol cotton blue stain revealed hyaline septate hyphae [Figure 3]. On day 44 of itraconazole treatment alone, the lesions became severely crusted, demonstrating no improvements. Thus, 250 mg of oral terbinafine was added to the treatment regimen. On day 60 of itraconazole use, a skin biopsy was performed. Grocott silver stain revealed rare samples of fungal structures [Figure 4]. Histopathology showed acanthosis of the epidermis, areas with perivascular mononuclear inflammatory infiltrate and fibrosis [Figure 5]. On day 226 of itraconazole and day 182 of terbinafine use, clinical improvement was noted, indicating the end of oral antifungal drugs [Figure 6]. The patient underwent Laser Erbium YAG, an ablative laser, to achieve favorable aesthetic results for the scar and uniformization of the skin of the nasal region.Figure 1: Infiltrated erythematous nodules of sporotrichosis on the nose with verrucous appearanceFigure 2: Culture at 25°C, showing colonies of membranous, beige, wrinkled with a blackened halo, resembling Sporothrix speciesFigure 3: The hyaline septate hyphae of Sporothrix spp. with one pyriform microconidia in daisy arrangement (lactophenol cotton blue stain, ×40)Figure 4: Grocott silver stain presenting a fungal structures (40x)Figure 5: Acanthosis of the epidermis, areas with perivascular mononuclear inflammatory infiltrate, and intense remodeling of dermal collagen with fibrosis. (H and E, 10x)Figure 6: Clinical improvement after terbinafine and itraconazole use. Only residual erythema, papules and nodulesSporotrichosis is a subcutaneous mycosis caused by a thermodimorphic fungus, Sporothrix spp., most commonly S. brasiliensis, S. schenckii, and S. globosa.[1] The lesions manifest in different clinical forms: mainly lymphocutaneous, fixed, cutaneous, disseminated, and extracutaneous. Recently, the incidence of various diseases caused by Sporothrix has been increasing in Brazil, particularly a high disease rate in urban areas. Felines have been reported as a new source of infection that spreads diseases.[2] Itraconazole is a first-line treatment for Sporothrix, but some strains, mainly S. brasiliensis, are resistant.[3–5] Moreover, itraconazole content sometimes does not match the concentrations indicated by manufacturers.[3] Itraconazole has certain pharmacokinetic concerns because of several drug interactions. For example, a high gastric pH reduces its bioavailability. Terbinafine is an alternative drug that can effectively treat cutaneous sporotrichosis, and it is affordable and has fewer interactions with other drugs.[1,4,5] To improve therapeutic outcome, itraconazole has been combined with a second drug and demonstrated good results, for example, with supersaturated potassium iodide (SSKI) solution.[6] SSKI is an alternative for cutaneous forms, which is primarily used for infants. However, compared with terbinafine, SSKI has side effects and issues, such as a lack of standardized commercial formulation and unknown mechanisms of action.[1,4] Studies describing the use of itraconazole with terbinafine are limited. In vitro, terbinafine and itraconazole have synergistic effects because both disrupt ergosterol synthesis in the cell membrane of fungi at different stages. This mechanism is beneficial due to accelerated response against chromoblastomycosis, onychomycosis, and sporotrichosis, where facial lesions can cause aesthetic stigmas and affect the quality of life of patients. In conclusion, the combination of terbinafine and itraconazole can effectively inhibit disease progression faster and thus prevent excessive fibrosis and scars.[5,7–10] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Use of Gastrointestinal Simulator, Mass Transport Analysis, and Absorption Simulation to Investigate the Impact of pH Modifiers in Mitigating Weakly Basic Drugs' Performance Issues Related to Gastric pH: Palbociclib Case Study.

