Higher Daily Dose Research Articles

Testing the unintended cost effects of health policies for generic substitutions: the case of China’s National Volume-Based Procurement (NVBP) policy

Abstract Generic substitutions are globally considered to contain health expenditures. Yet it is uncertain whether the costs would spill over to other medicines or health services. Contextualizing China’s National Volume-Based Procurement (NVBP) policy, which promoted generic substitution, this study tests the changes in patients’ utilisation of generic medicines and whether the costs shift to other pharmaceutics or health services post-policy. This population-based, matched, cohort study uses claims data from Tianjin, China in 2018-2020. We focus on Amlodipine, the most commonly used calcium channel blocker with the largest volume. We build comparable post-policy cohorts: Non-switchers who kept using originator Amlodipine, Pure-switchers who loyally switched to generic Amlodipine, and Back-switchers who switched back-and-forth; and compare between each matched pair, respectively, of their annual healthcare costs and that broken down by components, and patients’ use of and adherence to Amlodipine post-policy. 1185 Pure-switchers, 1398 Back-switchers, and 2330 Non-switchers are identified (mean age: 63.0 years; 58.5% men). For the matched pairs, Pure-switchers (N=772) incurred an annual total medical costs of CNY 9213.5, 12.2% lower than Non-switchers (N=1544, absolute difference CNY -1309.3, 95%CI: [-2645.8, -19.6]). The cost reduction only results from Amlodipine prescriptions in outpatient encounters, and are equally born on health plans and the enrolees. Pure-switchers and Non-switchers are not different in costs from other medicines, nor from other items including tests, surgeries, beds, and medical consumables for hypertension-related encounters/admissions. Pure-switchers had higher daily dosage and better adherence to Amlodipine than Non-switchers as well. The differences between Back-switchers and Non-switchers show similar trends but are less profound. China’s NVBP policy is effective to control pharmaceutical costs. No unintended cost effects have yet been identified in the short run. Other countries may learn from China on the comprehensive sets of auxiliary policies, including listing, bidding, purchasing, and reimbursing, to better promote generic substitutions.

6923 Case Report: Long Standing Type 2 Diabetes with TOFI Phenotype Successfully Weaned Off One Hundred Units of Basal-Bolus Insulin Therapy With Glucagon-Like Peptide 1 Receptor Agonist Therapy

Abstract Disclosure: Y.C. Kon: None. A 60-year-old Indian male was diagnosed with type 2 diabetes in 1997. In July 2017, his fasting blood glucose level (FBGL) was 10.3 mM, paired C-peptide 719 pM, eGFR measured as more than 60 ml/min. Since Sep 2017, he had been compliant on the same stable regimen of sc insulatard 20 units om and 20 units at 10 pm, sc actrapid 20 units t.i.d premeal, PO metformin 850 mg t.i.d and PO dapagliflozin 10 mg om. In the past, he had suffered myocardial infarction, with left ventricular ejection fraction 35%, and had left anterior descending coronary artery stenting. In 2017, he had automatic cardioverter defibrillator implanted for primary arrhythmia prevention. His cardiac medications included bisoprolol fumarate 5 mg om, losartan 25 mg om, spironolactone 25 mg om, aspirin 100 mg om and high intensity statin therapy. Since 2020, his HbA1c had measured 8% to 9% with FBGL at 6 mM to 11 mM. Hence he was referred by his cardiologist in Oct 2022 to optimize glycaemic control. Once every few months, he experienced hypoglycaemic symptoms with corresponding low capillary blood glucose (CBG) of 3 mM, reversed with glucose intake. On physical examination, he weighed 81.6 kg, BMI was 25.4 kg/m2, BP 110/67 mmHg, pulse rate 69/min regular, waist circumference 106 cm. There was no acanthosis nigricans. He did not appear Cushingoid nor acromegalic. As he had “thin outside, fat inside (TOFI)” type 2 diabetes phenotype, he was started on sc liraglutide 1.8 mg om. His actrapid dose was halved to 10 units premeal, and insulatard dose halved to 10 units bid. His dapagliflozin was switched to subsidised empagliflozin 25 mg om. Subsequently, his premeal CBG measured 4 to 7 mM, bedtime CBG 4-6 mM, with occasional minor hypoglycaemic episodes with CBG at 3-4 mM. In July 2023, HbA1c measured 6.3%, FBGL was 5.5 mM and paired C-peptide measured as 554 pM. Basal insulatard was discontinued and he was switched from liraglutide to sc dulaglutide 1.5 mg once weekly. In Oct 2023, his FBGL was 5.2 mM and HbA1c had improved markedly to 5.7%. His weight had reduced from 81.6 kg to 70.0 kg, BMI decreased from 25.4 kg/m2 to 22.9 kg/m2 and waist circumference reduced from 106 cm to 97 cm. As he continued to experience occasional minor hypoglycemic episodes, actrapid insulin was discontinued. On his current therapy of sc dulaglutide 1.5 mg once weekly, PO empagliflozin 25 mg om, PO metformin 850 mg tid, and PO acarbose 50 mg t.i.d, his fasting CBG measured 6.7-7.7 mM, premeal CBG 6.4 to 10.1 mM, off all insulins and without further episodes hypoglycaemia. Conclusion: Patients with long standing “TOFI” type 2 diabetes and robust C-peptide may be trialled on GLP1-receptor agonist therapy to wean off high daily doses of insulin, thus avoiding hypoglycaemia, achieving weight and abdominal fat loss, whilst maintaining glycaemic control. This is especially important in patients with established coronary artery disease. Presentation: 6/3/2024

