Twice-daily Dosing Research Articles

Effects of probiotics on selected anthropometrics and biochemical measures in overweight or obese Saudi subjects: a double-blind, placebo-controlled, randomised clinical trial.

This study aimed to assess the effects of multi-strain probiotics on anthropometric and biochemical measures in Saudi adults with overweight or obesity. Single-centre, double-blind, placebo-controlled, randomised clinical trial. Occupational Health Clinics at King Saud University Medical City, Riyadh, Saudi Arabia. Ninety-three Saudi participants with overweight or obesity were randomly assigned to receive twice-daily doses of either placebo (n 49) or 30 × 109 CFU/g of HEXBIO® containing three Lactobacillus and three Bifidobacterium species (n 44) in a double-blind manner over a 12-week period, respectively. Both groups adhered to a hypoenergetic diet. Anthropometric measurements, glycaemic indices and lipid profiles were evaluated at baseline and post-intervention. Following the 12-week intervention, no statistically significant differences were found in all between the probiotic group and placebo group comparisons, except for fat intake, where the group*time interaction showed a significant decrease in favour of the probiotic group (P = 0·02). However, significant within-group reductions were observed in the probiotic group: body weight (-0·9 kg, P = 0·02), HC (-1·5 cm, P = 0·002), energy intake (-387·3 kcal/d, P = 0·002), fasting glucose (-0·7, P = 0·002) and LDL-cholesterol (-0·7, P = 0·02). Consumption of multi-strain probiotic supplementation over 12 weeks significantly decreased fat intake in Saudi adults with overweight or obesity, with the probiotic group highlighting improved anthropometric and biochemical parameters. Further research is needed to evaluate the long-term clinical significance of this dietary practice and whether it has a meaningful impact on overall health beyond the placebo effect.

Safety of an Accelerated Ferric Gluconate Inpatient Infusion Regimen.

Inpatient use of intravenous iron has been increasing. Ferric gluconate is traditionally given once daily. Twice-daily dosing provides faster iron repletion, but there are limited data to support the safety of twice-daily dosing. The aim of this study was to investigate the safety of twice-daily dosing for ferric gluconate compared with daily dosing. This was an institutional review board-approved retrospective observational study of hospitalized adult patients who received intravenous ferric gluconate 250 mg daily or twice daily between January 1 and April 3, 2022. The primary composite safety outcome included hypotension, infusion reaction, rapid response alert, or escalation in level of care. Secondary outcomes included total amount of iron received, hospital length of stay, and changes in laboratory values. A total of 126 patients were included in this study, with 63 patients in each group. The primary outcome occurred in 29 patients (46%) in the twice-daily group compared with 36 patients (57.1%) in the daily group (relative risk = 0.81; 95% CI, 0.57-1.13; P = 0.212). Changes in iron, hemoglobin, and transferrin saturation were similar between the 2 groups. Median length of stay was statistically shorter in the twice-daily group (7.79 days) compared with the daily group (12.9 days; p = 0.006). In this retrospective single-center study of hospitalized adult patients, those who received intravenous ferric gluconate twice daily did not experience an increased rate of a composite safety outcome of hypotension, infusion reactions, or escalation in level of care compared with those with daily dosing.

Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis?

Guidelines for bacterial meningitis in children recommend intravenous ceftriaxone 50 mg/kg (max 2 g) twice daily (BD) or 100 mg/kg (max 4 g) once daily (OD), leaving the decision regarding the dose frequency to the prescriber. We investigated the cerebrospinal fluid (CSF) penetration of ceftriaxone to evaluate whether one dosing regimen is superior. Unbound ceftriaxone concentrations were measured in serum and CSF samples from children aged 0-18 years treated with ceftriaxone if there was a sample remaining after clinical tests were performed. A serum-CSF population pharmacokinetic model was developed using non-linear mixed-effects modeling. The once- and twice-daily dosing regimens were simulated, and the probability of target attainment (PTA) was determined for maintaining a CSF concentration above a minimum inhibitory concentration (MIC) of 1 mg/L for common meningitis pathogens and 4 mg/L for Staphylococcus aureus for 100% of the dosing interval. Sixteen serum and 87 CSF samples were collected from 98 children (age range 0.1-18.5 years). The final two-compartment serum-CSF model included a renal maturation function with weight scaling on clearance and volume of distribution. The estimated serum:CSF uptake was 20.1%. For MIC 1 mg/L, the 24 h PTA was higher for OD (88%) compared with BD (53%) dosing, although both achieved a 100% PTA at steady state. For S. aureus (MIC 4 mg/L), neither dosing regimen was sufficient. Our findings support the use of a 100 mg/kg once daily regimen for empirical treatment of bacterial meningitis due to earlier achievement of the pharmacodynamic target. Neither dosing regimen was adequate for S. aureus meningitis.