It is well known that reduced gastric acidity, for example with concomitant administration of acid reducing agents, can result in variable pharmacokinetics and decreased absorption of weakly basic drugs. It is important to identify the risk of reduced and variable absorption early in development, so that product design options to address the risk can be considered. This article describes the utilization of in vitro and in silico tools to predict the effect of gastric pH, as well as the impact of adding pH modifiers, in mitigating the effect of acid reducing agents on weak base drugs' dissolution and absorption. Palbociclib, a weakly basic drug, was evaluated in low and high gastric pH conditions in a multicompartmental dissolution apparatus referred to as a gastrointestinal simulator (GIS). The GIS permits the testing of pharmaceutical products in a way that better assesses dissolution under physiologically relevant conditions of pH, buffer concentration, formulation additives, and physiological variations including GI pH, buffer concentrations, secretions, stomach emptying rate, residence time in the GI, and aqueous luminal volume. To predict drug dissolution in the GIS, a hierarchical mass transport model was used and validated using in vitro experimental data. Dissolution results were then compared to observed human clinical plasma data with and without proton pump inhibitors using a GastroPlus absorption model to predict palbociclib plasma profiles and pharmacokinetic parameters. The results showed that the in silico model successfully predicted palbociclib dissolution in the GIS under low and high gastric pH conditions with and without pH modifiers. Furthermore, the GIS data coupled with the in silico tools anticipated (1) the reduced palbociclib exposure due to proton pump inhibitor coadministration and (2) the mitigating effect of a pH-modifying agent. This study provides tools to help in the development of orally administered formulations to overcome the effect of elevated gastric pH, especially when formulating with pH modifiers.

Effect of pre-operative oral paracetamol on gastric residual volume and pH in young children in the context of a 1-hour clear fluid fast: a randomised controlled trial.

High gastric residual volume and low pH are associated with increased mortality following pulmonary aspiration in animal studies. The use of pre-operative oral paracetamol has not been investigated in younger children and infants in the context of a prescriptive 1-h clear fluid fast aimed at reducing the risk of pulmonary aspiration while improving patient experience. Children aged 1 month up to a weight of 25 kg and scheduled for elective surgery were randomly allocated to receive a prescribed 3.6 ml.kg-1 drink of water alone (water group) or 3 ml.kg-1 water and oral Infant Calpol® syrup (24 mg.ml-1 concentration, equivalent volume 0.6 ml.kg-1 , paracetamol group) 1 h before the induction of anaesthesia. Following induction, a nasogastric tube was used to aspirate gastric contents and the volume and pH were recorded. Ninety-seven children, median (IQR [range]) age 24 (12-45 [1-96]) months and weight 12.4 (9.7-16.0 [2.9-27.0]) kg, were analysed. Median time from drink to induction was 54 (45-60 [21-113]) min. There was no significant difference in gastric residual volume (p = 1) or pH (p = 0.99) between the water and the paracetamol groups. Sub-group analysis revealed no significant difference in gastric residual volume or pH for 29 children who weighed < 10 kg compared with > 10 kg. Using a prescriptive fluid regime of 3 ml.kg-1 of water, the addition of oral paracetamol syrup did not significantly alter gastric residual volume or pH in the context of a 1-h fast in infants and young children.

A Novel Multilayer Natural Coating for Fed-State Gastric Protection.

Several nutraceutical products require gastric protection against the hostile environment in the stomach. Currently marketed synthetic and semi-synthetic coatings suffer from major shortcomings such as poor gastric protection, slow-release response to pH change, and the use of artificial ingredients. The challenge of coating natural products is further exacerbated by the relatively high gastric pH in the fed state. In this work, a novel natural enteric coating is presented as a breakthrough alternative to current solutions. Two coating systems were devised: (i) a triple-layer coating that comprises a wax layer embedded between two alginate-based coatings, and (ii) a double-layer coating, where an overcoat of organic acids (fumaric or citric acid) is applied to an alginate-based coating. The multi-layer architecture did not impact the pH-responsive nature of the coating even when more biologically relevant Krebs bicarbonate buffer of lower buffer capacity was used. Interestingly, the gastric protection barrier of organic acid-based coating remained resistant at elevated gastric pH 2, 3, or 4 for 2 h. This is the first report of using an alginate-based coating to provide gastric protection against fed-state stomach conditions (pH 2–4). Being biodegradable, naturally occurring, and with no limit on daily intake, the reported novel coating provides a superior platform to current coating solutions for pharmaceutical and nutraceutical products.

