Dosing Regimens Research Articles

Tranexamic dosing for major joint arthroplasty in adult patients with chronic kidney disease: A pharmacokinetic study and new dosing regimen.

Tranexamic acid is an anti-fibrinolytic agent routinely used during hip and knee joint replacement surgery to minimize bleeding. Chronic kidney disease is a common chronic health problem seen among adults requiring major arthroplasty surgery. Tranexamic acid is renally cleared and may accumulate in chronic kidney disease. Optimal tranexamic acid dosing and dose adjustment for chronic kidney disease patients needing major arthroplasty is unknown. The objective of this study was to serially measure plasma tranexamic acid concentrations in patients with varied kidney function undergoing hip or knee replacement surgery for population pharmacokinetic modelling and to guide new dosing recommendations. Prospective cohort study enrolled 21 adults undergoing hip or knee replacement surgery between June 2020 - September 2022. Based on estimated glomerular filtration rate (eGFR), patients were stratified into good (≥ 60 mL/min/1.73 m2) and poor (< 60 mL/min/1.73 m2) renal function. Serial blood samples were taken to measure plasma tranexamic acid concentration levels (primary outcome) after an intravenous tranexamic acid 20 mg/kg bolus dose post anesthesia induction. Secondary clinical outcomes included adverse events (thromboembolic events, seizures), red cell transfusion, mortality, length of hospital stay. Analyses used curve stripping and population pharmacokinetic modelling and simulation. Plasma tranexamic acid concentration levels were higher in patients with poor renal function and clearance compared to good renal function. Population pharmacokinetic modelling tested various tranexamic acid bolus and maintenance infusion regimens. Simulations revealed single bolus tranexamic acid administration leads to rapid rise and decline in plasma concentrations. We identified that plasma tranexamic acid levels of 50-75 mg/L were maintained for approximately 4 hours using a tranexamic acid bolus infusion of 15 mg/kg over 15 min together with a maintenance infusion of 7.5 mg/kg/h or 5 mg/kg/h for 2 hours for the good and poor renal function groups, respectively. There was no difference in secondary outcomes. Using population pharmacokinetic modelling and simulation, we recommend a new dosing regimen to optimize the anti-fibrinolytic effect of tranexamic acid and avoid excessive dosing.

Characteristics of Patients with Hereditary Angioedema Who Reduced Lanadelumab Treatment Administration Frequency: A Retrospective Observational Study of US Claims Data.

Lanadelumab is the only long-term prophylaxis indicated for reduced administration frequency in patients with hereditary angioedema who have been well controlled for > 6 months. Understanding the characteristics of patients who reduce administration frequency will help identify populations where frequency modifications may be appropriate. We aimed to describe characteristics of patients who did and did not reduce lanadelumab administration frequency to inform real-world dosing regimens, and characteristics indicative of sustained frequency reduction. A retrospective observational study using healthcare insurance data in the USA from the Merative™ MarketScan® Commercial and Medicare Databases identified patients persistent on lanadelumab for ≥ 18 months. Reduced administration frequency was defined as a ≥ 25% decrease in lanadelumab costs during months 7-12 or 13-18 versus 0-6. Hereditary angioedema attack triggers/symptoms and hereditary angioedema-related healthcare encounters, treatment, and costs were assessed. Of 54 identified patients, 25 reduced administration frequency. Two patients returned to initial dosing frequency during months 13-18 after reducing during months 7-12. Patients who reduced administration frequency experienced fewer hereditary angioedema attack triggers/symptoms before lanadelumab initiation (baseline) and during months 0-6 than those who did not; they also had a lower mean number of hereditary angioedema-related inpatient admissions, emergency room visits, and outpatient visits during baseline, had fewer claims for acute treatment (60.0% vs 65.5%) and prior long-term prophylaxis (20.0% vs 27.6%), and had lower mean hereditary angioedema treatment costs at baseline ($139,520 vs $233,815) than those who did not. This real-world analysis suggests that patients with less frequent hereditary angioedema-related healthcare encounters, lower disease activity, and lower costs within 6 months before lanadelumab initiation are more likely to achieve reduced dosing frequency.

The Effectiveness of Budesonide Once Daily as Maintenance Treatment of Eosinophilic Esophagitis.

