Delay Release Research Articles

Pricing dynamics of anti-seizure medications in the U.S.

BackgroundThe median cost of anti-seizure medications (ASM) in the United States (U.S.) nearly doubled per person between 2006 and 2021. This increase, combined with shifts in ASM usage and the impact of the COVID-19 pandemic on drug supply chains amid rising inflation, underscored the urgent need to scrutinize ASM pricing dynamics. This study aimed to analyze the complex dynamics of ASM pricing in the U.S. over the past decade (2013–2023); this included how the entry of generic ASMs influenced the pricing of brand-name counterparts and what impacted price variations across different ASM formulations (e.g., significant inflation, the COVID-19 pandemic). MethodsThis study utilized National Average Drug Acquisition Cost (NADAC) data from November 2013 to July 2023. We adjusted ASM prices for inflation using the Consumer Price Index for Medicinal Drugs - Seasonally Adjusted (CPI-MDS). Statistical analyses included fixed effects regressions and multivariable regression analysis to evaluate the impact of inflation, the number of medication labelers, and the COVID-19 pandemic on ASM prices. ResultsOur study analyzed 23 ASMs approved by the U.S. Food and Drug Administration (FDA), which encompassed 223 oral formulations:112 brand-name and 111 generics. From 2013–2016 to 2020–2023, accounting for standard deviations (SD), the average price of brand-name ASMs increased from $8.71 (SD 5.9) to $15.43 (SD 10.7), while generic ASMs saw a slight decrease from $1.39 (SD 1.8) to $1.26 (SD 1.6). Consequently, the price gap between brand-name and generic ASMs surged from 1452.39 % to 3399.26 %. The proportion of matched brand-name and generic ASMs with a price difference of 1000 %–9999 % increased from 32.88 % (2013–2016) to 41.43 % (2020–2023), while those exceeding 10,000 % rose from 16.44 % to 20 % in the same period. Generic immediate-release (IR) formulations were significantly less expensive than extended-release (ER) or delayed-release (DR) counterparts, with cost differences reaching up to 7751.20 %. The number of medication labelers was inversely related to generic ASM prices, which decreased by 5.45 % (p = 0.001) with each additional generic labeler, while brand-name ASM prices increased by 2.46 % (p < 0.001) with each additional generic labeler. The COVID-19 pandemic led to a 24.4 % increase in brand-name ASM prices and a 23.1 % decrease in generic ASM prices. ConclusionsThe findings reveal an expanding price disparity between brand-name and generic oral ASMs. An inverse relationship was observed between the number of medication labelers and generic ASM prices, with additional labelers driving down generic prices. However, introducing more generic labelers led to a significant increase in brand-name ASM prices. Furthermore, following patent expirations, brand-name ASM prices rose—a trend explained by the "generics paradox," where, contrary to expectations, brand prices do not decrease and may even increase when generics enter the market. These findings underscore the need for targeted interventions in drug pricing policies to manage the rising costs associated with epilepsy treatment. To ensure equitable access to ASMs, stakeholders must understand and address the factors driving these pricing dynamics.

Effect of postprandial gastric conditions on in vitro drug release from modified release mesalamine formulations

The effect of gastric prandial conditions on in vitro drug release from oral, locally acting, colon-targeted, mesalamine formulations has not been previously evaluated. In vitro dissolution of four mesalamine formulations were investigated using a USP II paddle apparatus. Fed gastric conditions were simulated under three consecutive phases of milk/buffer at different ratios to simulate changes in physicochemical, gastric composition during food digestion. Drug release was not observed from enteric coated preparations in the fasted state. Under simulative postprandial gastric conditions, however, drug release from Apriso® extended release (ER) capsules was 19 ± 4.7 %. As for Lialda® delayed release (DR) tablets, following two hours of exposure to simulative ileo-colonic media comprising bicarbonate buffer, drug release in the fed and fasted states was 55.7 ± 22.4 % and 12.4 ± 6.4 %, respectively. Significant differences in in vitro dissolution profiles were not observed between fasted and fed conditions for Pentasa® ER capsules and Asacol® HD DR tablets. Published pharmacokinetic data for Apriso and Lialda show higher systemic absorption of mesalamine in fed compared to fasted individuals. Our in vitro data is consistent with these pharmacokinetic findings since fed conditions may give rise to a higher extent of proximal drug release and therefore greater systemic absorption. Furthermore, extent of systemic exposure to mesalamine from Pentasa and Asacol was found not to be affected by food intake. In vitro dissolution studies simulating the gastric prandial state can possibly predict the impact of food on drug release from delayed and sustained release, locally acting formulations.