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract's physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm. 2018 and Bermejo, et al. M. Mol. Pharm. 2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds' dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pKa) and its interplay with the pH modifier pKa or pKas. As an example of this complex interaction, for basic drugs with high pKa and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pKa, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model's predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

10 powodów, dla których warto wybrać pantoprazol u pacjentów z polipragmazją

Proton pump inhibitors are the most effective therapy for all the acid-dependent diseases. Pantoprazole has been used since 1997 and it has a precise and predictable profile of activity. Pantoprazole maintains its stability in higher gastric pH with concomittant antiacids. Its constant bioavaibility and maximal blood levels are achieved after the first dose. Pantoprazole is approved for a variety of gastric acid-related diseases: gastroesophageal reflux disease, peptic ulcer disease, Helicobacter pylori eradication, functional dyspepsia, NSAID-induced gastropathy treatment and prevention, and Zollinger-Ellison syndrome. Pantoprazole has been shown to have no significant interactions with other medications: especially important with antiplatelet drugs (clopidogrel), but also antipyrine, carbamazepine, ciclosporin, clarithromycin, diclofenac, naproxen, nifedipine, oral contraceptives, tacrolimus, theophylline, warfarin, and also ethanol. Pantoprazole is the very good choice particularly in patients taking multiple concomitant medications – such as the elderly or those receiving drugs with a narrow therapeutic window. Even in the long-term therapy, pantoprazole seems to be well tolerated with no identified safety concerns.

The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs.

There is evidence that use of drugs with anticholinergic properties increases the risk of cognitive impairment, and increased exposure to these drugs potentiates this risk. Anticholinergic drugs are commonly used even with associated risk of adverse events. Aging, sex, and genetic polymorphisms of cytochrome P450 (CYP) enzymes are associated with alterations in pharmacokinetic processes, which increase drug exposure and may further increase the risk of adverse drug events. Due to the increasing burden of cognitive impairment in our aging population and the future of personalized medicine, the objective of this review was to provide a critical clinical perspective on age, sex, and CYP genetic polymorphisms and their role in the metabolism and exposure to anticholinergic drugs. Age‐related changes that may increase anticholinergic drug exposure include pseudocapillarization of liver sinusoidal endothelial cells, an approximate 3.5% decline in CYP content for each decade of life, and a reduction in kidney function. Sex‐related differences that may be influenced by anticholinergic drug exposure include women having delayed gastric and colonic emptying, higher gastric pH, reduced catechol‐O‐methyl transferase activity, reduced glucuronidation, and reduced renal clearance and men having larger stomachs which may affect medication absorption. The overlay of poor metabolism phenotypes for CYP2D6 and CYP2C19 may further modify anticholinergic drug exposure in a significant proportion of the population. These factors help explain findings of clinical trials that show older adults and specifically older women achieve higher plasma concentrations of anticholinergic drugs and that poor metabolizers of CYP2D6 experience increased drug exposure. Despite this knowledge neither age, sex nor CYP phenotype are routinely considered when making decisions about the use or dosing of anticholinergic medications. Future study of anticholinergic medication needs to account for age, sex and CYP polymorphisms so that we may better approach personalized medicine for optimal outcomes and avoidance of medication‐related cognitive impairment.

Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs.

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

In Vitro Sensitivity Analysis of the Gastrointestinal Dissolution Profile of Weakly Basic Drugs in the Stomach-to-Intestine Fluid Changing System: Explanation for Variable Plasma Exposure after Oral Administration.

An in vitro methodology for simulating the change in the pH and composition of gastrointestinal fluid associated with the transition of orally administered drugs from the stomach to the small intestine was developed (the stomach-to-intestine fluid changing system (the SIFC system)). This system was applied to in vitro sensitivity analysis on the dissolution of weakly basic drugs, and the obtained results were discussed in relation to the intrasubject variability in the plasma exposure in human bioequivalence (BE) study. Three types of protocols were employed (steep pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, gradual pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, and high gastric pH: pH 4.0 FaSSGF → pH 6.5 FaSSIF). Regardless of the protocols and the forms of drug applied in active pharmaceutical ingredient powder or formulation, dissolution profiles of pioglitazone after fluid shift were similar and the final concentrations in FaSSIF were approximately equal to the saturation solubility in FaSSIF, supporting its small intrasubject variance in human BE study. In contrast, dissolved concentration of terbinafine in the SIFC system became less than half in the high gastric pH protocol than that in other protocols, suggesting the fluctuation of gastric pH as one of the factors of high intrasubject variance of terbinafine in human. Plasma exposure of telmisartan was highly variable especially at the high dose. Although the dissolution of telmisartan in the SIFC system was greatly improved by formulation, it considerably fluctuated during fluid shift especially at the high dose, which corresponds well to in vivo results.