Swallowed topical corticosteroids (STC) are an effective first-line therapy for patients with eosinophilic esophagitis (EoE), both for induction and maintenance of remission. All interventional trials with STC used twice-daily dosing regimens. However, in other inflammatory gastrointestinal disorders, corticosteroids are given once daily (OD) with equal outcomes and improved compliance. To evaluate the effectiveness of topical budesonide maintenance treatment in a once-daily dosing schedule. Retrospective analysis of confirmed patients with EoE, treated with topical budesonide as maintenance therapy OD, with adequate follow-up available. Patients currently treated with budesonide were contacted to fill out online questionnaires regarding symptoms and health-related quality of life (HRQOL). The primary end point was histologic remission, defined as peak eosinophil count (PEC) <15 eosinophils per high power field (HPF) after >12 weeks of budesonide OD. We included 29 patients on STC OD (1mg, N=28; 0.5mg, N=1), either budesonide orodispersible tablet (BOT, Jorveza, Dr. Falk Pharma; N=12) or budesonide viscous solution (BVS; N=17). After a median follow-up of 767 days on OD dosing (range: 103 to 2396), 86% of patients were in histologic remission. Four patients had histologic disease activity, of which one was treated with BOT. Two patients experienced a slight increase in PEC after dose reduction of BVS to OD (to PEC of 25 and 35/HPF, respectively). However, after switching the formulation to BOT OD they achieved histologic remission. In this retrospective study, we demonstrated favorable results in the majority of patients treated with budesonide 1mg OD as maintenance treatment for eosinophilic esophagitis.

Model-Informed Recommendation of Mavacamten Posology for Chinese Adults With Obstructive Hypertrophic Cardiomyopathy.

Mavacamten is a cardiac myosin inhibitor for adults with obstructive hypertrophic cardiomyopathy (HCM). Dose optimization is performed 4 weeks after starting mavacamten, guided by periodic echo measurements of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Previously, a population pharmacokinetic (PPK) model was developed and exposure-response (E-R) of VLVOTg (efficacy) and LVEF (safety) was used to identify the mavacamten titration regimen with the optimal benefit/risk ratio, now included in the US prescribing information. Mavacamten is metabolized primarily by cytochrome P450 2C19 (CYP2C19) (74%), a highly polymorphic enzyme. China has a higher prevalence of poor CYP2C19 metabolizer phenotype compared with the global population; therefore, a previous model was adapted to include Chinese patients with obstructive HCM to identify the optimal dosing regimen for this population. Data from a phase I (healthy Chinese volunteers) and a phase III (EXPLORER-CN, NCT05174416; Chinese patients with obstructive HCM) trial of mavacamten were added to the previous PPK and E-R models, and the observed VLVOTg and LVEF from EXPLORER-CN were successfully simulated. Next, five echocardiography-guided titration regimens (plus the EXPLORER-CN regimen) using representative or equal CYP2C19 phenotypes were simulated. The final simulated regimen recommended with an optimal benefit/risk profile across CYP2C19 phenotypes included: down-titration at Week 4 (if VLVOTg < 20 mmHg), restart at Week 12, and up-titration at Week 12 (for VLVOTg ≥ 30 mmHg and LVEF ≥ 55%), and every 12 weeks thereafter. This supports the previously recommended regimen for Chinese patients with obstructive HCM, now approved by the National Medicinal Products Administration.

Corticosteroids in severe alcohol-associated hepatitis? Not so fast: A systematic review of randomized controlled trials.

Severe alcohol-associated hepatitis (AH) is rising in incidence with a high mortality burden. While corticosteroids are recommended for eligible patients with severe AH, no guidance exists for the timing of steroid initiation, tapering regimens, and surveillance of adverse events. We aim to systematically review these variables and provide evidence-based recommendations for the inpatient and outpatient management of severe AH. We performed a literature search from inception to 5/30/2024 to include clinical trials published in full form and assessed the quality of evidence using the Cochrane Risk of Bias tool. Data were collected on the timing of initiation, rate, and complications following steroid therapy, and taper regimens in the setting of severe AH. Of 28 studies that fulfilled our inclusion criteria, median time from admission to steroid initiation was 6.5 days. The most common steroid dosing regimen was prednisolone 40mg daily for 28 days. Twenty-five studies containing 3,196 subjects reported adverse events, with exactly 50% in the steroid arm and the other half in the comparison arm. Infections, gastrointestinal bleeds, and renal impairment were the most frequently reported adverse events. Most infections occurred within the first month of the study. A two-week steroid taper was the most frequently reported regimen. We recommend taking up to a week to systematically and thoroughly evaluate patients before initiating steroids, and vigilant monitoring in the first month of treatment. We also recommend the lowest possible steroid exposure with a two-week steroid taper and close outpatient follow-up.

Semi-mechanistic efficacy model for PARP + ATR inhibitors-application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs.

Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges. A semi-mechanistic pharmacokinetic-pharmacodynamic model of tumour growth inhibition was developed to investigate the efficacy of PARP and ATR inhibitors as monotherapies, and in combination. Key features of the DNA damage response were incorporated into the model to allow the emergence of synthetic lethality, including redundant DNA repair pathways that may be impaired due to genetic mutations, and due to PARP and ATR inhibition. Model parameters were calibrated using preclinical in vivo data for PARP inhibitors rucaparib and talazoparib and the ATR inhibitor gartisertib. The model successfully captured the monotherapy efficacies of rucaparib and talazoparib, as well as the combination efficacy with gartisertib. The model was evaluated against multiple tumour xenografts with diverse genetic backgrounds and was able to capture the observed heterogeneity of response profiles. By enabling simulation of in vivo tumour growth inhibition with PARP and ATR inhibitors for specific tumour types, the model provides a rational approach to support the optimisation of dosing regimens to stratified populations.

Lipid-Lowering Efficiency and Safety of Alirocumab 300 mg Using a 2-mL Autoinjector Device in Real-World Practice: The MARS Study.

Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 used for the reduction of low-density lipoprotein cholesterol (LDL-C) in high-risk patients not reaching their LDL-C target. Recently, a 2-mL prefilled autoinjector has been developed to support the monthly 300-mg dosing regimen with a single-injection administration. Monthly application of 300 mg AlirRocumab (Praluent®) using the 2-mL SYDNEY Device (MARS) is a non-interventional, open, prospective, multi-center cohort study conducted in Germany between 2021 and 2023 with an observational period of 12 weeks. Patients included had primary hypercholesterolemia (heterozygous familial or non-familial) or mixed dyslipidemia and confirmed vascular disease and other risk factors or confirmed familial heterozygous hypercholesterolemia. Primary objectives were to assess the effectiveness of the 2-mL SYDNEY autoinjector measured by the lipid-lowering effect of alirocumab and to document therapy satisfaction, patient adherence, and persistence. Secondary objectives were to assess safety (adverse events) and tolerability. A total of 146 patients were analyzed: 110 (75.3%) patients were proprotein convertase subtilisin kexin type 9 inhibitor naïve and 36 (24.7%) were pre-treated with a proprotein convertase subtilisin kexin type 9 inhibitor. Patient mean age was 65.6 years with a preponderance of male gender (59.6%). At 12 weeks, the LDL-C value had decreased by a median of 59.5 mg/dL (1.5 mmol/L) in naïve patients (median relative decrease: -52.0%). In the pre-treated group, the LDL-C value remained mainly unchanged (median slight numerical relative increase: 1.6%). Treatment satisfaction was rated similarly in both groups with most patients being satisfied/very satisfied and rating the injection as effective, safe, and easy to handle. Twenty-three adverse events in 13 patients (8.0%) were documented. Three patients experienced one serious adverse event each; for five patients, an adverse drug reaction was observed, although none was serious. The occurrence of adverse events was similar in both groups. Alirocumab 300 mg administered with the 2-mL SYDNEY autoinjector was safe and effective in lowering LDL-C after 12 weeks in a routine clinical setting in Germany. The treatment schedule was perceived to be beneficial with excellent device acceptance and satisfaction, potentially increasing patient adherence. Clinicaltrials.gov: NCT05129241.

Cotadutide reversible self-assembly based long-acting injectable depot for sustained delivery of GLP-1 glucagon receptor agonists with controlled burst release.

Cota is a lipidated dual GLP-1 and Glucagon receptor agonist that was investigated for the treatment of various metabolic diseases, it is designed for once daily subcutaneous administration. Invasive daily injections often result in poor patient compliance with chronic disease, and here, we demonstrate an innovative strategy of encapsulating reversible cota self-assembled fibers within an in-situ forming depot of low molecular weight poly(lactic-co-glycolic) acid (LWPLGA) for sustained delivery GLP-1 and Glucagon receptor agonist with controlled burst release. This could be a suitable alternative to other sustained delivery strategies for fibrillating peptides. We investigated a range of cationic ions (Na+, Ca2+, Zn2+) and studied their influence on the secondary structure, morphology and the monomer release profile of cota fibers. Fibers forming hierarchy structures such as twisted filament and ribbons with beta sheet secondary structure resulted in better controlled burst. The subcutaneous (SC) administration of Ca2+ fiber/LWPLGA depot formulation in rats resulted in 60-fold reduction in maximum concentration (Cmax) compared with cota immediate release (IR) SC formulation and a prolonged plasma exposure over a month with plasma half-life extended from the 10 h observed with the cota daily formulation to 100 h. This extended-release formulation also maintains smaller peak and trough fluctuation within therapeutic window, and PK modelling of repeated dose indicates this formulation could enable a possible dose frequency of 14 days in rat with assumed therapeutic concentration (ratios of the maximum concentration and the trough concentration) Cmax/Ctrough window. This new long-acting injectable (LAI) method could open the door to transforming short-life peptides with sub-optimal half-life into candidates for weekly or even monthly dosing regimens, potentially leading to novel drug products which and increased patient comfort.

