Dosing Strategies Research Articles

Encuesta nacional y elaboración de un documento de consenso sobre estrategias de dosificación de antibióticos beta-lactámicos frente a bacterias gramnegativas multirresistentes (BGN-MDR) en pacientes críticos sometidos a técnicas de soporte vital extracorpóreas: protocolo de estudio DOSEBL

IntroductionInfections caused by multidrug-resistant gram-negative bacilli (MDR-GNB) in critically ill patients present a challenge for timely and appropriate antibiotic treatment. This is particularly important in patients undergoing extracorporeal life support techniques such as renal replacement therapy and extracorporeal membrane oxygenation. These techniques can introduce additional pharmacokinetic alterations, potentially leading to suboptimal exposure to antibiotics. This study aims to outline dosing strategies and therapeutic drug monitoring protocols for new β-lactam antibiotics effective against MDR-GNB in critically ill patients undergoing extracorporeal life support techniques at a national level. Additionally, the study seeks to develop a consensus document, based on available evidence. MethodsThe project will comprise two main phases: I) A national survey, and II) the development of a consensus document. This consensus document, undertaken according to ACCORD guidelines, will encompass: a) establishment of a multidisciplinary panel of experts, b) prospective registration of the consensus, c) evidence synthesis, d) modified Delphi rounds. The antimicrobials to be included will be: meropenem, ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, and aztreonam. Extracorporeal life support techniques will include continuous renal replacement therapy, conventional intermittent hemodialysis, and extracorporeal membrane oxygenation. DiscussionThe availability of extracorporeal life support techniques has expanded significantly in recent years, alongside a rise in the prevalence of infections caused by multidrug-resistant gram-negative bacilli (MDR-GNB). There is a need to develop evidence-based tools of high quality to standardize dosing and monitoring strategies for new β-lactam antibiotics.

A Dose-Finding, Biomarker Validation, and Effectiveness Study of Transcranial Magnetic Stimulation for Adolescents With Depression

Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder (MDD) has advanced slowly. Significant gaps persist in our understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1 Hz versus 10 Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF). Participants with moderate-to-severe symptoms of MDD were randomized to 30 sessions of left prefrontal 1 Hz or 10 Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale, Revised (CDRS-R). The CDRS-R and ICF biomarker were collected weekly. Forty-one participants received either 1 Hz (n = 22) or 10 Hz (n = 19) TMS treatments. CDRS-R scores improved compared to baseline in both 1 Hz and 10 Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for the group treated with 1 Hz TMS than for those who received 10 Hz TMS. There were no significant changes in weekly ICF measurements across the 6 weeks of TMS treatment. Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate (NMDA) receptor activity that facilitates the therapeutic effect of 1 Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, trait-like measure of NMDA receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with MDD.

Impact of dosing strategy on clinical outcomes of patients with lupus nephritis initially treated with lower-than-recommended-dose cyclophosphamide

AimCyclophosphamide is the mainstay treatment for patients with lupus nephritis (LN); it can be prescribed at lower doses than the recommended regimen to avoid side effects. We aimed to investigate the impact of cyclophosphamide dosing strategies on treatment outcomes of patients with LN initially treated with a lower-than-recommended dose. MethodsWe retrospectively reviewed patients with proliferative LN (class III, IV, or mixed) initially treated with lower-than-recommended-dose cyclophosphamide. Patients who received a titrated dose of cyclophosphamide ≥0.5 g/m2 were categorized into the titrate group, while those who received doses <0.5 g/m2 were categorized into the non-titrate group. The primary outcome was primary renal response (PRR) at 52 weeks. ResultsOf the 78 patients included, 47 were assigned to the titrate group and 31 to the non-titrate group. The titrate group had a higher proportion of PRR achievement (23 of 47 patients [48.9 %] vs. 7 of 31 patients [22.6 %] in the non-titrate group). After adjusting for potential confounders, a baseline urinary protein-to-creatinine ratio ≥3 g/g (OR, 0.3; 95 % CI, 0.1–0.9; P = 0.030), and titrating the dose of cyclophosphamide to ≥0.5 g/m2 (OR, 4.7; 95 % CI, 1.5–15.2; P = 0.010) were independent factors for PRR. Additionally, the titrate group had a lower rate of infection (8 of 47 patients [17.0 %] vs. 12 of 31 patients [38.7 %], respectively; OR, 0.3; 95 % CI, 0.1–0.9; P = 0.036) and death associated with LN (4 of 47 patients [8.5 %] vs. 8 of 31 patients [25.8 %], respectively; OR, 0.3; 95 % CI, 0.1–0.9; P = 0.047) compared with the non-titrate group. LN flare and the need for rescue therapy did not differ between the groups. ConclusionFor patients with LN initially treated with lower-than-recommended-dose cyclophosphamide, titration of the cyclophosphamide dose ≥0.5 g/m2 was beneficial on renal response, while reducing infection leading to hospitalization and LN-associated death.