8798 How Low Can You Go: Suspected Methadone-Induced Hyperinsulinemia

Abstract Disclosure: L. Ravindra: None. M.G. Fernandez: None. V. Cheng: None. Background: Studies have shown that methadone use can result in severe hypoglycemia. This is thought to be related to methadone having antagonistic activity at NMDA receptors, resulting in increased pancreatic insulin release, suppressed glucagon and epinephrine, and inhibition of hepatic glycogenolysis. These mechanisms affect the normal physiologic response to hypoglycemia and can result in hyperinsulinemic-induced hypoglycemia. Clinical case: We present a case of a 56-year-old male with complex regional pain syndrome managed with a high daily dose of methadone (345 mg) who presented to the hospital for evaluation of failure to thrive and hypoglycemia. During the hospital admission, evaluation of hypoglycemia included a serum blood glucose level of 41 mg/dL (normal >60 mg/dL), with an inappropriately normal level of insulin 10 (Reference Range (RR) 3-25 mU/L), C-peptide 2.9 (RR 0.5-3.3 ng/ml), Pro-insulin 2.9 (RR 3-20 pmol/L), an undetectable level of Beta-hydroxybutyrate <0.10 (RR 0.02-0.27 mMol/L) negative insulin antibodies <0.4 (RR 0.0 - 0.4 U/mL), and negative sulfonylurea screen. Additional labs included a normal TSH of 2.8 (RR 0.3-5.5 mIU/ml) and appropriate morning cortisol of 23 (RR >14-15 μg/dL). The abdominal CT and follow-up MRI did not reveal any definite abnormalities in the pancreas. Given persistent evidence of hyperinsulinemic-induced hypoglycemia, a PET Dotatate scan was performed, confirming the absence of a neuroendocrine tumor. While admitted, management included nutritional optimization, close glucose monitoring, and an intravenous dextrose infusion. Diazoxide was also initiated and gradually increased to 150 mg three times a day. Addiction Medicine assisted in tapering down the methadone dose from 115 mg to 105 mg three times a day. With these interventions, the patient had no further episodes of hypoglycemia. On discharge, the patient was provided with a continuous glucose monitor. On follow-up, the patient has continued to show improvement and the diazoxide dose has been decreased without recurrent hypoglycemia. Given this, a selective arterial calcium stimulation test was not pursued. Conclusion: Methadone is an uncommon cause of hyperinsulinemic-induced hypoglycemia. Suspicion should arise, particularly in patients on high doses. Current evidence suggests tapering methadone dosage as the primary intervention, as insulin levels can decrease drastically and improve hypoglycemia. This therapeutic approach should be considered before pursuing invasive and costly diagnostic testing. Presentation: 6/3/2024

Predictive Model for Opioid Use Disorder in Chronic Pain: A Development and Validation Study.