Optimising pirfenidone dosage regimens in idiopathic pulmonary fibrosis: towards a guide for personalised treatment

Idiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disorder for which pirfenidone is the recommended first-line anti-fibrotic treatment. While pirfenidone has demonstrated efficacy in slowing the progression of IPF, its use is associated with several challenges and unresolved issues that impact patient outcomes. Pirfenidone administration can result in gastrointestinal side effects, photosensitivity reactions, and significant drug interactions, particularly in patients with hepatic impairment. For those who experience intolerable side effects, dose reductions or temporary discontinuations are frequently employed. However, there is limited data on the efficacy of reduced doses, creating uncertainty about the balance between tolerability and therapeutic benefit. The aim of this study is to evaluate the currently proposed dosage adjustments and to develop new dosage regimens tailored to the needs of patients. Simulations were conducted to explore pirfenidone pharmacokinetics under various challenging conditions, including dose titration, withdrawal, retitration, moderate and severe hepatic impairment, co-administration of moderate (e.g. omeprazole) and strong (e.g. smoking) inducers of the CYP1A2 enzyme, gastrointestinal adverse events, and photosensitivity reactions. Simulations led to specific recommendations for physicians regarding dosage regimens in each condition. The recommended dosage adjustments are designed to maintain concentrations within acceptable levels, ensuring both safe and effective treatment.

Population Pharmacokinetic Modelling of Apixaban in End-Stage Kidney Disease Patients with Atrial Fibrillation Receiving Haemodialysis.

Apixaban is increasingly being usedfor stroke prevention in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis, but no pharmacostatistical model is available for dosage adjustment. This study aimed to develop a population pharmacokinetic model of apixaban in these patients to characterise its dialytic clearance and determine optimal dosing regimens and discontinuation timing before surgery. Patients received 2.5 mg of apixaban twice daily for 9 days, followed by 5 mg twice daily for 8 days after a 5-day washout period (NCT02672709). Apixaban concentrations were measured on and off dialysis. A population pharmacokinetic model was developed using parametric and non-parametric methods. Simulations were performed to assess plasmatic exposure and the time to reach clinically relevant apixaban concentrations after treatment discontinuation for seven dosing regimens and 13 dialysis schedules. A total of 289 apixaban concentrations were measured, including 85 during haemodialysis. The best model was a two-compartment model with first-order elimination. Dialytic clearance was estimated at 1.20 L/h with high inter-individual variability. Apixaban daily exposure was proportional to the total daily dose, independent of dosing frequency and dialysis timing. The standard discontinuation period of 48-72 h before surgery was insufficient to achieve clinically negligible concentrations in patients undergoing haemodialysis. We propose the first pharmacokinetic model to characterise apixaban clearance in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis. Simulations suggest that dialysis timing is not critical for monitoring apixaban, and the discontinuation period before surgery should be extended beyond current recommendations.

Biodegradable polymeric microsphere formulations of full-length anti-VEGF antibody bevacizumab for sustained intraocular delivery.

Age-related macular degeneration (AMD) is one of the leading causes of central vision loss in the elderly population. Bevacizumab, a full-length humanized monoclonal anti-VEGF antibody, is commonly used off-label drug to treat AMD. However, the dosing regimen of bevacizumab and other anti-VEGF antibodies requires monthly intravitreal injections followed by regular intravitreal injections at 4-16-week intervals. In 2021, the FDA approved an innovative port delivery system of ranibizumab (Susvimo®) that can be implanted intravitreally to slowly release the active ingredient anti-VEGF antibody and reduce injection frequency to once every 6 months. An approach utilizing polymeric slow-release microspheres encapsulating a full-length antibody, such as bevacizumab, would be much more patient-friendly because it could be injected intravitreally, avoiding surgical implantation. While microsphere encapsulation is traditionally successful for small molecule hydrophobic drugs, we assessed two different polymers, namely poly(D, L-lactide-co-glycolide) (PLGA) and poly(epsilon-caprolactone) (PCL) and discovered the benefits of utilizing a slow degrading hydrophobic polymer such as PCL for large protein therapeutic. Using the traditional double emulsion fabrication method with PCL polymer, we could produce microspheres that encapsulate bevacizumab antibody and demonstrate the release of biologically active therapeutic agent for up to 60 days. This novel approach could lead to significant advancements in our field and potentially open new avenues for future research.