Influence of patient body weight on the probability of return of spontaneous circulation following out-of-hospital cardiac arrest: an exploratory analysis.

In addition to key interventions, including bystander CPR and defibrillation, successful resuscitation of out-of-hospital cardiac arrest (OHCA) is also associated with several patient-level factors, including a shockable presenting rhythm, younger age, Caucasian race and female sex. An additional patient-level factor that may influence outcomes is patient weight, yet this attribute has not been extensively studied within the context of OHCA, despite globally increasing obesity rates. To assess the relationship between patient weight and return of spontaneous circulation (ROSC) during OHCA. This retrospective study included adult patients from a national emergency medical services (EMS) patient record, with witnessed, non-traumatic OHCA prior to EMS arrival from January to December 2020. Logistic regression was used to evaluate the relationship between patient weight and ROSC. Complete records were available for 9096 patients, of which 64.3% were males and 25.3% were ethnic minorities. The mean age of the participants was 65.01 years (SD = 15.8), with a mean weight of 93.52 kg (SD = 31.5). Altogether, 81.8% of arrests were of presumed cardiac aetiology and 30.3% presented with a shockable rhythm. Bystander CPR and automated external defibrillator (AED) shock were performed in 30.6% and 7.3% of cases, respectively, and 44.0% experienced ROSC. ROSC was less likely with patient weight >100 kg (OR = 0.709, p <0.001), male sex (OR = 0.782, p <0.001), and increasing age and EMS response time (OR = 0.994 per year, p <0.001 and OR = 0.970 per minute, p <0.001, respectively). Patients with shockable rhythms were more likely to achieve ROSC (OR = 1.790, p <0.001), as were patients receiving bystander CPR (OR = 1.170, p <0.001) and defibrillation prior to EMS arrival (OR = 1.658, p <0.001). Although the mean first adrenaline dose (mg/kg) followed a downward trend due to its non-weight-based dosing scheme, the mean total adrenaline dose administered to achieve ROSC demonstrated an upward linear trend of 0.05 mg for every 5 kg of body weight. Patient weight was negatively associated with ROSC and positively associated with the total adrenaline dose required to attain ROSC.

Remimazolam-Update on basic pharmacologic principles and clinical potential

In recent years the still relatively new short-acting benzodiazepine remimazolam has been approved and clinically implemented in several countries and regions. Remimazolam is also now approved in the EU and the market launch in Germany is expected in the not too distant future. This is therefore a good point in time to summarize the current evidence for various areas of application, including general anesthesia, sedation and intensive care medicine as well as different dosing schemes.

A Simulation-Based Assessment of Levetiracetam Concentrations Following Fixed and Weight-Based Loading Doses: A Meta-Regression and Pharmacokinetic Modeling Analysis.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

The impact of hemoadsorption on antimicrobials

Hemoadsorption (HA) is used for supportive blood purification therapy for conditions such as sepsis and immunological diseases. However, it may cause unintentional removal of antimicrobial drugs, potentially offsetting its therapeutic benefits. This review provides an overview of the impact of HA on the clearance of antimicrobials. We reviewed in vitro and in vivo studies on antimicrobial drug removal by HA. Current evidence suggests that HA can significantly affect the clearance of antimicrobials. However, the adsorptive clearance varies widely across different drugs and sorbents, and these interactions cannot be predicted based on molecular weight or characteristics. Drug removal by HA typically decreases over time. Also, the impact of HA on overall clearances is likely highly heterogeneous, depending on the sorbents used, patient, and the intervention applied. Some clinical studies, though limited, suggests the necessity of dose adjustments during HA. Clinicians need to understand these effects and appreciate their magnitude to deliver optimal care. Further investigation is required to provide comprehensive information for dosing, timing, and monitoring strategies during HA.