There are several questionnaires for the challenge of anticipating opioid use disorder (OUD). However, many are not specific for chronic non-cancer pain (CNCP) or have been developed in the American population, whose sociodemographic factors are very different from the Spanish population, leading to scarce translation into clinical practice. Thus, the aim of this study is to prospectively validate a predictive model for OUD in Spanish patients under long-term opioids. An innovative two-stage predictive model was developed from retrospective (n = 129) and non-overlapping prospective (n = 100) cohorts of real-world CNCP outpatients. All subjects used prescribed opioids for 6 or more months. Sociodemographic, clinical and pharmacological covariates were registered. Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were also analyzed. The model performance and diagnostic accuracy were calculated. The two-stage model comprised risk factors related to OUD (younger age, work disability and high daily opioid dose) and provided new useful information about other risk factors (low quality of life, OPRM-G allele and CYP2D6 extreme phenotypes). The validation showed a satisfactory accuracy (70% specificity and 75% sensitivity) for our predictive model with acceptable discrimination and goodness of fit. Our study presents the results of an innovative model for predicting OUD in our setting. After external validation, it could represent a change in the paradigm of opioid treatment, helping clinicians to better identify and manage the risks and reduce the side effects and complications.

Primaquine for uncomplicated Plasmodium vivax malaria in children younger than 15 years: a systematic review and individual patient data meta-analysis

Primaquine, the only widely available treatment to prevent relapsing Plasmodium vivax malaria, is produced as 15 mg tablets, and new paediatric formulations are being developed. To inform the optimal primaquine dosing regimen for children, we aimed to determine the efficacy and safety of different primaquine dose strategies in children younger than 15 years. We undertook a systematic review (Jan 1, 2000-July 26, 2024) for P vivax efficacy studies with at least one treatment group that was administered primaquine over multiple days, that enrolled children younger than 15 years, that followed up patients for at least 28 days, and that had data available for inclusion by June 30, 2022. Patients were excluded if they were aged 15 years or older, presented with severe malaria, received adjunctive antimalarials within 14 days of diagnosis, commenced primaquine more than 7 days after starting schizontocidal treatment, had a protocol violation in the original study, or were missing data on age, sex, or primaquine dose. Available individual patient data were collated and standardised. To evaluate efficacy, the risk of recurrent P vivax parasitaemia between days 7 and 180 was assessed by time-to-event analysis for different total mg/kg primaquine doses (low total dose of ∼3·5 mg/kg and high total dose of ∼7 mg/kg). To evaluate tolerability and safety, the following were assessed by daily mg/kg primaquine dose (low daily dose of ∼0·25 mg/kg, intermediate daily dose of ∼0·5 mg/kg, and high daily dose of ∼1 mg/kg): gastrointestinal symptoms (vomiting, anorexia, or diarrhoea) on days 5-7, haemoglobin decrease of at least 25% to less than 7g/dL (severe haemolysis), absolute change in haemoglobin from day 0 to days 2-3 or days 5-7, and any serious adverse events within 28 days. This study is registered with PROSPERO, CRD42021278085. In total, 3514 children from 27 studies and 15 countries were included. The cumulative incidence of recurrence by day 180 was 51·4% (95% CI 47·0-55·9) following treatment without primaquine, 16·0% (12·4-20·3) following a low total dose of primaquine, and 10·2% (8·4-12·3) following a high total dose of primaquine. The hazard of recurrent P vivax parasitaemia in children younger than 15 years was reduced following primaquine at low total doses (adjusted hazard ratio [HR] 0·17, 95% CI 0·11-0·25) and high total doses (0·09, 0·07-0·12), compared with no primaquine. In 525 children younger than 5 years, the relative rates of recurrence were also reduced, with an adjusted HR of 0·33 (95% CI 0·18-0·59) for a low total dose and 0·13 (0·08-0·21) for a high total dose of primaquine compared with no primaquine. The rate of recurrence following a high total dose was reduced compared with a low dose in children younger than 15 years (adjusted HR 0·54, 95% CI 0·35-0·85) and children younger than 5 years (0·41, 0·21-0·78). Compared with no primaquine, children treated with any dose of primaquine had a greater risk of gastrointestinal symptoms on days 5-7 after adjustment for confounders, with adjusted risks of 3·9% (95% CI 0-8·6) in children not treated with primaquine, 9·2% (0-18·7) with a low daily dose of primaquine, 6·8% (1·7-12·0) with an intermediate daily dose of primaquine, and 9·6% (4·8-14·3) with a high daily dose of primaquine. In children with 30% or higher glucose-6-phosphate dehydrogenase (G6PD) activity, there were few episodes of severe haemolysis following no primaquine (0·4%, 95% CI 0·1-1·5), a low daily dose (0·0%, 0·0-1·6), an intermediate daily dose (0·5%, 0·1-1·4), or a high daily dose (0·7%, 0·2-1·9). Of 15 possibly drug-related serious adverse events in children, two occurred following a low, four following an intermediate, and nine following a high daily dose of primaquine. A high total dose of primaquine was highly efficacious in reducing recurrent P vivax parasitaemia in children compared with a low dose, particularly in children younger than 5 years. In children treated with high and intermediate daily primaquine doses compared with low daily doses, there was no increase in gastrointestinal symptoms or haemolysis (in children with 30% or higher G6PD activity), but there were more serious adverse events. Medicines for Malaria Venture, Bill & Melinda Gates Foundation, and Australian National Health and Medical Research Council.