Exploratory Study on Lercanidipine Hydrochloride Polymorphism: pH-Dependent Solubility Behavior and Simulation of its Impact on Pharmacokinetics

This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (CI/CII) is particularly large for chloride buffer (CI/CII = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 μm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions.

Effect of Food on MDM2 Inhibitor KRT-232 Pharmacokinetics and Macrophage Inhibitory Cytokine-1 (MIC-1) Response in Healthy Volunteers

Background: KRT-232 is a potent, selective, orally available, small-molecule drug that binds to mouse double minute 2 homolog (MDM2) and inhibits its interactions with tumor suppressor protein p53. KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia, and Merkel cell carcinoma. Increased serum MIC-1 (pg/mL) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with KRT-232 (Allard,HemaSphere, 2020;4:S1, Abstract EP519). The aim of this study was to assess the safety and effect of a high-fat meal on KRT-232 pharmacokinetics (PK) and MIC-1 PD of a new tablet formulation in healthy volunteers. This is the first characterization of a MDM2-inhibitor-induced MIC-1 response in healthy volunteers. Methods: KRT-232-105 was a single-center, open-label, 60-mg single-dose, 3-treatment, 4-period, and 3-sequence study with a partial replicate crossover design. Volunteers (N=30) were randomized to three treatment groups: A: new tablet, fasted (reference, dosed twice in Periods 2-4); B: new tablet, 30 min after a high-fat, high-calorie meal (test 1, dosed once in periods 2-4); C: current tablet, fasted (test 2, period 1 only). Plasma KRT-232, its acyl glucuronide metabolite (M1) and serum MIC-1 concentrations were measured over 0-96 h. Urine from group C was collected over 0-48 h. Doses were one week apart. All volunteers had aH pyloribreath test and were genotyped for UGT1A1*28 polymorphisms. Results: Volunteers were 43% female, 7% African American and 77% Hispanic/Latino. Mean age was 38.1 y (range, 18-54), and mean body mass index was 26.9 kg/m2 (range, 21.4-30.9). No deaths, serious adverse events (SAEs), or discontinuations were reported. Twenty-one treatment-emergent AEs (TEAEs) were observed in 13 (43%) volunteers; constipation was the most frequent AE, followed by headache. All TEAEs were grade 1 (n=17) or grade 2 (n=4: 1 headache event [possibly study drug-related] and 3 events of headache, influenza-like illness, and pharyngitis). Mean (SD) concentration-time plots of KRT-232 and M1 were similar across the 3 groups (Figure 1a and b). A second peak was observed, consistent with enterohepatic recirculation. With a meal (test 1), KRT-232 geometric least-squares mean (GLSM) maximum concentration (Cmax) was similar (431 and 442 ng/mL (GLSM ratio [90% CI], 103% [87.4-121]) and KRT-232 GLSM area under the curve (AUC0-t) decreased from 2858 to 2325 ng∙h/mL (GLSM ratio [90% CI], 81.4 [76.2-86.9]). Median time of Cmax (Tmax) was 2 h fasted and 3 h fed. Geometric mean half life (t1/2) was unchanged (17.0 vs 17.1 h). Under fasting conditions, the current tablet (C, test 2) vs new tablet (A, reference), KRT-232 GLSM Cmax decreased from 431 to 337 ng/mL (GLSM ratio [90% CI], 78.4% [72.0-85.3]) and KRT-232 GLSM AUC0-t had a possible small decrease (2858 and 2455 ng∙h/mL, GLSM ratio [90% CI], 85.9 [80.5-91.7]). Median Tmax (~2 h) and geometric mean t1/2 (17 h) were unchanged. The fraction of the KRT-232 dose in urine as KRT-232 and M1 was negligible at 0.0201% and 0.0220% of dose, respectively. KRT-232 is a carboxylic acid with pH-dependent solubility that increases with increasing pH.H pyloriinfection, which can increase stomach pH, did not have any discernable impact on KRT-232 PK. KRT-232 and M1 exposure in heterozygous UGT1A1*28 poor metabolizers (6/7 TA repeats, N=16) was generally comparable to exposure in wild-type (WT) UGT1A1*28 (6/6 TA repeats, N=12) subjects. MIC-1 concentrations in serum were variable and followed the PK time course with a median Tmax lag of ~8-12 h. Group A: Mean Cmax 2115 pg/mL, C0 (Baseline) 170 pg/mL, AUC0-T 89267 pg*h/mL and mean t1/2 27 h. MIC-1 Cmax and AUC were generally comparable over 96 h across groups (Figure 1c).Figure 1dshows the statistically significant correlation between KRT-232 AUC0-t and MIC-1 AUC0-t. Conclusions: Based on generally comparable PK, KRT-232 can be administered with or without food, and no dose adjustment is warranted with a new tablet formulation. KRT-232 PK was not affected byH pylori, inferring that higher gastric pH did not alter absorption of KRT-232. KRT-232 exposure in UGT1A1*28 heterozygous poor metabolizers was generally comparable to WT UGT1A1*28 wild type healthy volunteers. The 60-mg KRT-232 dose elicited a reproducible and robust MIC-1 response that correlated with KRT-232 exposure, indicating MDM2-p53 target engagement. Disclosures Wong: Kartos Therapeutics:Current Employment;AbbVie Biotherapeutics:Ended employment in the past 24 months.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Lee:Kartos Therapeutics:Current Employment.Harris:Gilead Sciences:Current equity holder in publicly-traded company;Kartos Therapeutics:Current Employment, Current equity holder in private company;BeiGene:Ended employment in the past 24 months;Clovis:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Simard:Certara:Current Employment;AltaScience:Ended employment in the past 24 months.Wang:Certara:Current Employment.Rubets:Certara:Current Employment.Allard:Certara:Consultancy, Ended employment in the past 24 months;CytomX Therapeutics:Ended employment in the past 24 months;Telios Pharma:Current Employment, Current equity holder in private company.Podoll:IV/PO, LLC:Consultancy.O'Reilly:Celerion:Current Employment.Slatter:Amgen:Divested equity in a private or publicly-traded company in the past 24 months;Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor.