Lifting With Neuromodulators.

The use of botulinum toxins for facial rejuvenation and improvement of dynamic wrinkles has become a mainstay in the aesthetic treatment armamentarium. However, using these same neuromodulators (NMs) for lifting the structures of the face, is a newer addition to antiaging protocols. The muscles of facial animation all interplay with each other. Lifting can be accomplished by treating those muscles that are responsible for depression, leaving the elevators unopposed and resulting in a rejuvenated, lifted outcome. Brow lifting, cheek lifting, and even contouring of the lower face and jawline are all possibilities using NMs. To review the literature and current practices in techniques for lifting the different anatomic facial zones. The authors present and discuss the published data and personal experiences of using NM for lifting and retraining of the facial musculature. This article will discuss the effects and approaches to lifting with botulinum toxin injections, including the potential success and side effects associated with these off-label injections. The use of botulinum toxins has expanded beyond its traditional use as a reducer of dynamic wrinkles. A significant amount of published data now exists for the off-label use of botulinum toxins for lifting and shaping the face. These can be considered advanced techniques as each region has its own anatomic intricacies and side effects can occur. More placebo-controlled objective data would also help elucidate exact dosing strategies for each region.

Torsemide in the Management of Essential Hypertension.

Torsemide, a loop diuretic, is increasingly recognized for its role in managing essential hypertension. Its mechanism of action involves inhibiting the reabsorption of sodium and chloride ions in the ascending loop of Henle in the kidneys. By doing so, torsemide promotes diuresis, which refers to increased urine production, and subsequently lowers blood pressure. Studies have shown that torsemide is comparably effective to other antihypertensive agents in lowering blood pressure, with the added benefit of potentially improving renal function. However, while torsemide shows promise in hypertensive management, further research is necessary to fully understand its long-term effects and to establish optimal dosing strategies. Future research should focus on clarifying its role in long-term blood pressure control and refining its use in clinical practice to maximize efficacy and minimize adverse effects.

Effects of Switching Dose, Dose Variation, and Warfarin Interaction on the Incidence of Stroke Recurrence in Stroke Patients with Atrial Fibrillation

Atrial fibrillation (AF) significantly increases the risk of stroke, necessitating anticoagulation therapy. Warfarin, a commonly prescribed anticoagulant regimen, requires careful monitoring to ensure patient safety. This study aimed to assess the impact of dose switching, dose variation, and potential interactions with warfarin on the incidence of stroke recurrence in stroke patients with AF. The study retrospectively analyzed the treatment records of stroke patients with AF in outpatient settings over one year. The subjects comprised 314 patients who received warfarin prescriptions at two Indonesian Hospitals from January 1, 2015, to December 31, 2019. Out of these patients, 50 had recorded data regarding dose adjustments, variations, and interactions. They were divided into two groups: a case group (n=11) with stroke recurrence and a control group (n=39) without recurrence. Statistical analysis, including chi-square tests and odds ratio calculations, revealed that both warfarin dose switching (OR=7.6) and dose variation (OR=6.6) significantly influenced the incidence of stroke recurrence. It implies that inconsistencies or alterations in warfarin dosing substantially elevate the likelihood of experiencing another stroke, potentially due to inadequate anticoagulation leading to clot formation. Interestingly, the analysis of drug interactions did not significantly impact stroke recurrence. In summary, the recurrence of stroke in patients with AF is notably influenced by warfarin dose adjustments and variations rather than drug interactions. This study highlights the critical importance of precise dosing strategies and vigilant monitoring to enhance the efficacy of anticoagulant therapy in this high-risk population.

Population pharmacokinetics of eptinezumab in paediatric patients with migraine and dose selection for phase 3 paediatric migraine studies.

