Psoriasis is a chronic immune-mediated inflammatory systemic disease that mainly affects skin. Secukinumab is an anti-interleukin-17A agent approved for the treatment of moderate-to-severe psoriasis that has probed efficacy and safety both in clinical trials and in real-world practice. Secukinumab data sheet dose approved in maintenance response phase for adults with psoriasis is 300mg monthly. Recently, dose optimization for biologic therapies in psoriasis has been proposed in order to individualise the treatment looking for better treatment adherence and better cost-effectiveness due to their high costs. In this scenario, we report our real-world experience in dose optimization for patients with moderate-to-severe psoriasis treated with Secukinumab.

Dose optimization in computed tomography (CT) is crucial, especially in CT fluoroscopy (fluoro-CT) used for real-time navigation, affecting both patient and operator safety. This study evaluated the impact of spectral X-ray filtering using a tin filter (Sn filter), and a method called partial-angle computed tomography (PACT), which involves segmentally switching off the X-ray tube current at the ambient dose rate H˙*(10) at the interventional radiologist\'s (IR) position. Measurements were taken at two body regions (upper body: head/neck; lower body: lower legs/feet) using a 120 kV X-ray tube voltage, 3 × 5.0 mm CT collimation, 0.5 s rotation speed, and X-ray tube currents of 43 Eff.mAs (without Sn filter) and 165 Eff.mAs (with Sn filter). The study found significant dose reductions in both body regions when using the Sn filter and PACT together. For instance, in the upper body region, the combination protocol reduced H˙*(10) from 11.8 µSv/s to 6.1 µSv/s (p < 0.0001) compared to the protocol without using these features. Around 8% of the reduction (about 0.5 µSv/s) is attributed to the Sn filter (p = 0.0005). This approach demonstrates that using the Sn filter along with PACT effectively minimizes radiation exposure for the IR, particularly protecting areas like the head/neck, which can only be insufficiently covered by (standard) radiation protection material.

OBJECTIVE: To describe nurse preparation and administration of intermittent carbapenem infusions.
METHODS: This observational study documented the carbapenem infusion process to adult patients in three general intensive care units.
METHODS: Timing and duration of infusions were observed. Volumetric analysis of infusion items was conducted to determine loss of reconstituted carbapenem during preparation and administration phases.
RESULTS: Carbapenem infusions (n = 223) administered to twenty adult patients were observed. Infusion duration guidance was variable, with two ICUs following current literature recommendations, and one ICU referring to medication package insert information. Within these parameters, only 60 % of infusions complied with infusion duration. Non-compliance with planned time of administration impacted on desired dosing intervals. Incomplete delivery of intended dose was found during: sub-optimal reconstitution of vials, incorrect number of vials reconstituted, failure to administer a dose (missed dose), and discarding antibiotic residue in infusion items. Volumetric analysis of infusion items showed mean dose losses of 4.9 % and 1.2 % in discarded vials and syringes. Mean drug losses of 6.3 % and 30.8 % occurred in discarded infusion bags and infusion lines respectively. No flushing guidance or practice was observed.
CONCLUSIONS: Incorrect nurse administration of antibiotics resulted in varying durations of infusions and the non-delivery of prescribed dose. Under-dosing has the potential to contribute to selection pressure for bacterial antibiotic resistance. The increasing frequency of intravenous delivery of antimicrobial agents through infusions requires an understanding of the required duration of administration and how to manage residual drug remaining in the intravenous line once the infusion is completed.
CONCLUSIONS: Flushing of administration lines is not common practice following intermittent antimicrobial infusions. Although there are multi-factorial risk factors for antimicrobial resistance in the critical care arena, nurse infusion practice must ensure that patients receive intended antimicrobial treatment. Attention must be given to the potential for antimicrobial resistance from environmental contamination with the disposal of infusion items containing undelivered antimicrobial medication.