Gastrointestinal release site for delayed release and gelatin capsules in healthy dogs.

Gelatin capsules deliver their contents to the stomach, while delayed-release (DR) capsules are designed to allow delivery to the small intestine. This study evaluated the gastrointestinal release site of DR capsules in six healthy adult dogs compared to gelatin capsules. Both gelatin and DR capsules were filled with barium-impregnated polyethylene spheres (BIPS™), and following enteral administration, release site was assessed using abdominal radiographs at baseline, immediately after ingestion, 15 min post-ingestion, 30 min post-ingestion, and then every 30 min thereafter. The evaluated phases included fasted conditions (phase 1, n = 6), increased meal size (phase 2, n = 2), double encapsulation (phase 3, n = 2), and altered capsule size (phase 4, n = 1). The released site was the stomach in all phases for both capsule types. In phase 1, DR capsules had a significantly prolonged time (median 60 min, range 60-90) to release BIPS™ compared to gelatin capsules (15 min, range 15-30; p = .03). In phase 2 (full meal size), 3 (double encapsulation), and 4 (smaller capsule size) pilot studies, release time was prolonged but still occurred in the stomach. This is similar to the release site for gelatin capsules but differs from the release site for DR capsules in people. This has implications for pharmacologic outcomes for products that are affected by gastric physiology (e.g. fecal microbiota transplantation). Based on this pilot data, clinicians and researchers should not assume DR capsules will allow for intestinal delivery of contents in dogs. Future studies should be conducted on larger and varied populations of dogs.

Fibrosing colonopathy associated with cysteamine bitartrate delayed-release capsules in cystinosis patients

BackgroundThe objective of this report is to identify and characterize cases of fibrosing colonopathy, a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis.MethodsWe searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the medical literature for postmarketing reports of fibrosing colonopathy associated with cysteamine through August 2, 2023.ResultsWe identified four cases of fibrosing colonopathy reported with the use of cysteamine DR. The time to onset ranged from 12 to 31 months. In one case, the patient required surgery to have a resection of a section of the strictured colon and a diverting ileostomy. Fibrosing colonopathy was diagnosed by histopathology in two of the cases.ConclusionsOur case series identified the risk of fibrosing colonopathy in patients taking cysteamine DR and prompted regulatory action by the FDA. As outlined in changes to the U.S. prescribing information for cysteamine DR, healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

P571 The Effect of NLRX1 Activation on Eosinophils in Ulcerative Colitis and Inflammation: Translational Learnings Across Diseases and from Mouse to Human

Abstract Background Although the precise role of eosinophils in IBD is debated, elevated eosinophils may influence response to therapy and clinical outcomes1. Thus, therapeutic agents which affect both neutrophil and eosinophil recruitment may provide more robust clinical improvement in patients with UC. NLRX1 is an immunometabolic protein which reduces oxidative stress, shifts cellular metabolism, and decreases inflammation in multiple cell types implicated in ulcerative colitis (UC). Studies of NLRX1 agonists (gut-selective NX-13 &amp; systemic LABP-73) in diverse disease models identified novel cellular targets of NLRX1 activation. We compared NLRX1’s effect on eosinophils in 2 disease states, UC and the more prototypical eosinophilic disease, asthma, and evaluated the findings. Methods In the 4-week NX-13 Phase 1b, a double-blind trial of 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) who were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo QD for 4 weeks, histology was assessed using the Geboes score by a blinded pathologist2. For allergic asthma models, mice were immunized with ovalbumin or house dust mite followed by antigen challenge concurrent with LABP-73 or vehicle. Cells isolated from the lung were analyzed by flow cytometry using the BD FACS Celesta/Diva. Data are represented as means (standard error). Results In the 1b clinical trial, both the Geboes score and neutrophil subscores were reduced in the IR NX-13 group compared to placebo, consistent with the effects seen in preclinical IBD models. Upon examination, eosinophil infiltration was reduced in both the IR dose cohorts compared to placebo (Fig1A). In the subset of patients with active eosinophil infiltration at baseline (defined as Geboes subscore ≥2A.1), eosinophil reduction was seen in all NX-13 doses (Fig1B). Importantly, a numerically increased clinical response rate (decrease in total Mayo score of ≥3 or ≥30%) was seen in patients that demonstrated effective eosinophil reduction, compared to patients without improvement (75% versus 29%; Fisher’s Exact Test, p=0.08). In two allergic asthma models, NLRX1 activation by LABP-73 significantly reduced the fraction of eosinophils within the lung relative to vehicle control (n=7-8; p&amp;lt; 0.05), confirming NLRX1 activation can regulate eosinophilic inflammation in Th2-mediated responses. Conclusion Neutrophil and eosinophil infiltration were reduced in UC patients treated with the gut selective NLRX1 agonist, NX-13, and was coupled with better clinical outcomes. The effect of NX-13 on eosinophils will be evaluated further in the ongoing phase 2 NEXUS trial in patients with UC. 1 A Mookhoek, et al. JCC (16). 2 L Peyrin-Biroulet, et al. JCC (17) Supp

The blood acid base and gastrointestinal response to three different forms of sodium citrate encapsulation

ABSTRACT Enterically coated (ENT) or delayed-release (DEL) capsules may lessen gastrointestinal symptoms (GIS) following acute sodium citrate (SC) ingestion, although the effects on blood acid-base balance are undetermined. Fourteen active males ingested 0.4 g.kg−1 body mass (BM) SC, within gelatine (GEL), DEL and ENT capsules or 0.07 g.kg−1 BM sodium chloride control (CON). Blood acid-base balance and GIS were measured for 4 h. Ingestion form had no significant effect on total GIS experienced (GEL: 2 ± 7; DEL: 1 ± 8; ENT: 1 ± 4 AU). Most (7/14) participants experienced zero symptoms throughout. Peak GIS typically emerged ≤100 min post-ingestion, with a similar time to reach peak GIS between ingestion form (GEL: 36 ± 70; DEL: 13 ± 28; ENT: 15 ± 33 AU). Blood [HCO3 −] was significantly higher with ENT versus GEL (ENT: 29.0 ± 0.8; GEL: 28.5 ± 1.1 mmol.L−1, P = 0.037). Acute ingestion of a reduced SC dose elicited minimal GIS, producing significant changes in blood [HCO3 −] from rest, irrespective of ingestion form (GEL: 6.0 ± 0.9; DEL: 5.1 ± 1.0; ENT: 6.2 ± 0.8 mmol.L−1). The necessity of individualized ingestion strategies is also challenged, with sustained increases in blood [HCO3 −] of ≥4 mmol.L−1 for up to 153 min highlighted. If commencing exercise at peak alkalosis augments subsequent performance above starting at a standardized time point where HCO3 − is still elevated remains unclear.

Retrospective analysis of the biopharmaceutics characteristics of solid oral Modified-Release drug products in approved US FDA NDAs designated as Extended-Release or Delayed-Release formulations

BackgroundModified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug’s rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers’ understanding regarding the biopharmaceutics properties that supported approval of these products’ ER claims, as per 21 CFR 320.25(f), and DR claims. MethodsA comprehensive search was conducted using the FDA’s internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping. ResultsOut of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results—most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label. ConclusionThe results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA’s assessment of ER claims.

Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study.

Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.

Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial.

Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM. 43 client-owned cats with subclinical HCM. Cats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA. No demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups. Results demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.

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.

The effect of food vehicles on in vitro performance of pantoprazole sodium delayed release sprinkle formulation

Certain patient populations, including children, the elderly or people with dysphagia, find swallowing whole medications such as tablets and capsules difficult. To facilitate oral administration of drugs in such patients, a common practice is to sprinkle the drug products (e.g., usually after crushing the tablet or opening the capsule) on food vehicles before consumption which improves swallowability. Thus, evaluation of the impact of food vehicles on the potency and stability of the administered drug product is important. The aim of the current study was to evaluate the physicochemical properties (viscosity, pH, and water content) of common food vehicles used for sprinkle administration (e.g., apple juice, applesauce, pudding, yogurt, and milk) and their impacts on the in vitro performance (i.e., dissolution) of pantoprazole sodium delayed release (DR) drug products. The food vehicles evaluated exhibited marked difference in viscosity, pH and water content. Notably, the pH of the food as well as the interaction between food vehicle pH and drug-food contact time were the most significant factors affecting the in vitro performance of pantoprazole sodium DR granules. For example, the dissolution of pantoprazole sodium DR granules sprinkled on food vehicles of low pH (e.g., apple juice or applesauce) for short durations remained unchanged compared with the control group (i.e., without mixing with food vehicles). However, use of high pH food vehicles (e.g., milk) with prolonged contact time (e.g., 2 h) resulted in accelerated pantoprazole release, drug degradation and loss of potency. Overall, a thorough assessment of physicochemical properties of food vehicles and formulation characteristics are a necessary part of the development of sprinkle formulations.