This population pharmacokinetics (PopPK) analysis of eptinezumab used data from a paediatric study and a prior adult PopPK model to compare eptinezumab pharmacokinetics between adult and paediatric populations to determine dose recommendations for the phase 3 paediatric studies in migraine. The data consisted of 16 adolescents and 12 children with migraine, with corresponding demographics and 278 plasma concentrations in total. PopPK analysis was performed through nonlinear mixed effect modelling and with prior knowledge taken from a previous PopPK model in adults. A two-compartment model-adjusted for body weight impact on clearances and volumes of distributions and scaled to the power of 0.75 and 1.0, respectively-was found to adequately describe the paediatric pharmacokinetic data. The simulated population showed overlap in area under the plasma concentration-time curve and maximum plasma concentration between the paediatric and adult populations, with paediatric exposures within 10%-15% above adult levels on average. To provide comparable exposure to the approved adult doses, weight-based dosing adjustments are recommended for paediatric patients weighing ≤40 kg, while no adjustments are needed for patients weighing >40 kg. These results support the dosing strategy being used in the ongoing efficacy and safety studies with eptinezumab in children and adolescents with migraine.

Evaluation of Anti-Xa Target Attainment with Prophylactic Enoxaparin Dosing Regimens for Venous Thromboembolism Prophylaxis in Morbidly Obese Patients.

Subcutaneous enoxaparin has been shown to reduce the risk of venous thromboembolism (VTE) among hospitalized patients. However, alternative enoxaparin dosing strategies may be necessary in morbid obesity. The objective of this study was to assess the rate of target anti-Xa attainment with three enoxaparin dosing regimens for venous thromboembolism (VTE) prophylaxis in morbidly obese patients. In this retrospective study, anti-Xa target attainment was assessed among adult patients with a body mass index (BMI) ≥ 40 kg/m2 receiving enoxaparin 40 mg twice daily (BID), 60 mg BID, or 0.5 mg/kg BID. Univariate and multivariate analyses were conducted. Target anti-Xa levels were defined as a steady-state, peak level of 0.2-0.5 IU/mL. This study included 120 patients with 55 patients receiving 40 mg BID, 44 patients receiving 60 mg BID, and 21 patients receiving 0.5 mg/kg BID. Target anti-Xa levels were achieved in 29.1% of patients in the 40 mg BID arm, 54.5% in the 60 mg BID arm, and 90.5% in the 0.5 mg/kg BID arm. Anti-Xa target attainment was significantly increased in both the 60 mg BID arm (p = 0.01) and the 0.5 mg/kg arm (p < 0.0001), compared to the 40 mg BID arm. In morbidly obese patients, weight-based dosing was associated with a greater attainment of target anti-Xa levels. Further studies are needed to determine the impact of these dosing regimens on clinical outcomes.

Analysis of Intravenous Ketamine Bolus in Pediatric Emergency Care

Considering the increasing use of intravenous ketamine in pediatric emergency care, particularly for sedation, analgesia, and management of severe conditions such as traumatic brain injury and suicidal ideation, there is a need to critically evaluate its efficacy and safety in these settings. This study aims to systematically review and analyze various studies that have investigated the use of intravenous ketamine bolus in pediatric emergency care, focusing on its clinical outcomes, safety profile, and overall effectiveness. To achieve this, a narrative literature review was conducted, examining studies published between 2014 and 2023. The review included randomized controlled trials, observational studies, and case reports sourced from reputable databases such as PubMed, Scopus, and Web of Science. The results of the review indicate that intravenous ketamine is effective in providing rapid sedation and analgesia, with a favorable safety profile when administered by trained healthcare professionals. Specifically, it was observed that ketamine significantly reduces pain intensity, lowers suicidal ideation, and effectively manages intracranial pressure in children with severe traumatic brain injury. However, the review also highlights the variability in recovery times and the incidence of mild to moderate side effects, such as dizziness, nausea, and drowsiness. In addition, the need for rescue doses was more frequent in intravenous administration compared to intramuscular routes, though intravenous administration offered quicker onset and shorter duration of action. It is concluded that while intravenous ketamine is a valuable tool in pediatric emergency care, its administration should be carefully monitored, particularly in high-risk patients, to mitigate potential adverse effects. Further research is needed to refine dosing strategies, explore long-term outcomes, and establish standardized protocols to maximize the therapeutic benefits of ketamine while minimizing risks.

Optimal weight-based epinephrine dosing for patients with a low likelihood of survival following out-of-hospital cardiac arrest.