Loratadine is metabolized to desloratadine. Both of them have been used for allergy treatment in children. Anatomical, physiological, and biological parameters of children and clearance of drugs vary with age. We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to simultaneously predict the pharmacokinetics of loratadine and desloratadine in children. Following validation using 11 adult data sets, the developed PBPK model was extrapolated to children. Plasma concentrations following oral loratadine or desloratadine to children of different ages were simulated and compared with six children data sets. After scaling anatomy/physiology, protein binding, and clearance, pharmacokinetics of the two drugs in pediatric populations were satisfactorily predicted. Most of the observed concentrations fell within the 5th-95th percentile range of the simulations in 1000 virtual children. The predicted area under the concentration-time curve (AUC) and Cmax fell within 0.5-2.0-fold range of the observations. Oral doses of loratadine or desloratadine for children of different ages were simulated based on similar AUCs following 10 mg of loratadine or 5 mg of desloratadine for adults. Pediatric PBPK model was successfully developed to simultaneously predict plasma concentrations of loratadine and desloratadine in children of all ages. The developed pediatric PBPK model may also be applied to optimize pediatric dosage.

Dose optimization is a critical challenge in drug development. Historically, dose determination in oncology has followed a divergent path from other non-oncology therapeutic areas due to the unique characteristics and requirements in Oncology. However, with the emergence of new drug modalities and mechanisms of drugs in oncology, such as immune therapies, radiopharmaceuticals, targeted therapies, cytostatic agents, and others, the dose-response relationship for efficacy and toxicity could be vastly varied compared to the cytotoxic chemotherapies. The doses below the MTD may demonstrate similar efficacy to the MTD with an improved tolerability profile, resembling what is commonly observed in non-oncology treatments. Hence, alternate strategies for dose optimization are required for new modalities in oncology drug development. This paper delves into the historical evolution of dose finding methods from non-oncology to oncology, highlighting examples and summarizing the underlying drivers of change. Subsequently, a practical framework and guidance are provided to illustrate how dose optimization can be incorporated into various stages of the development program. We provide the following general recommendations: 1) The objective for phase I is to identify a dose range rather than a single MTD dose for subsequent development to better characterize the safety and tolerability profile within the dose range. 2) At least two doses separable by PK are recommended for dose optimization in phase II. 3) Ideally, dose optimization should be performed before launching the confirmatory study. Nevertheless, innovative designs such as seamless II/III design can be implemented for dose selection and may accelerate the drug development program.

OBJECTIVE: To provide data on radiation exposure in paediatric interventional cardiology procedures, addressing the scarcity of valuable Local Diagnostic Reference Levels (LDRLs),established according to the standardized approach proposed by the Radiation Protection 185 report (RP185).
METHODS: Paediatric catheterization procedures conducted at the University-Hospital of Padua from September 2019 to December 2022 were stratified by body weight (BW) classes and procedure type. LDRLs were calculated for groups with at least 20 patients as the 75th percentile of Kerma-Area Product (PKA) and Air Kerma at reference point (Ka,r) values. Kruskal-Wallis test was applied to evaluate differences in the dose-related quantities among BW groups for a selected procedure and among procedures for the same BW class. Results were compared with recent literature.
RESULTS: A total of 838 procedures were analysed. LDRL were provided for five therapeutic procedures. The 75th percentile of PKA and Ka,r increases with weight, regardless procedure type. PKA and Ka,r are generally statistically different between BW groups, for both diagnostic and therapeutic procedures, and between different procedures at fixed weight group. Angioplasty and Right Ventricular Outflow Tract treatments (PVR) showed exposure values approximately doubled then other procedures. PKA/(BW·FT) is not statistically different among procedures except for Atrial Septal Defect (ASD) closures. LDRL values from this study are generally lower than the published ones.
CONCLUSIONS: The study stands out as one of the few that presents a considerable number of LDRLs for weight categories and procedure types with a sample size of at least 20 patients per group, in agreement with RP185. PKA shows strong correlation with the product BW·FT.