Acetazolamide Therapy and Kidney Function in Persons with Nonalbuminuric Diabetes Mellitus Type 1.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower the risk of kidney failure in persons with type 2 diabetes. The presumed mechanism of action is through greater delivery of sodium to the distal tubule, activation of tubuloglomerular feedback which lowers glomerular filtration rate (GFR) and intra-glomerular pressure. SGLT2is are not approved for use in persons with type 1 diabetes due to the risk of diabetic ketoacidosis. Acetazolamide, a proximal tubule diuretic, delivers more sodium to the distal nephron, and may activate tubuloglomerular feedback in a similar way to SGLT2is without a higher risk of diabetic ketoacidosis. The kidney effects and safety of acetazolamide in persons with type 1 diabetes have not been well studied. Methods: We conducted a dose-escalation trial to determine the effects of 3 dosages of oral acetazolamide (62.5mg, 125mg, and 250mg, all twice-daily) in 12 persons with type 1 diabetes. Participants were treated for 2 weeks followed by a 2-week washout before exposure to the next dosage level. Blood and urine chemistries, as well as iohexol measured GFR, were assessed before and after each treatment interval. We aimed to identify a dose that maximized measured GFR reductions while minimizing adverse effects. Results: The mean age was 46±17 years, 100% were White, and 75% were female. The mean measured GFR was 89±18ml/min/1.73m2 at baseline. Acetazolamide reduced measured GFR by 15% (95% CI 9, 21), 14% (95% CI 7, 21), and 15% (95% CI 10, 21) after 2 weeks at the 62.5mg, 125mg, and 250mg twice-daily dosage levels respectively. The measured GFR reduction was fully reversed after each 2-week washout. Serum bicarbonate was reduced by 2.3, 4.2 and 4.4 mEq/L with escalating doses, and no episodes of hypokalemia (< 3.5 mEq/L) were observed. Conclusions: Among persons with type 1 diabetes and preserved kidney function, acetazolamide caused an acute, reversible reduction in measured GFR without effects on glucose metabolism.

Treatment of iron deficiency and iron deficiency anaemia in menstruating women

Iron deficiency and anaemia affect premenopausal women's quality of life. Daily oral iron supplements are standard treatment, causing gastrointestinal side effects, which could be overcome by an alternate-day dosing regimen. In this review, we compare dosing strengths and frequencies in trials: Twice-daily doses of 160 mg of elemental iron increases the ferritin- but not the haemoglobin level significantly and is poorly tolerated compared to 60-80 mg elemental iron taken daily or every other day, in mild to moderate anemia, although evidence for severe anaemia is limited.

5132 Unraveling the Enigma: A COVID-19 Triggered Revelation of Adult Idiopathic ACTH Deficiency

Abstract Disclosure: K.A. Arao: None. A.E. Gadbois: None. Introduction: Adult idiopathic ACTH deficiency (AIAD) is a rare and potentially life-threatening condition that is frequently misdiagnosed or even missed. We present a case of AIAD in a patient who exhibited altered mental status alongside a COVID-19 infection and was fortunately diagnosed after responding to empiric treatment with oral steroids for another condition. Case Presentation: A 76-year-old man was admitted to the hospital for bilateral leg weakness. His hospital stay was complicated by the development of febrile episodes and delirium. He tested positive for COVID-19, and the rest of infectious work-up yielded negative results. He then received a course of remdesivir. In the evaluation of his delirium, a CT scan of the brain, MRI of the brain, and lumbar puncture with CSF analysis were done, all of which were unremarkable. Initially, the delirium was attributed solely to COVID-19 infection. After consultation with neurology and rheumatology, the patient received empiric treatment with prednisone 5 mg twice daily for possible polymyalgia rheumatica as a cause of his bilateral leg weakness. His mental status significantly improved following steroid administration. With the improvement in symptoms, an AM cortisol test was added on his morning blood tests, revealing a cortisol level of 2.56 mcg/dL with an albumin level of 2.3 g/dL, raising concerns for adrenal insufficiency. An outpatient endocrinology evaluation recommended transitioning from prednisone to physiologic twice-daily dosing of hydrocortisone. An ACTH stimulation test was performed, which peaked at an AM cortisol of 6.1 mcg/dL, with a baseline ACTH level of 4.1 pg/mL. A review of the recent brain MRI showed no pituitary pathology. Other pituitary hormones were normal, and he was eventually diagnosed with AIAD. He was subsequently maintained on physiologic dosing of hydrocortisone, resulting in clinical stability. Discussion: AIAD is characterized by secondary adrenal insufficiency, normal production of other pituitary hormones, and the absence of structural pituitary pathology. The etiology of AIAD remains unknown, with most cases attributed to an autoimmune process. AIAD can have diverse clinical manifestations and may only become more apparent with triggers like infections or illnesses. As in our case, the COVID-19 infection likely unmasked the underlying AIAD, presenting with altered mental status. Identifying AIAD can be challenging, leading to high rates of misdiagnosis and clinical omission. Physicians should consider AIAD when dealing with unexplained altered mental status, as the administration of a simple treatment with steroids can be life-changing. Presentation: 6/3/2024

Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer.

Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers. A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks. A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics. The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model. NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

CML-282 Asciminib Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Updated Results From the AIM4CML Study in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With Prior Tyrosine Kinase Inhibitor (TKI) Treatment

CML-282 Asciminib Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Updated Results From the AIM4CML Study in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With Prior Tyrosine Kinase Inhibitor (TKI) Treatment

Asciminib Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Updated Results From the AIM4CML Study in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With Prior Tyrosine Kinase Inhibitor (TKI) Treatment

Asciminib Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Updated Results From the AIM4CML Study in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With Prior Tyrosine Kinase Inhibitor (TKI) Treatment

The Effect of Renaltec on Serum Uremic Toxins in Cats with Experimentally Induced Chronic Kidney Disease.

Serum uremic toxins markedly increase in cats with chronic kidney disease (CKD) and have deleterious consequences. Renaltec is an oral adsorbent that binds uremic toxin precursors in the gut. In this prospective cohort study utilizing 13 purpose-bred cats with remnant kidney model-induced CKD (12 IRIS Stage 2, 1 IRIS Stage 3) eating a standardized renal diet, we aimed to assess the effect of Renaltec administration on serum indoxyl sulfate (IDS) and p-cresol sulfate (pCS) concentrations. Cats were sequentially treated with standard of care for 56 days, 500 mg Renaltec orally once daily for 56 days, and then three months later, 500 mg Renaltec orally twice daily for 56 days. Serum IDS and pCS concentrations were measured 28 and 56 days after the administration of Renaltec. Blood pressure and kidney function were measured before and 56 days after the administration of Renaltec. Significant decreases in serum IDS and pCS concentrations were observed for both once- and twice-daily dosing, particularly during the first 28 days of administration. More cats with BID dosing had clinically significant reductions in serum IDS and pCS concentrations than with SID dosing. Renaltec can reduce the serum concentrations of deleterious gut-derived uremic toxins in cats with CKD.

Efficacy, safety, and tolerability of lifitegrast 5% eye drops: A randomized, double-blind, active-controlled trial in Indian patients with dry eye disease.

To compare the efficacy, safety, and tolerability of lifitegrast 5% versus carboxymethylcellulose (CMC) 0.5% in adult patients with dry eye disease (DED). A total of 370 eligible patients with DED were randomized equally to receive twice-daily doses of a single drop in each eye of either lifitegrast 5% or CMC 0.5% for 12 weeks. Follow-up at weeks 2, 6, and 12 evaluated changes from baseline in primary [eye dryness score (EDS), ocular discomfort score (ODS), ocular surface disease index (OSDI), and tear film break-up time (TFBUT)] and secondary [Schirmer tear test (STT) score and corneal fluorescein staining (CFS) score] endpoints. Global improvement, safety, and tolerability were also assessed. At week 2, values of ocular discomfort score, OSDI, and conjunctival redness were significantly more favorable in patients treated with lifitegrast compared to CMC. At week 6, values of all study variables were better in patients treated with lifitegrast compared to CMC; differences between the groups were statistically significant for all except photophobia. This trend was also maintained at week 12. Global improvement and tolerability were found to be better with lifitegrast than with CMC. No serious safety concerns were reported in any treatment group. To our knowledge, this is the first active-controlled trial informing on the efficacy, safety, and tolerability of lifitegrast 5%. Significantly more favorable values for EDS (except photophobia), ODS, OSDI, TFBUT, STT score, CFS score, and conjunctival redness score were achieved at week 12 with lifitegrast 5% compared to CMC 0.5%.