Cardiac arrest patients presenting with non-shockable rhythms have a low probability of survival, and epinephrine is one of the few pharmaceutical options for this group. The recommended 1.0mg adult dose is extrapolated from early animal studies and lacks adjustment for patient weight. Although several prior studies have investigated "low-" and "high-" dose epinephrine, none have identified a benefit to either strategy. To identify an optimal weight-based epinephrine dose for return-of-spontaneous-circulation (ROSC) after a single bolus among patients with low likelihood of survival. Included were adult patients who experienced a witnessed, non-traumatic out-of-hospital cardiac arrest prior to EMS arrival. Patients with shockable presenting rhythms or receiving bystander CPR were excluded. The AUROC was used to assess the predictive value of epinephrine dose (mg/kg) for ROSC following a single bolus. From the ROC curve, the optimal threshold dosage (OTD) was determined using the Youden Index. A logistic regression model calculated the adjusted odds ratio of OTD on ROSC. A total of 2,463 patients met inclusion criteria, of which 190 (7.7%) attained ROSC after the first epinephrine administration. The dosage AUROC for ROSC was 0.603 (p < 0.01). As calculated by the Youden index, the OTD was 0.013mg/kg. Patients receiving ≥ OTD were more likely to attain ROSC after a single epinephrine bolus (OR = 2.25,p < 0.001). Among patients with a low likelihood of survival, the optimal dose of epinephrine for attaining ROSC with a single bolus of epinephrine was 0.013mg/kg. These findings should inspire further investigation into optimal dosing strategies for epinephrine.

Finding individualised treatment in obese needing enoxaparin (FIT ONE): a multicentre study of therapeutic enoxaparin and the role of anti-factor Xa monitoring.

Enoxaparin is dosed according to actual body weight in treatment of arterial and venous thrombosis. Due to its hydrophilic nature, it distributes according to lean body mass which may be problematic when dosing obese patients as this may increase the risk of bleeding events in this population. The aimwasto evaluate current therapeutic enoxaparin dosing strategies, including Antifactor Xa (AFXa) level monitoring, in obese patients and to identify factors that contribute to treatment failure and excess anticoagulation. A retrospective cohort study was conducted reviewing patients administered therapeutic enoxaparin between May 2020 and April 2021. Data were collected on patient characteristics, enoxaparin therapy, AFXa monitoring, and outcomes. Regression models were constructed to assess variables of interest to estimate any association with AFXa levels. In total 762 patients were included in the analysis. The mean initial weight-based dose was 0.95mg/kg twice daily (SD: ± 0.12, IQR 0.92-1.01) and 1.04mg/kg once daily (SD: ± 0.26, IQR 0.93-1.12) and 14.4% of patients had AFXa monitoring. Treatment failure was experienced by 2.2%, 5% experienced bleeding. There was no association between the mean actual milligram per kilogram weight-based twice daily doses and subtherapeutic, therapeutic and supratherapeutic AFXa levels(P = 0.135). Obesity was not includedin the final regression models due to lack of significance. At a mean therapeutic enoxaparin dose of 0.95mg/kg twice daily and 1.04mg/kg once daily no excess in treatment failure or bleeding events were observed in obese patients compared to the product information. Obesity was not an independent variable that affected the achievement of target AFXa levels.

Prostatic Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime: Dosing Strategy for Bacterial Prostatitis.

This study aimed to develop a prostatic pharmacokinetic model of ceftazidime and suggest more effective dosing strategy for the bacterial prostatitis, based on a site-specific pharmacokinetic and pharmacodynamic perspective. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-h infusion of 1.0 g or 2.0 g ceftazidime before transurethral resection of the prostate. Plasma and prostate samples were premeditatedly collected after the administration and the concentrations were measured by high-performance liquid chromatography. The prostate tissue/plasma ratio in area under the drug concentration-time curve was approximately 0.476. The prostatic population pharmacokinetic model incorporated creatinine clearance (CLcr) into ceftazidime clearance was developed, and adequately predicted prostate tissue concentrations by diagnostic scatter plots and visual predictive checks. Aiming for a bactericidal target of 70% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 2.0 g twice daily achieved ≥90% expected probability against main pathogens like Escherichia coli and Proteus species in patients regardless of renal function (CLcr = 60 and 90 mL/min). However, since the expected probability of attaining the bactericidal target of 0.5-h infusion dosing regimen did not achieve 90% against Pseudomonas aeruginosa in patients with CLcr = 60 and 90 mL/min, 4-h infusion dosing regimen of 2.0 g three times daily (6 g/day) might be required for empirical treatment. Based on site-specific simulations, the present study provides more effective dosing strategy for bacterial prostatitis.