Co-amorphous systems of sulfasalazine with matrine-type alkaloids: Enhanced solubility behaviors and synergistic therapeutic potential

Sulfasalazine (SULF), a sulfonamide antibiotic, has been utilized in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) since its discovery. However, its poor water solubility causes the high daily doses (1–––3 g) for patients, which may lead to the intolerable toxic and side effects for their lifelong treatment for RA and IBD. In this work, two water-soluble natural anti-inflammatory alkaloids, matrine (MAR) and sophoridine (SPD), were employed to construct the co-amorphous systems of SULF for addressing its solubility issue. These newly obtained co-amorphous forms of SULF were comprehensively characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). We also investigated their dissolution behavior, including powder dissolution, in vitro release, and intrinsic dissolution rate. Both co-amorphous systems exhibited superior dissolution performance compared to crystalline SULF. The underlying mechanism responsible for the enhanced dissolution behaviors in co-amorphous systems were also elucidated. These mechanisms include the inhibition of nucleation, complexation, increased hydrophilicity, and robust intermolecular interactions in aqueous solutions. Importantly, these co-amorphous systems demonstrated satisfactory physical stability under various storage conditions. Network pharmacological analysis was utilized to investigate the potential therapeutic targets of both co-amorphous systems against RA, revealing similar yet distinct multi-target synergistic therapeutic mechanisms in the treatment of this condition. Our study suggests these drug-drug co-amorphous systems hold promise for optimizing SULF dosage in the future and providing a potential drug combination strategy.

Daily and Weekly "High Doses" of Cholecalciferol for the Prevention and Treatment of Vitamin D Deficiency for Obese or Multi-Morbidity and Multi-Treatment Patients Requiring Multi-Drugs-A Narrative Review.

Daily vitamin D supplementation using higher than normal dosing (up to the upper limit value) and intermittent (once or twice per week) dosing were studied in patients with increased risk of vitamin D deficiency. Using a PubMed database, a thorough search for published randomized controlled trials and other studies was conducted, and the results were analyzed. This review provides an overview of the use of 7000 IU daily, 30,000 IU per week or twice weekly, and 50,000 IU weekly of vitamin D for obtaining and maintaining 25(OH)D concentrations of at least 30 ng/mL in patients at high risk of vitamin D deficiency. The abovementioned dosages should be considered in adults with obesity, liver disease or malabsorption syndromes, or multi-diseased patients, mainly seniors requiring multi-drug treatment, including drugs affecting vitamin D metabolism. The simple schedules of 7000 IU/day, 30,000 IU/week or twice weekly, and 50,000 IU/week for use by patients with an increased risk of vitamin D deficiency were provided for consideration. Without monitoring of 25(OH)D, daily doses of 7000 IU or intermittent doses of 30,000 IU/week should be considered for a prolonged time as prophylactic or maintenance doses, mainly in obese patients, patients with liver disease and patients with malabsorption syndromes. For the treatment of possible vitamin D deficiency without assessment of 25(OH)D in these groups, intermittent doses of 30,000 IU twice weekly or 50,000 IU per week should be considered for a 6-8-week period only. The higher daily doses or the intermittent doses suggested above are effective, safe and responsive based on patient's preferences.

Pharmacokinetic/pharmacodynamic model-based optimization of temocillin dosing strategies for the treatment of systemic infections.

Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections. We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time-kill data. Temocillin effects on four Escherichia coli strains were evaluated using static time-kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time-kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens. Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed. Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development.

