Half-life is a significant pharmacokinetic parameter included in the excretion phase of absorption, distribution, metabolism, and excretion. It is one of the key factors for the successful marketing of drug candidates. Therefore, predicting half-life is of great significance in drug design. In this study, we employed eXtreme Gradient Boosting (XGboost), randomForest (RF), gradient boosting machine (GBM), and supporting vector machine (SVM) to build quantitative structure-activity relationship (QSAR) models on 3512 compounds and evaluated model performance by using root-mean-square error (RMSE), R2, and mean absolute error (MAE) metrics and interpreted features by SHapley Additive exPlanation (SHAP). Furthermore, we developed consensus models through integrating four individual models and validated their performance using a Y-randomization test and applicability domain analysis. Finally, matched molecular pair analysis was used to extract the transformation rules. Our results revealed that XGboost outperformed other individual models (RMSE = 0.176, R2 = 0.845, MAE = 0.141). The consensus model integrating all four models continued to enhance prediction performance (RMSE = 0.172, R2 = 0.856, MAE = 0.138). We evaluated the reliability, robustness, and generalization ability via Y-randomization test and applicability domain analysis. Meanwhile, we utilized SHAP to interpret features and employed matched molecular pair analysis to extract chemical transformation rules that provide suggestions for optimizing drug structure. In conclusion, we believe that the consensus model developed in this study serve as a reliable tool to evaluate half-life in drug discovery, and the chemical transformation rules concluded in this study could provide valuable suggestions in drug discovery.

The pharmacokinetics of contrast media (CM) will determine how long safe waiting intervals between successive CT or MRI examinations should be. The Contrast Media Safety Committee has reviewed the data on pharmacokinetics of contrast media to suggest safe waiting intervals between successive contrast-enhanced imaging studies in relation to the renal function of the patient. CLINICAL RELEVANCE STATEMENT: Consider a waiting time between elective contrast-enhanced CT and (coronary) angiography with successive iodine-based contrast media administrations in patients with normal renal function (eGFR > 60 mL/min/1.73 m2) of optimally 12 h (near complete clearance of the previously administered iodine-based contrast media) and minimally 4 h (if clinical indication requires rapid follow-up). KEY POINTS: • Pharmacokinetics of contrast media will guide safe waiting times between successive administrations. • Safe waiting times increase with increasing renal insufficiency. • Iodine-based contrast media influence MRI signal intensities and gadolinium-based contrast agents influence CT attenuation.

Pharmacokinetic (PK) studies in pregnant, postpartum, and breastfeeding people are critical to informing appropriate medication use and dosing. A key component of translating PK results in these complex populations into clinical practice involves the systematic review and interpretation of data by guideline panels, composed of clinicians, scientists, and community members, to leverage available data for informed decision making by clinicians and patients and offer clinical best practices. Interpretation of PK data in pregnancy involves evaluation of multiple factors such as the study design, target population, and type of sampling performed. Assessments of fetal and infant drug exposure while in utero or during breastfeeding, respectively, are also critical for informing whether medications are safe to use during pregnancy and throughout postpartum in lactating people. This review will provide an overview of this translational process, discussion of the various factors considered by guideline panels, and practical aspects of implementing certain recommendations, using the HIV field as an example.

Fixed-dose and body mass index (BMI)-based enoxaparin regimens provide inadequate venous thromboembolism (VTE) prophylaxis for many trauma patients. The purpose of this study was to evaluate the effectiveness of a novel blood volume (BV)-based enoxaparin guideline vs a historical BMI-based guideline for VTE prophylaxis in trauma patients.
This was a retrospective pre/post study completed at a large academic level 1 trauma center. All adult trauma patients admitted from October through December 2019 and August through October 2020 who received prophylactic enoxaparin per guideline were included. The BV dosing was as follows: patients with a BV of 3 to 4.9 L received enoxaparin 30 mg every 12 hours, those with a BV of 5 to 6.9 L received 40 mg every 12 hours, and those with a BV of ≥7 L received 60 mg every 12 hours. The primary outcome was the percentage of patients who attained a target anti-factor Xa (anti-Xa) postdosing level at the first steady-state assessment (0.2 to 0.5 IU/mL).
A total of 241 patients (99 for the BMI group and 142 for the BV group) were included. The study groups had a median age of 38 vs 42 years, a mean BMI of 27.4 vs 27.7 kg/m2, and a mean BV of 5.1 vs 5.1 L, respectively. A total of 63 patients (62.6%) in the BMI group attained target anti-Xa levels compared to 115 patients (81%) in the BV group (P = 0.008). In multivariate regression, the BV-based guideline was the only variable associated with attainment of target anti-Xa levels (adjusted odds ratio, 2.02; P = 0.01). Clinically relevant bleeding and VTE rates were similar between the groups.
Dosing prophylactic enoxaparin using a BV-based dosing guideline significantly increased attainment of target anti-Xa levels.

Although aminoglycosides are frequently prescribed to neonates and children, the ability to reach effective and safe target concentrations with the currently used dosing regimens remains unclear. This study aims to evaluate the target attainment of the currently used dosing regimens for gentamicin in neonates and children. We conducted a retrospective single-center cohort study in neonates and children receiving gentamicin between January 2019 and July 2022, in the Beatrix Children\'s Hospital. The first gentamicin concentration used for therapeutic drug monitoring was collected for each patient, in conjunction with information on dosing and clinical status. Target trough concentrations were ≤1 mg/L for neonates and ≤0.5 mg/L for children. Target peak concentrations were 8-12 mg/L for neonates and 15-20 mg/L for children. In total, 658 patients were included (335 neonates and 323 children). Trough concentrations were outside the target range in 46.2% and 9.9% of neonates and children, respectively. Peak concentrations were outside the target range in 46.0% and 68.7% of neonates and children, respectively. In children, higher creatinine concentrations were associated with higher gentamicin trough concentrations. This study corroborates earlier observational studies showing that, with a standard dose, drug concentration targets were met in only approximately 50% of the cases. Our findings show that additional parameters are needed to improve target attainment.