Long-Acting Injectable Antipsychotic Initiation in Child and Adolescent Patients with Psychiatric Disorders.

Objectives: There are currently no long-acting injectable antipsychotics (LAIAs) that are approved by the Food and Drug Administration for use in child and adolescent patients, however these agents are used off-label for the treatment of various psychiatric disorders. This study aims to describe the initiation and maintenance dosing strategies of LAIAs in child and adolescent psychiatry inpatients. Methods: This was a single-site retrospective chart review of patients less than 18 years of age initiated on an LAIA during an acute psychiatric hospitalization between October 1, 2015, and October 31, 2022. Patient demographics and hospital encounter information were collected and analyzed using descriptive statistics. Results: Of the 6402 unique pediatric patients discharged from the acute psychiatric hospital within the specified timeframe, 45 (0.7%) were newly initiated on an LAIA. The average age was 15.6 years (range 10-17), with a greater proportion of male (n = 26, 57.8%) and Black or African American (n = 27, 60%) patients. The LAIA agents prescribed included paliperidone palmitate (n = 21, 46.7%), aripiprazole monohydrate (n = 15, 33.3%), aripiprazole lauroxil (n = 7, 15.6%), haloperidol decanoate (n = 1, 2.2%), and risperidone microspheres (n = 1, 2.2%). Primary diagnosis via International Classification of Diseases-10 code at discharge included schizophrenia spectrum and other psychotic disorders (n = 19, 42.2%); bipolar disorder (n = 14, 31.1%); disruptive, impulse control, and conduct disorders (n = 6, 13.3%); autistic disorder (n = 5, 11.1%); and attention-deficit/hyperactivity disorder (n = 1, 2.2%). Seventeen patients (37.8%) received a loading dose regimen and/or a maintenance dose regimen that differed from adult package-insert dosing. The mean length of stay was 23.7 days, and 14 patients (31.1%) were readmitted to the psychiatric hospital within 6 months of discharge. The mean number of days to readmission was 71.9 days. Conclusions: This retrospective study is the first to focus on LAIA initiation and maintenance dosing strategies of multiple agents in both a child and adolescent patient population. Further research is required to evaluate the impact of LAIAs on clinical outcomes in this patient population.

Optimized Dosing and Delivery of Bacteriophage Therapy for Wound Infections.

Lytic bacteriophages, viruses that lyse (kill) bacteria, hold great promise for treating infections, including wound infections caused by antimicrobial-resistant Pseudomonas aeruginosa. However, the optimal dosing and delivery strategies for phage therapy remain unclear. In a mouse wound infection model, we investigated the impact of dose, frequency, and administration route on the efficacy of phage therapy. We find that topical but not intravenous delivery is effective in this model. High-doses of phage reduces bacterial burden more effectively than low-doses, and repeated dosing achieves the highest eradication rates. Building on these insights, we developed "HydroPhage", a hyaluronan-based hydrogel system that uses dynamic covalent crosslinking to deliver high-titre phages over one week. HydroPhage eradicates infections five times more effectively than intravenous injection. We conclude that hydrogel-based sustained phage delivery enhances the efficacy of phage therapy and offers a practical, well-tolerated option for topical application.

Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study.

The optimal infliximabdose intensification strategy to address loss of response associated with subtherapeutic infliximabtrough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. This pharmacokineticsimulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis. A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (<3.00mg/L) trough levels after 30weeks of standard (5mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis >7.50 mg/L, Crohn's disease >9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease >10.10 mg/L) and clinical improvement (ulcerative colitis >3.70 mg/L, Crohn's disease >7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) and intensive (>10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) dosing strategies defined, respectively. The median pre-intensification infliximab trough level was 0.91mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p<0.01). When controlling for cumulative (mg/kg) infliximab dose over 32weeks, strategies that concurrently dose increased and interval shortened achieved the highestinfliximab trough levels (all p<0.01). This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.

Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma.

This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose-response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations.