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Clinical Pharmacokinetics Jul 2023Posaconazole (PSZ) is a triazole antifungal for the management of invasive fungal disease (IFD) in adults and children. Although PSZ is available as an intravenous (IV)...
BACKGROUND AND OBJECTIVE
Posaconazole (PSZ) is a triazole antifungal for the management of invasive fungal disease (IFD) in adults and children. Although PSZ is available as an intravenous (IV) solution, oral suspension (OS) and delayed-release tablets (DRTs), OS is the preferred formulation for pediatric use because of potential safety concerns associated with an excipient in the IV formulation and difficulty in swallowing intact tablets by children. However, poor biopharmaceutical characteristics of the OS formulation leads to an unpredictable dose-exposure profile of PSZ in children, potentially risking therapeutic failure. The goal of this study was to characterize the population pharmacokinetics (PK) of PSZ in immunocompromised children and assess therapeutic target attainment.
METHODS
Serum concentrations of PSZ were collected retrospectively from records of hospitalized patients. A population PK analysis was performed in a nonlinear mixed-effects modeling framework with NONMEM (v7.4). The PK parameters were scaled to body weight, then potential covariate effects were assessed. The final PK model was used to evaluate recommended dosing schemes through simulation of target attainment (as a percentage of the population having steady-state trough concentrations above the recommended target) using Simulx (v2021R1).
RESULTS
Repeated measurement data of 202 serum concentrations of total PSZ were acquired from 47 immunocompromised patients between 1 and 21 years of age receiving PSZ either intravenously or orally, or both. A one-compartment PK model with first-order absorption and linear elimination best fit the data. The estimated absolute bioavailability (95% confidence interval) for suspension (F) was 16% (8-27%), which was significantly lower than the reported tablet bioavailability (F) [67%]. F was reduced by 62% and 75% upon concomitant administration with pantoprazole (PAN) and omeprazole (OME), respectively. Famotidine resulted in a reduction of F by only 22%. Both fixed dosing and weight-based adaptive dosing provided adequate target attainment when PAN or OME were not coadministered with the suspension.
CONCLUSIONS
The results of this study revealed that both fixed and weight-based adaptive dosing schemes can be appropriate for target attainment across all PSZ formulations, including suspension. Additionally, covariate analysis suggests that concomitant proton pump inhibitors should be contraindicated during PSZ suspension dosing.
Topics: Adult; Humans; Child; Retrospective Studies; Administration, Oral; Invasive Fungal Infections; Antifungal Agents; Triazoles; Tablets; Suspensions
PubMed: 37179512
DOI: 10.1007/s40262-023-01254-2 -
Journal of Clinical and Experimental... 2023Up-to-date data about the role of acid suppression therapy e.g. proton-pump inhibitors; to reduce post-endoscopic variceal ligation (EVL) ulcer-bleeding are...
Efficacy of Vonoprazan vs. Pantoprazole or Non-acid Suppression in Prevention of Post-variceal Ligation Ulcer Bleeding in Portal Hypertension: A Multi-arm Randomized Controlled Trial.
BACKGROUND
Up-to-date data about the role of acid suppression therapy e.g. proton-pump inhibitors; to reduce post-endoscopic variceal ligation (EVL) ulcer-bleeding are conflicting. Vonoprazan; a recently introduced potassium-competitor acid blocker, has not been studied to prevent post-EVL ulcer/bleeding. The aim was to evaluate the efficacy of vonoprazan vs. pantoprazole or non-acid suppression to prevent post-EVL ulcer/bleeding in portal hypertension patients.
MATERIAL AND METHODS
We enrolled 275 portal hypertension patients undergoing EVL in a three-arm randomized, single-blind, controlled study. A clinico-laboratory baseline evaluation was performed. Following EVL, patients were randomly and equally assigned to receive vonoprazan 20mg once daily, pantoprazole 40 mg once daily, or no acid suppression therapy. Post-EVL ulcer bleeding, ulcer dimensions, odynophagia as well as vonoprazan safety were evaluated after 2 weeks of EVL.
RESULTS
Post-EVL ulcer bleeding occurred among 2.15% of vonoprazan, 8.7% of pantoprazole, and 14.2% of the non-acid suppression groups ( < 0.001). Post-ligation ulcer frequency and dimensions were higher among non-acid suppression and pantoprazole groups vs. vonoprazan ( < 0.05). Chest pain and odynophagia were encountered among 73.6% and 54.9% of the non-acid suppression group vs. 39.6% and 45.1% in pantoprazole, and 17.2% and 21.5% in vonoprazan groups, respectively ( < 0.05). There were no vonoprazan-related adverse events. Non-use of vonoprazan was the strongest independent predictor for post-EVL bleeding.