UNASSIGNED: Traditional dose selection for oncology registration trials typically employs a one- or two-step single maximum tolerated dose (MTD) approach. However, this approach may not be appropriate for molecularly targeted therapy, which tends to have toxicity profiles that are markedly different than cytotoxic agents. The US Food and Drug Administration launched Project Optimus to reform dose optimization in oncology drug development and has recently released a related guidance for industry.
UNASSIGNED: We propose a \"three steps toward dose optimization\" procedure, in response to these initiatives, and discuss the details in dose-optimization designs and analyses. The first step is dose escalation to identify the MTD or maximum administered dose with an efficient hybrid design, which can offer good overdose control and increases the likelihood of the recommended MTD being close to the true MTD. The second step is the selection of appropriate recommended doses for expansion (RDEs), based on all available data, including emerging safety, pharmacokinetics, pharmacodynamics, and other biomarker information. The third step is dose optimization, which uses data from a randomized fractional factorial design with multiple RDEs explored in multiple tumor cohorts during the expansion phase to ensure a feasible dose is selected for registration trials, and that the tumor type most sensitive to the investigative treatment is identified.
UNASSIGNED: We believe using this three-step approach can increase the likelihood of selecting an optimal dose for a registration trial that demonstrates a balanced safety profile while retaining much of the efficacy observed at the MTD.

Effective treatment of sepsis not only demands prompt administration of appropriate antimicrobials but also requires precise dosing to enhance the likelihood of patient survival. Adequate dosing refers to the administration of doses that yield therapeutic drug concentrations at the infection site. This ensures a favorable clinical and microbiological response while avoiding antibiotic-related toxicity. Therapeutic drug monitoring (TDM) is the recommended approach for attaining these goals. However, TDM is not universally available in all intensive care units (ICUs) and for all antimicrobial agents. In the absence of TDM, healthcare practitioners need to rely on several factors to make informed dosing decisions. These include the patient\'s clinical condition, causative pathogen, impact of organ dysfunction (requiring extracorporeal therapies), and physicochemical properties of the antimicrobials. In this context, the pharmacokinetics of antimicrobials vary considerably between different critically ill patients and within the same patient over the course of ICU stay. This variability underscores the need for individualized dosing. This review aimed to describe the main pathophysiological changes observed in critically ill patients and their impact on antimicrobial drug dosing decisions. It also aimed to provide essential practical recommendations that may aid clinicians in optimizing antimicrobial therapy among critically ill patients.

It remains unclear whether dosage adjustment of intravenous lidocaine is necessary during general anesthesia for elderly patients over 75 years old. This study aimed to investigate the effects of age on the pharmacokinetics (PK) and safety of intravenous lidocaine in patients undergoing general anesthesia. A total of 599 plasma samples were collected from 76 general anesthesia patients across three age groups: 18-64, 65-74, and ≥ 75 years. Lidocaine was administered intravenously at a dose of 1.5 mg/kg for the 18-64 and 65-74 years groups, while the dose was adjusted to 1.0 mg/kg for the ≥ 75 years group. The plasma concentrations of lidocaine and its active metabolites were measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were analyzed using a noncompartmental analysis. The results revealed no significant age-related differences in the PK of lidocaine and its metabolites. Among the three age groups, over 90 % of patient achieved a lidocaine concentration within a safe and effective range when the dosage was normalized to 1.5 mg/kg. In conclusion, age-based dosage adjustment was unnecessary for intravenous lidocaine in patients below 86 years undergoing general anesthesia.

Dose selection and optimization in early phase of oncology drug development serves as the foundation for the success of late phases drug development. Bivariate Bayesian logistic regression model (BLRM) is a widely utilized model-based algorithm that has been shown to improve the accuracy for identifying recommended phase 2 dose (RP2D) based on dose-limiting-toxicity (DLT) over traditional method such as 3 + 3. However, it remains a challenge to optimize dose selection that strikes a proper balance between safety and efficacy in escalation and expansion phase of phase I trials. In this paper, we first use a phase I clinical trial to demonstrate how the variability of drug exposure related to pharmacokinetic (PK) parameters among trial participants may add to the difficulties of identifying optimal dose. We use simulation to show that concurrently or retrospectively fitting BLRM model for dose/toxicity data from escalation phase with dose-independent PK parameters as covariate lead to improved accuracy of identifying dose level at which DLT rate is within a prespecified toxicity interval. Furthermore, we proposed both model- and rule-based methods to modify dose at patient level in expansion cohorts based on their PK/exposure parameters. Simulation studies show this approach leads to higher likelihood for a dose level with a manageable toxicity and desirable efficacy margin to be advanced to late phase pipeline after being screened at expansion phase of phase I trial.