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with substance use (SU) and/or substance use disorder (SUD). Individuals with concurrent ADHD and SU/SUD can have complex presentations that may complicate diagnosis and treatment. This can be further complicated by the context in which services are delivered. Also, when working with young people and adults with co-existing ADHD and SU/SUD, there is uncertainty among healthcare practitioners on how best to meet their needs. In February 2022, the United Kingdom ADHD Partnership hosted a meeting attended by multidisciplinary experts to address these issues. Following presentations providing attendees with an overview of the literature, group discussions were held synthesizing research evidence and clinical experience. Topics included: (1) A review of substances and reasons for use/misuse; (2) identification, assessment and treatment of illicit SU/SUD in young people and adults with ADHD presenting in community services; and (3) identification, assessment and treatment of ADHD in adults presenting in SU/SUD community and inpatient services. Dis-cussions highlighted inter-service barriers and fragmentation of care. It was concluded that a multimodal and multi-agency approach is needed. The consensus group generated a table of practice recommendations providing guidance on: identification and assessment; pharmacological and psychological treatment; and multi-agency interventions.

Clinical guidelines for progestin-only pills (POPs) state that each pill should be taken at the same time each day, with only a \"three-hour window\" of tolerance before back-up contraception should be used. In this commentary, we summarize studies examining the timing of ingestion and mechanisms of action for various POP formulations and dosages. We found that different progestins have different properties that determine the effect of delayed or missed pills on effectiveness at preventing pregnancy. Our findings highlight that there is more margin for error for some POPs than guidelines suggest. The three-hour window recommendation should be re-evaluated in light of these findings. Since clinicians, potential POP users, and regulatory bodies rely on current guidelines to make decisions about POP use, a critical evaluation and update of these guidelines are urgently needed.

Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.
多黏菌素B是治疗广泛耐药革兰氏阴性细菌感染的最后“一道防线”，但因剂量限制性肾毒性及低剂量可能出现治疗失败和耐药性，临床上迫切需要通过治疗药物监测（TDM）优化其使用。多黏菌素B TDM专家共识以及规范操作程序的制定将有助于确保TDM的准确性并为其合理使用提供依据。中国药理学学会治疗药物监测研究专业委员会及上海医学会感染与化疗专科分会共同发起制定多黏菌素B的TDM专家共识。共识小组由来自中国不同省份的临床药学、临床医学和临床微生物学专家，及两位澳大利亚莫纳什大学专家组成，就多黏菌素B进行TDM的目标浓度、样本采集、测定、报告和TDM结果解释提出了建议。该指南共识的制定旨在指导多黏菌素B的个体化精准治疗。.

OBJECTIVE: Sophisticated scientific methods have facilitated dose individualisation with substantial advancements in therapeutic drug monitoring (TDM) practice. It is unclear whether these methods have translated to the clinical setting. This study aimed to determine current TDM practice for tobramycin monitoring in cystic fibrosis (CF) centres in the USA and Canada, UK and Ireland, and Australia and New Zealand due to a high prevalence of CF.
METHODS: A web-based survey was developed and circulated via CF specialist groups within the targeted geographical regions. Themes included centre demographics, tobramycin usage, dosing and infusion practices, TDM practices, and blood sampling methods.
RESULTS: In total 77 responses were received from 75 different CF centres over the 3-month evaluation period (October 2019-January 2020). Respondents were from the USA and Canada (60%), Australia and New Zealand (25%), and the UK and Ireland (15%). Tobramycin was used in 97% of sites, with an international variation in practice across all survey aspects including dosing and infusion practice. TDM-based dose adjustment in the UK and Ireland was most commonly based only on trough sample collection for avoidance of toxicity, where use of computer programs for targeting both efficacy and toxicity endpoints were most common in Australia and New Zealand. The underlying pharmacokinetic basis of that program was not known by 33% of sites who utilised a computer program for tobramycin dose individualisation.
CONCLUSIONS: There remains substantial heterogeneity in tobramycin management worldwide. Despite two decades of research into TDM of tobramycin, there has been a slow uptake of new technologies and evolution of practice. An improved understanding of TDM processes is required for translation of evidence-based research into clinical practice. International guidelines require updating due to the advances in research to support confidence in the changes in clinical practice.

OBJECTIVE: Chemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT3-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking. The current study was developed to investigate the effect of aprepitant on dexamethasone clearance (CL) in children, in order to assess if dexamethasone dose reduction for concomitant use of aprepitant is appropriate in the current antiemetic regimen.
METHODS: In total, 65 children (0.6-17.9 years), receiving intravenous or oral antiemetic therapy (dexamethasone ± aprepitant) as standard of care, were included. 305 dexamethasone plasma concentrations were determined using LC-MS/MS. An integrated dexamethasone and aprepitant pharmacokinetic model was developed using non-linear mixed effects modelling in order to investigate the effect of aprepitant administration on dexamethasone CL.
RESULTS: In this population, dexamethasone CL in patients with concomitant administration of aprepitant was reduced by approximately 30% of the uninhibited CL (23.3 L/h (95% confidence interval 20.4-26.0)). This result is not consistent with the results of adult studies (50% reduction). This difference was not age dependent, but might be related to the route of administration of dexamethasone. Future studies are needed to assess the difference in oral/intravenous dexamethasone.
CONCLUSIONS: When dexamethasone is given intravenously as a component of triple therapy to prevent CINV in children, we advise to reduce the dexamethasone dose by 30% instead of 50%.