Nanoparticle-based targeted therapy through EGFR tyrosine kinase inhibitors and their recent advances in lung cancer therapy

The emergence and subsequent advancement of nanotechnology in recent years have greatly benefited the healthcare sector, particularly in the treatment of cancer. As per study, major fatalities are related to the lung cancer. For many years, oral tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor (EGFR) family of receptors have been used in the clinic to treat human malignancies, although they observed some very serious adverse effects in the treatment of lung cancer, especially in non-small cell lung cancer (NSCLC). Despite EGFR-TKIs’ exceptional qualities as small-molecule targeted medications, their applicability is nevertheless limited by their poor solubility, inconsistent oral bioavailability, high daily dose needs, high plasma albumin binding propensity, and initial/acquired drug resistance. Article’s purpose is to investigate EGFR-TKI’s effects on lung cancer and get around some of its drawbacks, nanotechnology will be an innovative strategy. An effective tool to increase the effectiveness of these pharmaceuticals is nanotechnology by methods other than oral. This article signifies that a range of nanomedicine delivery systems have been developed to effectively distribute EGFR-TKIs with improved drug release kinetics and tissue-targeting capacity. This review article intends to present information regarding lung cancer and EGFR relation, mechanism of recently approved EGFR-TKI’s targeted therapy, an updated landscape of EGFR-TKIs and their clinical status over lung cancer, advantages and disadvantages of nanotechnology, and new breakthroughs in nano-delivery which mentioned as a significantly better over traditional drug chemotherapy and delivery.

Determining the optimal daily gonadotropin dose to maximize the oocyte yield in elective egg freezing cycles

ObjectiveOvarian stimulation (OS) with high daily gonadotropin doses are commonly offered to patients attempting social/elective egg freezing. However, the optimal daily gonadotropin dose that would allow a higher oocyte yield in the successive IVF cycle attempt was not settled and should be determined.Patients and methodsData from all women admitted to our IVF unit for social/EEF, who underwent two consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300IU were analyzed. Patients characteristics and OS variables were used in an attempt to build a logistic model, helping in determining the daily gonadotropin dose that should be offered to patient during their second EEF attempt, aiming to further increase their oocyte yield.ResultsThree hundred and thirteen consecutive women undergoing two successive IVF cycle attempts were evaluated. Using logistic regression model, two equations were developed using individual patient-level data that determine the daily gonadotropin dose needed aiming to increase the oocyte yield in the successive cycle. (a): X=-0.514 + 2.87*A1 + 1.733*A2–0.194* (E2/1000) and (b): P = EXP(X) / [1 + EXP(X)].ConclusionsUsing the aforementioned equations succeeded in determining the daily gonadotropin dose that might result in increasing oocyte yield, with an AUC of 0.85. Any additional oocyte retrieved to these EEF patients might get them closer to fulfil their desire to parenthood.

Posaconazole in paediatric malignancy and haematopoietic stem cell transplant: dosing to achieve therapeutic concentration.

Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects. In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included. Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified. The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses.

Experimental and theoretical study of the Favipiravir association in water solvent

Favipiravir, also known as T-705, is an antiviral prodrug that was first developed against the influenza virus and was later found to be effective against other RNA viruses, including arenaviruses, bunyaviruses, Zika, Ebola, Lassa, and COVID-19 viruses, in addition to influenza A and B. Due to the global prevalence of SARS-COV-2 in 2019, Favipiravir was used as an antiviral drug for treating COVID-19, but the challenges facing it, including its solubility, tablet ability, and bioavailability, remain. It is critical and challenging to develop a drug with appropriate bioavailability, improved oral absorption, and increased solubility without interfering with other functions and preventing the consumption of high daily doses. For this purpose, in the present study, the interactions of Favipiravir-Favipiravir and Favipiravir-H2O and the association of the Favipiravir molecules were investigated experimentally and theoretically. The theoretical results showed that under normal conditions, all structures were stable, but the most stable structure based on calculations of electronic energy, Gibbs, and solvation Gibbs free energies (minimum value), both in the gas phase and in the aqueous phase, is related to the B-enol isomer. Also, the change in dipole moment in the solvation process for this isomer was less than others. Also, the intense intermolecular hydrogen bonds O-H…O and N-H…O between the Favipiravir and water molecules showed that Favipiravir…Favipiravir interactions are stronger than Favipiravir…H2O interactions in aqueous solutions. These interactions indicate that Favipiravir can participate in the aggregation phenomena in high concentrations. Also, Stokeʼs shift values slightly increased with the decreasing the drug concentration in water (intramolecular charge transfer phenomenon).