CONCLUSION
Short course of vonoprazan 20 mg/day is safe and superior to pantoprazole 40 mg/day in the reduction of post-EVL ulcer dimensions at 2 weeks post-EVL, and prevention of ulcer-related bleeding. Acid suppression is superior to no acid suppression to prevent post-EVL complications.
PubMed: 37975046
DOI: 10.1016/j.jceh.2023.05.008 -
Medicina (Kaunas, Lithuania) Aug 2023: To examine the effects of the lockdown on diet adherence and stress levels in patients with laryngopharyngeal reflux (LPR). : Patients with a positive LPR diagnosis at...
: To examine the effects of the lockdown on diet adherence and stress levels in patients with laryngopharyngeal reflux (LPR). : Patients with a positive LPR diagnosis at the hypopharyngeal-esophageal impedance-pH monitoring were treated from a pre- to lockdown period with a 3-month high-protein, low-fat, alkaline, plant-based diet, with behavioral changes, and an association of pantoprazole (20 MG/d) and alginate (Gaviscon 3/d). The following patient-reported outcomes questionnaire and findings instrument were used: Reflux Symptom Score-12 (RSS-12) and Reflux Sign Assessment (RSA). At the posttreatment time, patients were invited to evaluate the impact of lockdown on diet adherence and stress management with a predefined grid of foods and beverages and the perceived stress scale (PSS), respectively. : Thirty-two patients completed the evaluations. RSS-12 and RSA significantly improved from baseline to 3-month posttreatment. Most patients experienced mild-to-severe stress levels at the end of the lockdown. The level of stress substantially increased in 11 patients (34%) due to the lockdown, while it did not change in 11 patients (44%). In 11 cases (34%), patients reported that the adherence to the anti-reflux diet was better than initially presumed thanks to the lockdown period, while 44% (N = 14) reported that the lockdown did not impact the adherence to a diet. PSS and RSS-12 were significantly correlated at the end of the pandemic (r = 0.681; < 0.001). The increase in stress level was positively associated with the lack of adherence to diet (r = 0.367; = 0.039). : During the lockdown, the diet habits of LPR patients were improved in one-third and unchanged in 44% of cases. The stress level was increased in one-third of patients, which was associated with an increase in symptom scores.
Topics: Humans; Laryngopharyngeal Reflux; Quarantine; COVID-19; Communicable Disease Control; Beverages
PubMed: 37629765
DOI: 10.3390/medicina59081475 -
Trials Dec 2023The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients.
OBJECTIVE
To outline the statistical analysis plan for the REVISE trial.
METHODS
REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated.
RESULTS
The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment.
CONCLUSIONS
This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide.
TRIAL REGISTRATION
www.
CLINICALTRIALS
gov NCT03374800. November 21, 2017.
Topics: Adolescent; Humans; Critical Illness; Gastrointestinal Hemorrhage; Intensive Care Units; Pantoprazole; Pneumonia, Ventilator-Associated; Proton Pump Inhibitors; Respiration, Artificial; Adult
PubMed: 38057875
DOI: 10.1186/s13063-023-07794-z -
Acta Anaesthesiologica Scandinavica Apr 2024Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for preventing upper gastrointestinal bleeding in critically ill patients. However, concerns have... (Review)
Review
BACKGROUND
Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for preventing upper gastrointestinal bleeding in critically ill patients. However, concerns have arisen about the possible harms of using PPIs, including potentially increased risk of pneumonia, Clostridioides difficile infection, and more seriously, an increased risk of death in the most severely ill patients. Triggered by the REVISE trial, which is a forthcoming large randomized trial comparing pantoprazole to placebo in invasively mechanically ventilated patients, we will conduct this systematic review to evaluate the efficacy and safety of PPIs versus no prophylaxis for critically ill patients.
METHODS
We will systematically search randomized trials that compared gastrointestinal bleeding prophylaxis with PPIs versus placebo or no prophylaxis in adults in the intensive care unit (ICU). Pairs of reviewers will independently screen the literature, and for those eligible trials, extract data and assess risk of bias. We will perform meta-analyses using a random-effects model, and calculate relative risks for dichotomous outcomes and mean differences for continuous outcomes, and the associated 95% confidence intervals. We will conduct subgroup analysis to explore whether the impact of PPIs on mortality differs in more and less severely ill patients. We will assess certainty of evidence using the GRADE approach.