Factors associated with subtherapeutic levels of oral posaconazole tablet: a detailed analysis from a tertiary care center in India

ObjectivesPosaconazole is a broad-spectrum triazole antifungal, with activity against various clinically important fungi. The delayed release (DR) tablet of posaconazole has been shown to have a superior pharmacokinetic profile in comparison with the oral suspension. MethodsWe retrospectively analyzed the factors associated with posaconazole levels <1.25 μg/ml in 164 patients receiving the DR tablet for therapeutic purposes. ResultsOf the 164 patients, 53 (32.3%) showed subtherapeutic trough levels of posaconazole. The use of proton pump inhibitors (95% CI 1.41-3.91; P-value = 0.028) and the presence of diarrhea (95% CI 1.95-6.93; P-value = 0.001) were significantly associated with subtherapeutic levels. A total of 13 of the 21 patients receiving posaconazole tablets through a nasogastric tube had therapeutic levels. ConclusionThis is the largest study from India that analyzed factors associated with subtherapeutic levels of the DR tablet of posaconazole. These findings reinforce the importance of therapeutic drug monitoring. Unlike in previous studies, obesity and hypoalbuminemia were not found to be significant factors in our settings. The use of proton pump inhibitors and diarrhea remained significant factors, as found in previous studies. Administering the DR tablet of posaconazole through a nasogastric tube may be a viable option.

Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review.

Solubility limited bioavailability is one of the crucial parameters that affect the formulation development of the new chemical entities. Thus the major constraint in the pharmaceutical product development is the suitable solubility enhancement technique for Active Pharmaceutical Ingredient. Solid dispersion (SD) is an established and preferred method for improving the solubility which ultimately may be helpful to enhance bioavailability. For long period of time Amorphous solid dispersion (ASD) have been preferred for improving solubility, but since last two decades, ASD approach have been combined with different modified release approaches to improvise the stability and site specificity of SD to grasp a hold over the specific advantages associated with such dosage forms. It is an established fact now that the SD technique not only improves solubility limited bioavailability, but it may be combined with other approaches to modify the drug release profile from the formulation as per the requirement based on the apt selection of SD carriers and suitable technology. This review covers the comprehensive overview of all such formulations where SD technology is used to serve dual purpose rather than only the sole purpose of solubility enhancement. The SD approach has been successfully implemented for some of the poorly soluble herbal drugs and still there is a vast scope of advancement in that area. The current review will provide a broad outcome in the area of SD technology for modified release formulations along with the description of current status and future prospective of SD. The SD formed by dispersing drug within the conventional carrier to form ASD increases solubility, dissolution rate and bioavailability; whereas fourth generation hydrophobic carriers provide added advantage of controlled release (CR) or sustained release (SR) profile along with enhanced stability of SD. On the other frontier, pH dependant carriers enable the SD to achieve site specificity or delayed release (DR) profile.

Enteral feeding tube administration with therapeutic drug monitoring of crushed posaconazole tablets and opened isavuconazonium sulfate capsules.

Isavuconazole and posaconazole are commonly used for both prophylaxis and treatment of invasive fungal infections. These agents are formulated for oral administration as a capsule and delayed release (DR) tablet or suspension, respectively. In patients unable to swallow, alternative means of administration, such as crushing posaconazole DR tablets and opening isavuconazole capsules, may be used to avoid IV administration or use of posaconazole suspension, which often produces subtherapeutic concentrations. To assess the feasibility of achieving target plasma drug concentrations with enteral feeding tube (EFT) administration of crushed posaconazole DR tablets and opened isavuconazole capsules. We retrospectively reviewed pharmacy records to identify patients receiving EFT administration of posaconazole or isavuconazole with concurrent therapeutic drug monitoring from October 2019 to June 2021. Plasma concentrations of either agent as well as clinical outcomes were documented. We identified 37 patients receiving 38 courses of EFT isavuconazole or posaconazole. The majority of patients received primary prophylaxis following lung transplantation (64.9%). Plasma concentrations upon first assessment were therapeutic in the majority of patients (posaconazole 71.5%, isavuconazole 83.3%) with a mean level of 1.61 ± 0.77 mg/L for posaconazole and 2.07 ± 1.1 mg/L for isavuconazole. Of those that were subtherapeutic on initial assessment, all but one subsequently achieved target levels upon dose titration. Standard maintenance doses were used in all isavuconazole and most posaconazole patients. Our case series demonstrates that isavuconazole and posaconazole can be administered via EFT with concurrent therapeutic drug monitoring to achieve target plasma concentrations in the majority of patients.