Early detection of liver injuries by the Serum enhanced binding test sensitive to albumin post-transcriptional modifications

Early and sensitive biomarkers of liver dysfunction and drug-induced liver injury (DILI) are still needed, both for patient care and drug development. We developed the Serum Enhanced Binding (SEB) test to reveal post-transcriptional modifications (PTMs) of human serum albumin resulting from hepatocyte dysfunctions and further evaluated its performance in an animal model. The SEB test consists in spiking serum ex-vivo with ligands having specific binding sites related to the most relevant albumin PTMs and measuring their unbound fraction. To explore the hypothesis that albumin PTMs occur early during liver injury and can also be detected by the SEB test, we induced hepatotoxicity in male albino Wistar rats by administering high daily doses of ethanol and CCl4 over several days. Blood was collected for characterization and quantification of albumin isoforms by high-resolution mass spectrometry, for classical biochemical analyses as well as to apply the SEB test. In the exposed rats, the appearance of albumin isoforms paralleled the positivity of the SEB test ligands and histological injuries. These were observed as early as D3 in the Ethanol and CCl4 groups, whereas the classical liver tests (ALT, AST, PAL) significantly increased only at D7. The behavior of several ligands was supported by structural and molecular simulation analysis. The SEB test and albumin isoforms revealed hepatocyte damage early, before the current biochemical biomarkers. The SEB test should be easier to implement in the clinics than albumin isoform profiling.

Risk of severe infection associated with immunoglobulin deficiency under rituximab therapy in immune-mediated inflammatory disease

ObjectivesWe evaluated the risk of severe infection in patients with immune-mediated inflammatory disease (IMID) treated with RTX and with Ig deficiency.MethodsThis was an observational, retrospective single-centre study of patients undergoing...

Economic burden and dosing trends of buprenorphine buccal film and transdermal patch in chronic low back pain.

Aim: Exploring prescribing trends and economic burden of chronic low back pain (cLBP) patients prescribed buprenorphine buccal film (Belbuca®) or transdermal patches. Methods: In the MarketScan® commercial insurance claims (employees and their spouses/dependents, 2018-2021), the first film or patch prescription date was an index event. The observation covered 6-month pre-index and 12-month post-index periods. Results: Patients were propensity-score matched (708 per cohort). Buprenorphine initiation had stable cost trends in buccal film and increasing trends in transdermal patch cohort. Between-cohort comparisons of healthcare expenditures, cost trends and resource utilization showed significant differences, mostly in favor of buccal film. Buccal film also had higher daily doses and wider dosing range. Conclusion: Buprenorphine film is more cost-effective cLBP treatment with more flexible dosing.

Limaprost and the Risk of Bleeding: A Self-Controlled Case Series Study.

To investigate the association between the use of limaprost and the risk of bleeding. A self-controlled case series analysis was conducted using the National Health Insurance Service-National Sample Cohort database in South Korea. We identified patients aged 18 years or older who had at least one prescription of limaprost and were diagnosed with at least one case of bleeding between 2003 and 2019. The incidence rate ratio (IRR) of bleeding was calculated by dividing the incidence rate in the exposed period to limaprost by that in the unexposed period and adjusted for age using conditional Poisson regression model. Among 72,860 patients with limaprost prescriptions and bleeding diagnoses, there were 184,732 events of bleeding. After adjusting for age, the IRR was 1.47 (95% confidence interval [CI], 1.43-1.50), wherein the IRR was the highest during the 0-7 days after limaprost initiation (IRR, 2.11; 95% CI, 2.03-2.18). Risk of bleeding was higher when limaprost was concomitantly used with antithrombotics or other drugs for spinal stenosis treatment, and when higher daily doses of limaprost were administered. Our findings suggest that the risk of bleeding increased by 1.5-fold in periods of limaprost exposure compared to unexposed periods, with particularly higher risks observed during the first week after limaprost initiation, with concomitant drugs related to bleeding, and with a higher daily dose. A careful risk-benefit assessment is warranted when initiating limaprost, especially when administered with other medications or in higher daily doses.