Impact of twice-daily budesonide foam administration on early clinical response and endoscopic remission in patients with ulcerative colitis: a post hoc analysis.

Early treatment response of ulcerative colitis (UC) symptom resolution is desirable. This post hoc analysis evaluated efficacy outcomes, including endoscopic remission, by responder status and the influence of once-daily (QD) versus twice-daily (BID) budesonide foam dosing in patients with UC. Data were pooled from phase 2 and phase 3 clinical trials of budesonide rectal foam QD or BID or placebo for up to 12weeks. Outcomes were evaluated by treatment and budesonide administration regimen and by responder group: early (rectal bleeding subscore [RBS] 0 from Week 2 through Week 6), delayed (RBS 0 at Week 6), and nonresponder (RBS>0 at Week 6). The main analysis set included 55 (QD) and 120 (BID) budesonide-treated patients and 116 placebo-treated patients. At Week 6, the trend in early response rate was significant among treatment groups (BID, 45.3%; QD, 32.1%; placebo, 12.8%; P<0.0001). Among BID recipients, trends for complete endoscopic remission rate (Mayo endoscopic score [MES]=0) and endoscopic remission rate (MES=0 or 1) were significant among responder status groups (early responder, 67.4% and 95.4%, respectively; delayed responder, 48.1% and 85.2%; nonresponder, 24.0% and 64.0%; P<0.001 for both). Regardless of the administration regimen, most early responders achieved endoscopic remission at Week 6. Among responder status groups, early responders' cumulative non-relapse period was greatest (P=0.07). A BID budesonide administration regimen is preferred to increase the probability of early response and, following endoscopic remission, a better prognosis after stopping treatment.

Real-World Adherence and Discontinuation of Oral Antipsychotics and Associated Factors in a National Sample of US Medicare Beneficiaries with Schizophrenia.

Little is known about adherence to and discontinuation of newly initiated oral antipsychotics (OAPs) as well as associated factors among Medicare beneficiaries with schizophrenia. This study aimed to examine rates of OAP adherence and discontinuation and associated factors in a national sample of fee-for-service Medicare beneficiaries with schizophrenia. This retrospective study used 100% fee-for-service Medicare claims data to identify adult beneficiaries with schizophrenia, initiating a new OAP between 01/01/2017 and 12/31/2019 (index date = date of new OAP prescription). Outcomes included adherence and discontinuation. Factors associated with adherence were assessed using logistic and linear regressions; Cox regressions were used to assess factors associated with discontinuation. In our final sample of 46,452 Medicare beneficiaries with schizophrenia, 35.4% were adherent to their newly initiated OAP (mean [SD] PDC: 0.52 [0.37]) over 12 months after initiation. Most patients (79.4%) discontinued their new OAP (median [IQR] time to discontinuation: 3.6 (1.0, 9.9) months). Factors associated with lower odds of adherence included younger age (OR: 0.43; 95% CI: 0.40-0.47, p <0.001 for patients aged 18-35 relative to patients aged ≥65 years); non-White race (OR: 0.72; 95% CI: 0.69-0.75, p <0.001 relative to White patients); and evidence of prior schizophrenia-related hospitalization (OR: 0.80; 95% CI: 0.77-0.83, p <0.001 relative to patients without evidence of prior schizophrenia-related hospitalization). Similar associations were observed for discontinuation outcomes. Twice-daily dosing frequency was also associated with lower odds of adherence (odds ratio [OR]: 0.93; 95% CI: 0.89-0.97, p = 0.0014) and higher hazard of discontinuation (hazard ratio [HR]: 1.03; 95% CI: 1.00-1.05, p = 0.0244) relative to once-daily dosing frequency. We found high rates of non-adherence and discontinuation among Medicare beneficiaries initiated on currently available OAPs. We also identified risk factors that contribute to increased odds of medication non-adherence. By identifying at-risk patient populations, targeted interventions can be initiated to facilitate treatment continuity.

Comparison of Routes of Administration, Frequency, and Duration of Favipiravir Treatment in Mouse and Guinea Pig Models of Ebola Virus Disease.

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013-2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic.

Characterizing Enoxaparin's Population Pharmacokinetics to Guide Dose Individualization in the Pediatric Population.

Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct. METHODS: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0-18 years, TBW) or fat-free mass (2-18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity. A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied. Using real-world data and PopPK modeling, enoxaparin's pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity.

Ultra-fast UPLC–MS/MS approach for estimating X-376 in human liver microsomes: Evaluation of metabolic stability via in silico software and in vitro analysis

X-376 is a novel anaplastic lymphoma kinase (ALK) inhibitor that is capable of penetrating the blood brain barrier. This makes it suitable for use in patients with ALK-positive non-small cell lung cancer (NSCLC) who have metastases in the central nervous system. This study developed a highly sensitive, fast, eco-friendly, and reliable UPLC-MS/MS approach to quantify X-376 in human liver microsomes (HLMs). This approach was used to evaluate X-376's metabolic stability in HLMs in vitro. The UPLC-MS/MS analytical technique validation followed US-FDA bio-analytical method validation guidelines. StarDrop software, containing P450 metabolic and DEREK modules, was utilized to scan X-376's chemical structure for metabolic lability and hazardous warnings. X-376 and Encorafenib (ENF as internal standard) were resoluted on the Eclipse Plus C18 column utilizing an isocratic mobile phase method. The X-376 calibration curve was linear from 1 to 3000 ng/mL. The precision and accuracy of this study's UPLC-MS/MS approach were tested for intra- and inter-day measurements. Inter-day accuracy was −1.32% to 9.36% while intra-day accuracy was −1.5% to 10.00%. The intrinsic clearance (Clint) and in vitro half-life (t1/2) of X-376 were 59.77 mL/min/kg and 13.56 min. The high extraction ratio of X-376 supports the 50 mg twice-daily dose for ALK-positive NSCLC and CNS metastases patients. In silico software suggests that simple structural changes to the piperazine ring or group substitution in drug design may improve metabolic stability and safety compared to X-376.

Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants.

There is an unmet need for safe and efficacious oral therapies for COVID-19 with low potential for drug-drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS-CoV-2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS-443902), which acts as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first-in-human, randomized, placebo-controlled, phase I study following oral administration of obeldesivir and a phase I, open-label absorption, distribution, metabolism, and excretion study following oral administration of [14C]-obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT-concentration analysis. The exposures to GS-441524 increased dose proportionally in the 100-900-mg dose range. GS-441524 accumulated by 35% after twice-daily and 12% after once-daily dosing for 5 days. Dose-proportional increases in the intracellular concentration of GS-443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS-441524 was not significantly altered by food intake. Following oral administration of [14C]-obeldesivir (500 mg; 100 μCi), the mean cumulative [14C]-dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS-441524 was the predominant plasma component (90% of 14C-area under the concentration-time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice-daily dosing regimen for further evaluation in phase III studies for COVID-19.

Pharmacokinetic Evaluation of Oral Viscous Budesonide in Paediatric Patients with Eosinophilic Oesophagitis in Repaired Oesophageal Atresia.

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.

Antihypertensive drug prescription patterns and their impact on blood pressure outcomes in a tertiary care teaching hospital

Background: The guidelines from the Joint National Committee (JNC-8) emphasize the importance of rapid blood pressure (BP) control to reduce morbidity and mortality. The success of hypertension treatment depends on various factors, with irrational prescription being strongly linked to poor BP control. This study aimed to evaluate the patterns of antihypertensive drug prescriptions among patients in a tertiary care teaching hospital. Methods: A hospital-based observational study was conducted in 2018, including all hypertensive patients on medication. Their prescription patterns were analyzed. Results: The study analyzed prescriptions from 240 hypertensive patients. The mean ages for male and female patients were 56.68±15.32 and 62.29±12.65 years, respectively. Physicians commonly prescribed monotherapy (34.60%) followed by two-drug (18.40%), three-drug (11.80%), and four-drug combinations (3.00%). The most frequent two-drug combination was ACE inhibitors + diuretics (4.40%), followed by angiotensin receptor blockers (ARBs) + diuretics (3.60%) and calcium channel blockers (CCBs) + ACE inhibitors (2.60%). Adherence to JNC 8 guidelines was 19.3% for pre-hypertension, 88.70% for stage 1 hypertension, and 73.29% for stage 2 hypertension. Conclusions: Monotherapies were the most commonly prescribed regimens. Twice-daily dosing and monthly appointments were associated with lower incidences of uncontrolled BP. However, complete adherence to standard guidelines was not observed in all cases, especially in patients with comorbid conditions.

Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial.

Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.