DISCUSSION
This systematic review will provide the most up-to-date evidence regarding the merits and limitations of stress ulcer prophylaxis with PPIs in critically ill patients in contemporary practice.
PubMed: 38581102
DOI: 10.1111/aas.14426 -
JGH Open : An Open Access Journal of... Jul 2023There is limited research on the use of histamine-H2 receptor antagonists and proton pump inhibitors for treating COVID-19. We compare clinical outcomes between patients...
BACKGROUND AND AIM
There is limited research on the use of histamine-H2 receptor antagonists and proton pump inhibitors for treating COVID-19. We compare clinical outcomes between patients hospitalized with COVID-19 receiving famotidine or pantoprazole.
METHODS
This retrospective study included 2184 patients (famotidine: = 638, pantoprazole: = 727, nonuse: = 819) aged 18 years or older treated for COVID-19 from March 2020 to March 2021. Patients who received both famotidine and pantoprazole treatments were excluded. Multivariate logistic regression was used for the primary outcome, namely all-cause mortality, and the secondary outcomes, namely mechanical ventilation, vasopressor use, acute kidney injury, and gastrointestinal bleeding. The main predictor variable was the use of famotidine or pantoprazole. Covariates were demographics, chronic diseases, and symptoms.
RESULTS
As compared to nonuse, famotidine (OR: 0.30, 95% CI: 0.20-0.44, < 0.001) and pantoprazole (OR: 0.47, 95% CI: 0.33-0.66, < 0.001) were significantly associated with lower odds for all-cause mortality. Comparison of famotidine and pantoprazole showed that the former had lower odds for all-cause mortality (OR: 0.65, 95% CI:0.45-0.95, < 0.05), mechanical ventilation (OR: 0.38, 95% CI: 0.25-0.58, < 0.001), vasopressor use (OR: 0.33, 95% CI: 0.22-0.48, < 0.001), acute kidney injury (OR: 0.40, 95% CI: 0.30-0.54, < 0.001), and gastrointestinal bleeding (OR: 0.15, 95% CI: 0.08, 0.29, < 0.001).
CONCLUSIONS
Famotidine is associated with lower odds for all-cause mortality, mechanical ventilation, vasopressor use, acute kidney injury, and gastrointestinal bleeding as compared to pantoprazole in patients hospitalized with COVID-19. We recommend that clinicians consider the use of famotidine over pantoprazole for hospitalized COVID-19 patients. Future research with a clinical trial would be beneficial to further support such use of famotidine.
PubMed: 37496815
DOI: 10.1002/jgh3.12905 -
Future Science OA 2024Ilaprazole due to its pharmacokinetic variability does not affect the clopidogrel efficacy during concomitant use. Prediction of DDI for Clopidogrel and PPIs performed...
Ilaprazole due to its pharmacokinetic variability does not affect the clopidogrel efficacy during concomitant use. Prediction of DDI for Clopidogrel and PPIs performed using (DDI-Pred) Way2Drug software. The probabilities ΔP, which estimate the potential DDIs resulting from interaction with CYP450 isoenzymes. Positive ΔP-values for CYP2C19 (0.955) indicate that it is involved in the drug interaction of Ilaprazole and Clopidogrel. Pantoprazole and Ilaprazole were found to have a low probability of CYP2C19 inhibition Compared with other PPIs, Pantoprazole and Ilaprazole were found to have a low probability of CYP2C19 inhibition; Since Ilaprazole has pharmacokinetic variability, further and studies are required on the ilaprazole and clopidogrel combination to assess the effect of drug-drug interaction.
PubMed: 38817377
DOI: 10.2144/fsoa-2023-0277 -
Qatar Medical Journal 2023Methotrexate (MTX) is a folic acid antagonist used to treat different immunological or proliferative illnesses because of its anti-proliferative and anti-inflammatory...
INTRODUCTION
Methotrexate (MTX) is a folic acid antagonist used to treat different immunological or proliferative illnesses because of its anti-proliferative and anti-inflammatory effects. MTX Toxicity is considered a severe problem. Although acute toxicity related to high-dose administration (doses ≥500 mg/m) can be predicted based on the given dose, chronic toxicity still has no specific factors to predict it, so treatment depends on the history and symptoms of toxicity. MTX was initially used for oncology indications with high cyclic doses, then expanded to non-oncology indications with different low doses and frequencies. This significant change in doses resulted in dosing errors that contributed to MTX toxicity reports. Measures to prevent the toxicity of MTX should be implemented.
CASE
A 66-year-old female patient ingested 10 mg of MTX daily for one month instead of the once-toxicity symptoms. The serum level of MTX was requested, and treatment with folinic acid was initiated until the patient improved with the discontinuation of MTX.