Effects of vonoprazan on gastric PH and clinical course after gastric ESD: A retrospective and prospective study

BackgroundVonoprazan has been more widely used for artificial ulcers after endoscopic submucosal dissection (ESD) for early gastric cancer; however, no reports have examined intragastric pH during ESD. The present study aimed to measure gastric pH at the time of ESD and the clinical course afterwards for patients treated with vonoprazan the night before undergoing ESD. Materials and methodsWe examined medication status regarding gastric acid secretion and antithrombotic drugs, post-ESD bleeding as a perioperative complication, and the timing of upper gastrointestinal endoscopy after ESD and ulcer healing in 156 patients who underwent gastric ESD at our hospital from January 2014 to December 2019. The gastric pH was measured at the time of ESD after administration of 20 mg vonoprazan on the night before gastric ESD. ResultsThere were 14 cases of post-ESD bleeding in patients treated with proton-pump inhibitors (PPIs), including oozing during second-look endoscopy compared to only 1 case of bleeding with vonoprazan administration (p < 0.05). Vonoprazan was also associated with better post-ESD ulcer healing than PPIs. Gastric pH during ESD after vonoprazan administration on the night before gastric ESD was ≥6.96 in all 11 patients. ConclusionPost-ESD bleeding was reduced, and ulcer healing was improved in patients treated with vonoprazan the night before their procedure. Our results suggest high gastric pH during ESD due to vonoprazan administration may be beneficial for hemostasis and ulcer healing following ESD.

An enteric polymer mitigates the effects of gastric pH on oral absorption of poorly soluble weak acid drugs from supersaturable formulations: A case study with dantrolene

This study demonstrated that an enteric polymer can mitigate the effects of gastric pH on the oral absorption of a poorly water-soluble weak acid drug, dantrolene (DNT). An amorphous solid dispersion (ASD) of DNT with hydroxypropyl methylcellulose (HPMC) acetate succinate (ASD-HPMCAS) was prepared as the enteric released ASD (ER-SF). ASD with HPMC (ASD-HPMC) and DNT sodium salt were also used as immediate-release supersaturable formulations (IR-SFs) with and without water-soluble polymer, respectively. In vivo study with rats and in vitro study with a dissolution/permeation (D/P) system were performed to evaluate oral DNT absorption from each formulation under normal and high gastric pH conditions in rats and humans, respectively. The oral absorption of DNT from both IR-SFs in rats with a high gastric pH was significantly higher than that in rats with a normal gastric pH. In contrast, ASD-HPMCAS attenuated the difference in oral absorption between normal and high gastric pH conditions with significant improvement of DNT absorption. In vivo results implied that an enteric polymer delayed the onset of dissolution until after gastric emptying. ASD-HPMCAS generated supersaturation in the small intestine irrespective of gastric conditions, which was supported bythe in vitrostudy using the D/P system. This study suggested that an enteric polymer is useful to mitigate the inter- and intra-individual differences in oral absorption of poorly water-soluble weak acid drugs.