Therapeutic drug monitoring of posaconazole delayed release tablet while managing COVID-19-associated mucormycosis in a real-life setting.

Along with COVID-19 pandemic, India has faced an outbreak of COVID-19-associated mucormycosis (CAM). Due to restricted availability of amphotericin B during this outbreak, clinicians were forced to use posaconazole or isavuconazole preparations as first-line or alternate therapy in many patients. We planned an early monitoring of posaconazole trough level while using delayed release (DR) tablet as first-line or alternate therapy. Primary objective of the study was to determine percentage of patients achieving arbitrarily decided therapeutic posaconazole levels (≥1.2μg/ml) after using standard dosages of posaconazole. Secondary objective was to identify potential factors associated with sub-therapeutic posaconazole levels. We performed retrospective chart review of the hospitalised patients, who received posaconazole DR tablet as first-line or alternate therapy to treat CAM during outbreak period (March 1 to May 31, 2021). High-performance liquid chromatographic (HPLC) method was used to measure trough level of posaconazole. Posaconazole serum levels of 29 patients were analysed, who received posaconazole DR tablet. Majority (n=23) were male with the median (range) age 53 (24-86) years. The mean (SD) posaconazole level was 1.66 (0.76)μg/ml. Sub-therapeutic posaconazole trough level was observed in 7 (24.1%) patients. Relatively younger patients were associated with lower posaconazole level (p=.046). Except two patients, all the patients tolerated posaconazole well. The study supports the posaconazole trough level measurement on day 4 while using posaconazole DR tablet as first-line or alternate therapy to treat mucormycosis during limited supply of amphotericin B.

Cysteamine bitartrate delayed-release capsules control leukocyte cystine levels and promote statural growth and kidney health in an open-label study of treatment-naïve patients

Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease that is characterized by accumulation of cysteine and formation of crystals within cells of different organs and tissues causing systemic manifestations in childhood that include poor linear growth, ocular involvement, hypothyroidism, and progressive kidney disease. This study was a long‐term, prospective open‐label evaluation of twice‐daily delayed release (DR) cysteamine capsules in cystinosis patients <6 years of age who were naïve to any form of cysteamine treatment. Fifteen treatment‐naïve patients <6 years old (mean age 2.2 ± 1.0 years, 53% male, 73% White) were enrolled and treated with DR‐cysteamine capsules for up to 18 months. Patients had clinically meaningful decreases in WBC cysteine concentration during treatment (3.2 ± 3.0 nmol ½ cystine/mg protein at Day 1 to 0.8 ± 0.8 nmol ½ cystine/mg protein at study exit), and anthropometric data improvements were consistently observed in height, weight and body surface area. Additionally, estimated glomerular filtration rate increased from 55.93 ± 22.43 ml/min/1.73 m2 at baseline to 63.79 ± 21.44 ml/min/1.73 m2 at study exit. Pharmacokinetic/Pharmacodynamic results support the use of the same starting, escalation, and maintenance doses according to body surface for children aged <6 years that are currently recommended in adults and older children. All patients experienced ≥1 adverse event(s) with vomiting (80%) and upper respiratory tract infection (53%) most frequently reported. Based on our study, patients <6 years of age with nephropathic cystinosis without prior treatment can safely and effectively initiate treatment with DR‐cysteamine, a delayed‐release form of cysteamine bitartrate that can be given every 12 h.

Supratherapeutic Posaconazole Concentration in a Pediatric Transplant Patient With Confirmed Rhizopus Infection.

There are a limited number of studies that guide dosing of posaconazole delayed-release (DR) tablets for the pediatric population. Current FDA-approved doses are only recommended for patients 13 years and older. For younger patients, providers are faced with the challenge of recommending posaconazole doses extrapolated from adult studies or choosing an alternative agent. We report on a case of a 10-year-old patient who experienced a supratherapeutic trough serum concentration and transaminitis after receiving the extrapolated adult dosage of posaconazole DR tablets (300 mg twice daily for the first day, followed by 300 mg daily) for 7 days. In the end, the patient required a smaller dose of 200 mg daily to achieve the desired trough target concentration for the treatment of a Rhizopus neck infection. Our findings highlight the need for additional studies to determine the optimal dosing of posaconazole DR tablets for children.