Clinical efficiency and safety of riamilovir under various dosage regimens for treatment of acute respiratory viral infections in adults

To evaluate the clinical efficacy and safety of antiviral drug riamilovir in patients with acute respiratory viral infections (ARVI) of non-coronavirus (SARS-CoV-2) etiology with different dosing regimens. The study included 150 patients with ARVI aged 18-27 years (50 patients received riamilovir in the regimen of 250 mg 3 times a day for 5 days, 50 patients received riamilovir in the off label regimen of 250 mg 5 times a day for 5 days, 50 patients received only pathogenetic treatment). The use of riamilovir in both treatment regimens led to a reduction in the duration of inpatient treatment. The shortest periods of hospitalization were noted in patients who received the study drug at higher daily dosages. The use of riamilovir reduced the duration and severity of general infectious manifestations of the disease, while the shortest total duration of fever and a number of respiratory tract syndromes was registered among people who received riamilovir in the regimen of 1250 mg per day for 5 days, no adverse events were registered, additionally, 100% elimination of ARVI pathogens was noted in 1250 mg per day group. Riamilovir has shown clinical efficacy and a good safety profile in in both treatment regimens. The dosage regimen of 1250 mg per day led to more significant clinical effects and to 100% elimination of ARVI pathogens in the study group by the 6th day of hospitalization.

Abstract C152: Preclinical and emerging Phase 1 study data indicates that novel deuterated MET kinase inhibitor DO-2 mitigates the side effects seen with current approved MET kinase inhibitors: Preventing deleterious ‘de-hinging’ to improve tolerability

Abstract Introduction. MNNG HOS transforming gene (MET) kinase inhibitors have demonstrated clinical activity in patients with non-small cell lung cancer (NSCLC) harboring exon14 (METex14) skipping mutations, validating this as an actionable drug target. High daily doses (500-800mg daily) are needed to reach sufficient plasma exposure of active drug to achieve sufficient target engagement to drive efficacy. However, these high doses are associated with toxicities that frequently lead to dose interruptions and reductions which negatively impact efficacy. Background. The 2nd generation of selective Type 1b MET inhibitors (capmatinib, tepotinib, savolitinib), with more soluble metabolites than the 1st generation inhibitors (SGX-523, JNJ-38877605, PF-04217903), have shown efficacy in the clinic. However, they still carry the metabolic liability of the 1st generation agents translating into high levels of circulating metabolites that are not active against the MET kinase, necessitating high daily doses to achieve sufficient active drug exposures. These inactive ‘de-hinged’ metabolites (which are unable to interact with a key recognition site located in the ‘hinge region’ of the MET kinase) remain in the circulation, leading to ‘off-target’ toxicities which are not linked to efficacy, but often necessitates dose reductions and/or-interruptions. Experimental procedures. Based on a detailed understanding of the metabolic liabilities of type 1b MET kinase inhibitors and using site specific deuteration of the key metabolic hotspot, we have used the Kinetic Deuterium Isotope Effect (KDIE) to overcome a metabolic liability that negatively impacts current agents. Summary of the new, unpublished data. The resulting deuterated compound DO-2, is well tolerated and highly potent in pre-clinical xenograft studies (MED ~0.2mg/kg: MTD >50mg/kg), brain penetrant (Kp, uu, brain ; 0.3 in rats), with low once daily doses (3mg/kg) causing complete and sustained cures of all animals (8/8) carrying well established ~300mm3 MET exon14 xenografts. IND enabling toxicology studies in rabbit (most relevant species for metabolism) have shown that the renal effects of the predecessor JNJ-38877605 were no longer apparent with DO-2 at efficacious exposure levels. Based on the pre-clinical efficacy and toxicology data, DO-2 has entered the clinic in a Phase 1 study (NCT05752552), where early data indicates that the improved preclinical profile translates into the clinic with increased active drug exposure when compared to the non-deuterated JNJ-38877605. Conclusion. Preclinical data and emerging clinical data from highly MET inhibitor sensitive MET exon14 tumours as well as in other less sensitive MET driven tumors indicate that DO-2 has the potential to mitigate the side effects seen with current approved MET kinase inhibitors, leading to better tolerability and lower inactive metabolite levels and at lower daily dose levels. Supporting preclinical data and emerging clinical data will be presented. Citation Format: Timothy P.S. Perera, Laurence Mevellec, Hans Prenen, Bernd Dekeyser, Debbie Robbrecht, Sander Bins, Barend Sikkema, Peter de Bruijn, Jean-Pascal Machiels, Rachel Galot, Damien Briol, Richard Knight, Irena Loryan, Yang Hu, Florence Wastelin, Jaap Verweij. Preclinical and emerging Phase 1 study data indicates that novel deuterated MET kinase inhibitor DO-2 mitigates the side effects seen with current approved MET kinase inhibitors: Preventing deleterious ‘de-hinging’ to improve tolerability [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C152.

Therapeutic Drug Level Monitoring of Antipsychotics at an Inpatient Psychiatric Hospital.

The American Psychiatric Association guidelines for the treatment of patients with schizophrenia state that the utility of antipsychotic therapeutic drug monitoring (TDM) remains unclear, except for clozapine or assessing adherence. The aim of this study was to investigate the extent and impact of antipsychotic TDM in inpatient practice to improve its utilization. Patients with antipsychotic blood levels drawn between May 1, 2021 and January 31, 2023 were invited to consent for retrospective chart data analysis to determine the influence of antipsychotic blood levels on their treatment. Approximately 42% of patients consented. Data collected from the patients' electronic medical records included age, ethnicity, race, sex, diagnosis, comorbidities, adverse drug reactions, medications, doses and frequency, antipsychotics and levels, laboratory values, and treatment history. Comparisons were made between antipsychotic levels that were within and outside the therapeutic range and the status of antipsychotic regimen adjustments. A total of 135 antipsychotic levels from 40 inpatients were analyzed. Approximately 48% of the levels were appropriately drawn, whereas 52% were inappropriately drawn. Clozapine had the highest TDM rate (59%) and the most common diagnoses were schizophrenia (45%) and schizoaffective disorder (32.5%). More levels were appropriately drawn for clozapine (47.3% versus 24.3%) than for risperidone (41% versus 46.2%). Appropriately drawn clozapine levels correlated with higher daily doses and levels at or above the therapeutic threshold of 350 ng/mL. Most antipsychotic drug levels were inappropriately drawn, emphasizing the complexity and potential for errors in TDM. Although more patients were prescribed risperidone, clozapine had the highest TDM rate. Clinicians were more likely to keep antipsychotic regimens unchanged for appropriately drawn levels and adjust doses for inappropriately drawn levels.

Beta-blockers effects according to sex: does selectivity and dose equally matter?

Abstract Background β-blockers are one of the four recommended disease-modifying classes of drugs for the treatment of heart failure with reduced ejection fraction (HFrEF). Although their efficacy and prognostic role is unquestionable in the general population of HFrEF patients, the differences in their effect in relation to sex have not been yet investigated in detail. The present study analyzed a large, real-world, Italian population of HFrEF patients aiming to highlight any prognostic difference between males and females in relation to dose and β-selectivity of the ongoing β-blocker treatment. Methods Out of the 7900 HFrEF patients included in the MECKI score registry, we retrospectively analyzed those treated with β-blockers. We investigated the prognostic role of β-selectivity, dividing the population in assuming β1/β2-receptor blockers (carvedilol) vs. β1-selective blockers (bisoprolol, nebivolol or metoprolol), according to sex, and the prognostic role of daily carvedilol-equivalent β-blocker dose in relation to sex. The primary outcome of the study was the composite of all cause mortality, urgent heart transplant and LVAD implant analyzed at 5 years, both as raw data and after correction of potential confounders. Results 6784 HFrEF patients treated with β-blockers were analyzed (1215 females, 5569 males). Patients median follow-up was 4.05 years [1.72-7.47]: 4.37 [1.6-8.13] for females and 3.99 [1.75-7.3] for males (p=ns). According to β-selectivity no prognostic differences were found in the general population, as in female or males (Fig. 1 right panel). Stratification of patients according to β-blockers equivalent dose showed significant difference among groups: mortality decreases with increasing β-blockers dose in both males and females (Fig. 1, left panel), both at baseline and after adjustment for the main confounders (LVEF, age, peakVO2, systolic pressure, hemoglobin, rest heart rate; VE/VCO2 slope, etiology. ICD, MDRD). Conclusions In a large, real-life population of chronic HFrEF patients analyzed according to sex, no prognostic differences were found between stratifying for β-selectivity. A better outcome was observed in subjects receiving a high daily dose, independently from sex.Fig 1Table 1