Effect of Target-Mediated Disposition on Iptacopan Clinical Pharmacokinetics in Participants with Normal or Impaired HepaticFunction.

Iptacopan, a first-in-class complement factor B inhibitor acting proximally in the alternative complement pathway, has been shown to be safe and effective for patients with complement-mediated diseases. Iptacopan selectively binds with high affinity to factor B, a soluble, plasma-based, hepatically produced protein. Factor B is abundant in the circulation but can be saturated at the iptacopan clinical dose of 200 mg twice daily. Iptacopan pharmacokinetics (PK) are influenced by target binding. This target-mediated drug disposition (TMDD) behavior makes PK data useful for understanding target occupancy and motivates modeling of drug-target binding to connect exposure with pharmacological effect. A phase I hepatic impairment (HI) PK study measuring both total and unbound iptacopan PK profiles provided an opportunity to characterize the effect of variation in target concentration (due to varying hepatic function) on iptacopan PK. HI caused no change in total iptacopan exposure but increased unbound iptacopan exposure 1.38- to 3.72-fold in participants with mild, moderate, or severe HI relative to demographically matched participants with normal hepatic function, with the largest increases in severe HI. A two-site competitive binding model was developed to elucidate the relationship between iptacopan PK and factor B occupancy to characterize exposure thresholds for maximal target engagement. The model was used to assess alternative dose regimens to provide insight into how to approach dose recommendations for patients with severe HI. This study provides an example of small-molecule TMDD, a behavior typically associated with targeted biologics; its importance is too often underappreciated in small-molecule drug development.

Toward effective oxytocin interventions in autism: Overcoming challenges and harnessing opportunities.

Intranasal administration of oxytocin is emerging as a potential pharmacological option for mitigating social difficulties and regulating stress in autism spectrum disorder. However, initial single-dose and multiple-dose trials showed mixed results, with some demonstrating improvements in social and repetitive behavior and others showing no benefit over placebo. This perspective aims to elucidate factors contributing to this variability and to highlight pitfalls and opportunities in the field. We identified two major factors: design-related elements and individual participant characteristics. Pertaining to design-related elements, optimal dosing regimens have yet to be established, but appear to favor moderate intervention durations (i.e., 4-6 weeks) with intermittent and intermediate dosing (i.e., 24-32 IU every other day). Also, the context of the intervention seems crucial, as enhanced outcomes are mainly observed when oxytocin administration is paired with a socially stimulating and supporting environment. In addition, more adequate outcome measures have to be established to effectively assess oxytocin's impact, including behavioral scales and objective biophysiological markers tapping into stress and neurophysiological regulation. Future research should also account for individual participant differences in biological sex, developmental stage and cognitive and adaptive functioning, and incorporate (epi)genetic screening to identify responders. Overall, refining study designs and personalizing intervention protocols are essential for optimizing oxytocin's prosocial and anxiolytic effect in autism.

Population pharmacokinetic analysis of teicoplanin in paediatric patients, including those receiving continuous kidney replacement therapy: a prospective cohort study.

Teicoplanin is a commonly used antibiotic in critically ill children. However, teicoplanin dosing is often inaccurate, especially in children undergoing continuous kidney replacement therapy (CKRT). This study aims to develop a population pharmacokinetic (PK) model to optimize teicoplanin dosing in critically ill children, including those on CKRT. Data from 26 critically ill children (12 with CKRT) receiving the standard dosing regimen were analysed. In total, 172 teicoplanin concentration measurements from plasma, pre- and post-filter ports were modelled simultaneously using NONMEM 7.4. Simulations were conducted to assess the target attainment (Cmin = 10 mg/L and AUC24/MIC > 800 h) of the current standard dosing regimen and of different alternative dosing regimens. A two-compartment model was selected. Weight significantly affected renal clearance and volume of distribution of the central compartment, while filter surface area affected haemofilter clearance. Only 16 patients (59%) achieved a Cmin of >10 mg/L with the standard dosing regimen, and only 1 achieved the target AUC/MIC. Based on simulation results, 3 × 15 mg/kg q12h + 10 mg/kg q24h (CKRT) and 3 × 15 mg/kg q12h + 15 mg/kg q24h (no CKRT) could be better alternative regimens. This population model is a good proof of concept to develop modelling approaches that could help in an individualized dosing approach that needs to be adopted in critically ill paediatric patients. The standard paediatric dosage for teicoplanin could be insufficient for optimal exposure, and higher doses may benefit both CKRT and non-CKRT patients.

Dexamethasone-based Prophylactic Therapy for Prevention of Post-Embolization Syndrome: A Systematic Review and Meta-Analysis Assessing its Efficacy and Influence of Dosage and Timing in Patients Undergoing Arterial Embolization.

Post-embolization syndrome (PES), characterized by pain, fever, nausea, and vomiting, is a common but non-serious adverse event following arterial embolization, negatively impacting patient satisfaction with the procedure. This study aimed to evaluate the efficacy of dexamethasone-based prophylactic therapy in preventing PES, as well as to assess the effects of its dosage and timing of administration. A systematic search was conducted across three databases, two trial registries, and citation searches to identify relevant studies. Data related to postoperative pain, fever, nausea, and vomiting were extracted and meta-analyzed using a random-effects model and the Mantel-Haenszel method. Meta-regression was performed to examine the role of dexamethasone dose and timing of administration as mediators. Dexamethasone-based prophylactic therapy significantly reduced the risk of postoperative pain (RR=0.58, 95% CI: 0.48-0.69; P<0.00001), fever (RR=0.36, 95% CI: 0.22-0.61; P<0.00001), nausea (RR=0.52, 95% CI: 0.41-0.67; P<0.00001), and vomiting (RR=0.54, 95% CI: 0.36-0.82; P=0.004) compared to placebo or no treatment. A higher dose of dexamethasone was associated with a significantly lower incidence of postoperative pain (P=0.038). Regarding timing, postoperative and continuous (extending throughout the perioperative period) administration, was more effective than preoperative administration (P=0.024; P=0.007). A dosage of 6-12 mg was particularly effective in reducing the risk for all four symptoms. Dexamethasone effectively prevents PES in patients undergoing arterial embolization. An optimal protocol may involve a divided dose regimen within the range of 6-12 mg, extending throughout the recovery period for maximum benefit.

Optimization of treatment of endothelial dysfunction and arterial stiffness in patients with arterial hypertension and ischemic heart disease

The relevance of complex correction of endothelial dysfunction and arterial stiffness in patients with arterial hypertension and coronary heart disease is associated with their leading role in the development of cardiovascular diseases. Endothelial dysfunction, characterized by a deficiency of vasodilators, such as nitric oxide, and an increase in vasoconstrictor mediators, contributes to atherogenesis and thrombosis. At the same time, an increase in arterial stiffness leads to an increase in systolic pressure and impaired diastolic filling of the myocardium, which aggravates myocardial ischemia and contributes to the progression of heart failure. The introduction of an integrative approach to optimizing endothelial function and reducing arterial stiffness into clinical practice can significantly improve the prognosis and quality of life of patients, reducing the risk of serious cardiovascular events, including myocardial infarction and stroke. Results from randomized clinical trials support the efficacy of such a strategy, demonstrating that normalization of endothelial function and reduction in arterial stiffness are achievable with modern antihypertensive and lipidlowering drugs, including polypills. These drugs improve treatment adherence through simplified dosing regimens and provide effective management of multifactorial risks in patients. In addition, ongoing research and development of new therapeutics and treatments continue to highlight the need for early detection and targeted therapy in this patient population. Such strategies not only address the underlying pathophysiological changes but also aim to prevent long-term complications associated with these cardiovascular risk factors. By focusing on an individualized treatment protocol that includes both pharmacologic interventions and lifestyle changes, healthcare providers can offer a more dynamic and effective treatment plan that meets each patient’s individual needs, thereby optimizing therapeutic outcomes and improving patient compliance.Background. Cardiovascular diseases are the leading cause of death in Russia, with hypertension, coronary heart disease, and cerebrovascular disease predominating. The prevalence of hypertension is 53.9 %, but disease control remains poor, with less than 30 % of patients achieving target blood pressure levels. Therapy often includes combinations of medications, such as ACE inhibitors and angiotensin receptor blockers, which demonstrate advantages over monotherapy. Approximately 70.7 % of patients require combination therapy to effectively manage their condition.Objective. Comparison of the effects of fixed combinations of amlodipine, atorvastatin and perindopril (Lipertance® 10/20/10 mg) with a combination of amlodipine, lisinopril and rosuvastatin (Equamer® 5/10/20 mg) on the clinical progression of grade 2 and 3 arterial hypertension and functional class II and III coronary heart disease. Also study the effect on arterial stiffness, endothelial function, ankle-brachial index, vascular age.Materials and methods. The study included 65 patients with uncontrolled hypertension with systolic blood pressure (BP) ≥160 mmHg and/or diastolic BP ≥90 mmHg in combination with stable angina, taking two antihypertensive drugs at the beginning of the study. Depending on the therapy, the participants were divided into II groups: I – 30 people receiving a fixed combination of Lipertance; II group – 35 people taking a fixed combination of Equamer. All patients also received bisoprolol at a dosage of 5–10 mg and an antiplatelet agent at a dosage of 75–100 mg.Conclusions. Fixed combinations of Lipertance® and Equamer® drugs were highly effective in controlling blood pressure in patients with hypertension and coronary heart disease, achieving target systolic and diastolic levels in more than 85 % of patients. Both groups showed significant improvements in arterial stiffness and endothelial function, demonstrating their potential to reduce cardiovascular complications. Thus, these combinations can be recommended for routine use in clinical practice to improve prognosis and quality of life in patients.