A comparison of immediate release and delayed release cysteamine in 17 patients with nephropathic cystinosis

BackgroundNephropathic cystinosis is a rare and severe metabolic disease leading to an accumulation of cystine in lysosomes which especially harms kidney function. A lifelong therapy with the aminothiol cysteamine can delay the development of end-stage renal disease and the necessity of kidney transplantation. The purpose of our study was to compare the effectiveness of immediate-release and delayed-release cysteamine on cystine and cysteamine levels as well as assessing the onset of adverse effects.MethodsWe retrospectively analysed cystine and cysteamine levels of 17 patients after a single dose of immediate-release cysteamine (Cystagon®, Mylan Pharmaceuticals, Canonsburg, PA and Recordati Pharma GmbH) as well as a single dose of delayed-release cysteamine (Procysbi®; Horizon Pharma USA and Chiesi Farmaceutici S.p.A., Parma, Italy) respectively. Data were collected during a period of three years in the context of optimizing the individual treatment regimens. The dose of DR-cysteamine was reduced to 70% of the equivalent dose of IR-cysteamine. The efficacy of both formulas in depleting white blood cells’ cystine levels and their side effects were compared.ResultsImmediate (IR)- and delayed-release (DR) cysteamine effectively decreased intracellular cystine levels under the target value of 0.5 nmol cystine/mg protein, while fewer side effects occurred under DR-cysteamine. Mean maximum levels of cysteamine were reached after 60 min with IR-cysteamine and after 180 min with DR-cysteamine.ConclusionA therapy with DR-cysteamine is as effective as IR-cysteamine while less side effects were reported. Our data show that DR-cysteamine should be dosed higher than 70% of the equivalent dose of IR-cysteamine in order to decrease cystine levels over an extended period of time. Moreover, our data suggest increasing the dosing scheme of Procysbi® to three times daily, to prevent a rapid decrease and achieve a steadier decline in cystine levels. Due to the more convenient dosing scheme, DR-cysteamine might ameliorate therapy adherence and improve patients’ quality of life.

Optimal Dosing Regimen of Osteoporosis Drugs in Relation to Food Intake as the Key for the Enhancement of the Treatment Effectiveness-A Concise Literature Review.

Bisphosphonates and selective estrogen receptor modulators (SERMs) represent the two most important groups of medications taken orally and employed in osteoporosis treatment. Effectiveness of the therapy may be affected by poor patient adherence, in particular, due to the inconvenient dosing regimen of oral bisphosphonates. With this review we aimed to assess the effects that food, beverages, and dietary supplements consumed during treatment, along with the dosing regimens, may have on pharmacokinetics and pharmacodynamics of oral drugs employed in treating osteoporosis; we also aimed to shape the recommendations valuable for professional patients’ counseling and education, to provide appropriate dosing regimens in order to improve adherence to the therapy. Food, beverages such as coffee, juices, and mineral water, as well as dietary supplements containing multivalent cations, e.g., calcium, magnesium, aluminium, iron, showed to have a deleterious effect on the bioavailability of all the investigated oral bisphosphonates, specifically alendronate, risedronate, ibandronate, minodronate, and etidronate. For risedronate, a delayed-release (DR) tablet was designed to solve the malabsorption problem in the presence of food, hence DR risedronate can be ingested following breakfast. For other oral bisphosphonates, the proper interval between drug and food, beverages, and dietary supplements intake should be maintained to minimize the risk of interactions. The effect of food on pharmacokinetic parameters of selective estrogen receptor modulators (SERMs) was found to be clinically irrelevant.

Preparation of delayed-release multiparticulate formulations of diclofenac sodium and evaluation of their dissolution characteristics using biorelevant dissolution methods

Diclofenac sodium was used as a model drug for preparation of delayed-release (DR) multiparticulates, which were further processed into solid oral dosage forms such as capsules and tablets. Multiple unit pellets systems (MUPS) were prepared from different types of starter pellets (inert cores) including microcrystalline cellulose pellets, sugar spheres, isomalt pellets and novel calcium phosphate-based pellets. The study results showed that the material of the inert cores affected both mechanical properties of the drug-loaded pellets and the dissolution characteristic of the model drug. Biorelevant dissolution method carried out with the help of a pHysio-grad device allowed thorough examination of the developed formulations in the environment mimicking pH conditions along gastrointestinal tract. This method revealed significant differences between the formulations and their sensitivity to variable hydrodynamic conditions.