Gastrointestinal diseases and their impact on drug solubility: Crohn's disease

In order to investigate differences in drug solubilisation and dissolution in luminal fluids of Crohn's disease (CD) patients and healthy subjects, biorelevant media representative of CD patients were developed using information from literature and a Design of Experiment (DoE) approach. The CD media were characterised in terms of surface tension, osmolality, dynamic viscosity and buffer capacity and compared to healthy biorelevant media. To identify which drug characteristics are likely to present a high risk of altered drug solubility in CD, the solubility of six drugs was assessed in CD media and solubility differences were related to drug properties. Identified differences in CD patients compared to healthy subjects were a reduced concentration of bile salts, a higher gastric pH and a higher colonic osmolality. Differences in the properties of CD compared to healthy biorelevant media were mainly observed for surface tension and osmolality. Drug solubility of ionisable compounds was altered in gastric CD media compared to healthy biorelevant media. For drugs with moderate to high lipophilicity, a high risk of altered drug solubilisation in CD is expected, since a significant negative effect of log P and a positive effect of bile salts on drug solubility in colonic and fasted state intestinal CD media was observed. Simulating the conditions in CD patients in vitro offers the possibility to identify relevant differences in drug solubilisation without conducting expensive clinical trials.

EVALUATION OF GASTROPROTECTIVE EFFECT OF COENZYME Q 10 AND L - GLUTAMINE IN STRESS AND ETHANOL-INDUCED PEPTIC ULCER IN WISTAR RATS: A NOVEL PRECLINICAL STUDY

Objective: Coenzyme Q 10 (CoQ10) and L-glutamine have antioxidant property their role in peptic ulcer diseases is not well known. Hence, the aim of present study is to evaluate the gastroprotective role of CoQ10 and L-glutamine in stress and ethanol-induced peptic ulcers in Wistar albino rats.Methods: A total of 90 rats were used for the conduct of study in two experimental models, the stress- and the ethanol-induced ulcer model. Each model consists of eight groups with six rats in each group. Sucralfate and pantoprazole were used as standard drugs along with CoQ10 and L- glutamine as test drugs. Drugs were administered for 10 days in stress model and 7 days in case of ethanol model. Statistically analyzed using analysis of variance and post-hoc test with significance as p&gt;0.05Results: CoQ10 and L- glutamine when used alone as well in combination with pantoprazole and sucralfate showed no ulcer formation. Test drugs showed decrease in gastric acid secretion, decreased total and free acidity levels, higher gastric pH, increased mucous secreting ability, higher levels of reduced glutathione levels in both tissue as well as blood and lower malondialdehyde levels when compared with pantoprazole and sucralfate suggestive of their antioxidative benefit, in both the models.Conclusion: Well-designed clinical trials can be done to evaluate the use of CoQ10 and L- glutamine in the treatment of peptic ulcer disease due to various etiology.

Ethanol effect on acid resistance of selected enteric polymers

The aim of this study was to investigate under in vitro conditions the influence of ethanol on acid resistance of four commercially-available enteric polymers (Acryl-EZE®, AQOAT®, Hypromellose phthalate, and Sureteric®). For this purpose, custom-prepared paracetamol tablets were coated with the enteric polymers and tested for release using the buffer-addition method. Ten different hydro-ethanolic media were used in the acid stage corresponding to five levels of ethanol (0, 5, 10, 20, and 40% v/v) in two acidic solutions representing low and high gastric pH (0.1 N HCl pH 1.2, LGpH, and phosphate buffer pH 4.0, HGpH, respectively). The coats were found to resist both types of acidic solution with ethanol percentages up to 10% leading to release profiles that conformed with the pharmacopeial requirements (<10% release after 2 h in acid stage) except for Acryl-EZE®, which showed a premature release in HGpH media. At the higher ethanol levels (20 and 40%), premature release associated with increased acid uptake by coated tablets was noticed for all polymers and more remarkably in HGpH media. ANOVA tests revealed significant effects of polymer type, acidic solution type, and ethanol level on the onset and extent of premature release.