Efficacy and safety of JMT103 in patients with bone metastases from solid tumors: A randomized Phase Ib clinical trial.

This study aimed to assess the efficacy and safety of three dosing regimens of JMT103 in patients with bone metastases from solid tumors. Eligible patients were randomly assigned to receive JMT103 subcutaneously, 120 mg every 4 weeks (Cohort 1), 120 mg every 8 weeks (Cohort 2), or 180 mg every 8 weeks (Cohort 3) for up to 49 weeks. The primary endpoint was change from baseline to Week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Two hundred and ninety-five patients were randomized, and 293 received at least one dose of JMT103, of whom 96 were assigned to Cohort 1, 97 were assigned to Cohort 2, and 100 were assigned to Cohort 3. The median (interquartile range) percentage reduction in uNTx/Cr at Week 13 was 80.0% (49.9%, 93.4%) in Cohort 1, 73.0% (34.5%, 94.0%) in Cohort 2, and 75.7% (40.4%, 92.0%) in Cohort 3, respectively. On-study skeletal-related events were reported by 3.1% of patients in Cohort 1, 6.2% in Cohort 2, and 7.0% in Cohort 3. Treatment-emergent adverse events occurred in 289 patients, 162 of whom were deemed treatment-related. The most common treatment-related adverse events were hypocalcemia (23.2%), hypophosphatemia (22.9%), and increased aspartate transaminase (11.9%). JMT103 demonstrated a good safety and a strong suppression of the bone turnover markers.

P0639 Population pharmacokinetics of subcutaneous vedolizumab in Crohn’s disease and Ulcerative Colitis

Abstract Background Vedolizumab is a monoclonal antibody used for the treatment of inflammatory bowel disease (IBD). The pharmacokinetics (PK) of intravenously (IV) administered vedolizumab have been described previously.1 We aimed to develop a population PK model for subcutaneous (SC) vedolizumab and to evaluate whether current dose regimens are appropriate for SC dosing. Methods Data for model development were prospectively collected in a cohort of 61 patients with IBD receiving IV vedolizumab (300mg at week 0-2-6, thereafter every 4-11 weeks) who switched to SC treatment (108 mg every 2 weeks, Q2W). The PRIOR subroutine in NONMEM2 was used to develop a two-compartment population PK model for IV and SC vedolizumab including linear and non-linear clearance. The model was validated with goodness of fit plots, a visual predictive check and bootstrapping (n = 1000). Final model estimates were used to perform simulations in a virtual population (n = 10 000) with a white blood cell count of 7 x 109/L, randomly sampled serum albumin (mean = 44 g/L, SD = 3.0) and bodyweight (mean 77 kg, SD = 14), based on the distribution of the original dataset. Trough concentrations for an IV regimen of 300 mg vedolizumab once in 8 weeks were compared with SC regimens of 108 mg once in 2, 3, 4 and 5 weeks. For SC vedolizumab, we defined a target serum concentration of 26 mg/L, based on previously reported exposure-efficacy data.3 Results A patient with a bodyweight of 70 kg, serum albumin of 40 g/L and a white blood cell count of 7 x 109/L had a bioavailability of 66.8%, an absorption rate constant of 0.0938/day and a linear clearance of 0.157 L/day. The inter-individual variability for linear clearance was 22.9%. Most important predictors for linear clearance were serum albumin with a negative, and bodyweight and white blood cell count with a positive correlation. In the virtual population, 2.3-fold higher average trough concentrations were estimated for the SC-Q2W regimen (32 mg/L) compared to the IV-Q8W regimen (14 mg/L). Trough concentrations of at least 26 mg/L were achieved in 76% of virtual patients receiving SC vedolizumab every 2 weeks. Virtual patients with a serum vedolizumab concentration higher than 42 mg/L with Q2W dosing could de-escalate to Q3W, while still achieving a trough concentration of 26 mg/L (18% of virtual patients). Conclusion The development and evaluation of a population PK model for IV and SC vedolizumab was successful. This model could be used in the considerations of an extended SC dose regimen. Our results highlight the importance of defining clear targets for SC vedolizumab in clinical practice.