DISCUSSION
There is limited literature about the lack the total cumulative dose, duration of intake, or serum level of MTX. All this information was provided in this case report, but drug-drug interactions were not reviewed, although aspirin and pantoprazole were identified as having interactions with methotrexate in this patient. Minimum total cumulative dose identification may help assess the toxicity risk in such patients.
CONCLUSION
Low-dose MTX chronic toxicity still needs further information to guide the patient's risk of toxicity and when to initiate treatment. Safety-practical measures should be implemented to prevent such administration errors.
PubMed: 38026729
DOI: 10.5339/qmj.2023.31 -
Iranian Journal of Basic Medical... 2024Long-term consumption of pump inhibitors causes osteoporosis. Some possible mechanisms are gastrin over-secretion and hypochlorhydria. Octreotide is a somatostatin...
OBJECTIVES
Long-term consumption of pump inhibitors causes osteoporosis. Some possible mechanisms are gastrin over-secretion and hypochlorhydria. Octreotide is a somatostatin analog that inhibits the secretion of many hormones such as gastrin. This study aimed to assess the effects of pantoprazole on the bone when used with octreotide in an animal model.
MATERIALS AND METHODS
Forty-eight male Wistar rats were randomly assigned into 4 groups: A) pantoprazole 3 mg/Kg/day orally; B) Sandostatin LAR 1 mg/month intramuscular injection; C) Pantoprazole and Sandostatin LAR; and D) Control group. After 90 days of the experiment, bone densitometry was done and serum and urine samples were collected for analysis.
RESULTS
The results indicated a significant decrease in the global, spine, femur, and tibia bone mineral density (BMD) and bone mineral content (BMC) in the pantoprazole group compared to the control group (<0.05). There was a significant increase in the levels of PTH, gastrin, and alkaline phosphatase (ALP) in the pantoprazole group compared to the control group (<0.05). There was no significant difference in the serum levels of gastrin, PTH, ALP, and also BMD in the rats that received sandostatin+ pantoprazole or sandostatin alone, compared to the control group.
CONCLUSION
This study showed that the pantoprazole-induced bone loss, through elevation of serum gastrin and PTH, was preventable by concomitant use of a long-acting somatostatin analog.
PubMed: 38234669
DOI: 10.22038/IJBMS.2023.71245.15571 -
Clinical Pharmacology and Therapeutics Nov 2023A novel haplotype composed of two non-coding variants, CYP2C18 NM_000772.3:c.*31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as "CYP2C:TG," was...
A novel haplotype composed of two non-coding variants, CYP2C18 NM_000772.3:c.*31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as "CYP2C:TG," was recently associated with ultrarapid metabolism of various CYP2C19 substrates. As the underlying mechanism and clinical relevance of this effect remain uncertain, we analyzed existing in vivo and in vitro data to determine the magnitude of the CYP2C:TG haplotype effect. We assessed variability in pharmacokinetics of CYP2C19 substrates, including citalopram, sertraline, voriconazole, omeprazole, pantoprazole, and rabeprazole in 222 healthy volunteers receiving one of these six drugs. We also determined its impact on CYP2C8, CYP2C9, CYP2C18, and CYP2C19 protein abundance in 135 human liver tissue samples, and on CYP2C18/CYP2C19 activity in vitro using N-desmethyl atomoxetine formation. No effects were observed according to CYP2C:TG haplotype or to CYP2C19*1+TG alleles (i.e., CYP2C19 alleles containing the CYP2C:TG haplotype). In contrast, CYP2C19 intermediate (e.g., CYP2C19*1/*2) and poor metabolizers (e.g., CYP2C19*2/*2) showed significantly higher exposure in vivo, lower CYP2C19 protein abundance in human liver microsomes, and lower activity in vitro compared with normal, rapid (i.e., CYP2C19*1/*17), and ultrarapid metabolizers (i.e., CYP2C19*17/*17). Moreover, a tendency toward lower exposure was observed in ultrarapid metabolizers compared with rapid metabolizers and normal metabolizers. Furthermore, when the CYP2C19*17 allele was present, CYP2C18 protein abundance was increased suggesting that genetic variation in CYP2C19 may be relevant to the overall metabolism of certain drugs by regulating not only its expression levels, but also those of CYP2C18. Considering all available data, we conclude that there is insufficient evidence supporting clinical CYP2C:TG testing to inform drug therapy.
Topics: Humans; Alleles; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Haplotypes
PubMed: 37528442
DOI: 10.1002/cpt.3012