Humoral and cellular immune durability of different COVID-19 vaccine platforms following homologous/heterologous boosters: one-year post vaccination

IntroductionThe durability of Hybrid immunity induced by natural infection and/or COVID-19 vaccines and evidence supporting further booster vaccination are crucial factors for pandemic response, yet remain poorly understood.MethodsWe measured the durability of immune response and neutralizing capacity of antibodies following Homologous/Heterologous vaccination by mRNA-based vaccines (Pfizer-BioNTech BNT162b2) or (Moderna mRNA-1273) and viral vector-based vaccines (ChAdox1 nCoV-19-Oxford-AstraZeneca) in infected and non-infected patients. We also evaluated the long-lasting specific humoral IgG levels and T-cell immunity of the Memory CD8 cells.ResultsWe found that heterologous prime boosters led to significantly higher IgG antibody levels)9.09(than homologous boosters)5.236) one year after vaccination. We measured SARS-CoV-2 anti-S IgG antibodies and then assessed their neutralizing capacity to inhibit the receptor-binding domain (RBD) of the SARS-CoV-2 wild-type strain and omicron B.1.1.529/BA.2 variants from binding to the ACE2 receptors. The heterologous regiment demonstrated superior ACE2-binding inhibition and consistently had higher mean ACE2-receptor binding inhibition across all dose regimens without the need for further doses. The CD8+ T cells producing IFN-γ to various COVID-19 vaccine dose regimens were evaluated. We found that robust T cell mediated immune responses were preserved and largely induced by a heterogeneous vaccination eliciting a significantly higher CD8+ T cells IFN-γ response in 100% of vaccinees regardless of previous natural infection. Indeed, the difference between infected and naïve groups was less pronounced suggesting a reduced infection-related response.DiscussionAcross three layers of evidence, this study showed that heterologous vaccination provides longer-lasting immunity than homologous doses, regardless of prior natural infection.

Variable temocillin protein binding and pharmacokinetics in different clinical conditions: Implications for target attainment.

The beta-lactam antibiotic temocillin is increasingly used to treat extended-spectrum beta-lactamase (ESBL-producing) strains; however, its protein binding is complex. This study aims to predict unbound temocillin concentrations in various participant groups to determine its impact on the probability of target attainment (PTA) and to improve dosing recommendations. The plasma pharmacokinetics were analysed using non-linear mixed-effects modelling. Data from individuals in four groups: healthy volunteers (HV), urinary tract infection patients (UTI), ventriculitis patients and sepsis-ICU patients were included. Simulations were performed to compare the PTA for different dosing regimens and participant-groups. A two-compartment protein-binding model best fitted the 1085 concentrations (543 unbound, 542 total). Temocillin clearance was influenced by creatinine clearance, serum albumin (ALB) and C-reactive protein (CRP). For 2g q8h intermittent infusion, the PTAs at an MIC of 16 mg/L were 2.3%, 39.5%, 10.0% and 72.5%, for HV, UTI, ventriculitis and sepsis-ICU patients, respectively. The effects of the covariates on the PTA were simulated for two example patients with intermittent infusion: the PTAs at an MIC of 8mg/L for a sepsis-ICU patient (CRP 300 mg/L, albumin 15 g/L) and a mild-UTI patient (CRP 30 mg/L, albumin 35 g/L) were 94.3% and 62.4%, respectively. Continuous infusion consistently outperformed intermittent infusion in achieving the desired pharmacodynamic target (time above MIC). Our study underscores the significant variation in temocillin clearance and unbound fractions among different participant groups, challenging the efficacy of traditional 2g q12h dosing. For patients with enhanced renal function and lower inflammation, continuous infusion emerges as a more effective strategy to achieve optimal target attainment.