Diclofenac sodium is a widely prescribed NSAID for inflammatory and rheumatoid diseases, and the dose adjustment, especially for elderly patients suffering from renal or hepatic impairment, is not a routine practice. In this study, a sensitive RP-HPLC bioanalytical method was developed and validated for quantifying diclofenac in human plasma. After quality assessment of different diclofenac sodium brands, a pharmacokinetic study was performed in 12 healthy human subjects and compared with predicted in silico PBPK models in healthy subjects and in patients with renal or hepatic impairment. The bioanalytical method demonstrated sensitivity and linearity from 20 to 3000 ng/mL, with 99.9% accuracy. Stability tests on plasma samples stored long term and subjected to freeze-thaw cycles showed considerable stability at -20°C. Pharmacokinetic parameters included Cmax, Tmax, AUC0-t and AUC0-∞. In silico PBPK modelling indicated that routine monitoring might not be necessary for patients with mild to moderate hepatic or renal impairment. However, significantly higher AUC0-t values were observed in severe cases, end-stage renal disease, cirrhosis B and cirrhosis C, suggesting a need for dose adjustments to mitigate dose-dependent toxicities. This study provides a comprehensive framework for generic manufacturers, regulatory agencies and clinicians for dose optimization, safety prediction and clinical decision support.

Metformin-associated lactic acidosis: Bridging pharmacokinetic determinants, metabolic pathways, and clinical outcomes.

Drug prescribing in critically ill children with kidney impairment: Comparing clinical practice with clinical decision support recommendations.

Relapsed or refractory rhabdomyosarcoma (RMS) has a poor prognosis, and optimal treatment remains an unmet need. Vinorelbine (VNR) and low-dose metronomic cyclophosphamide (CPM) have shown clinical efficacy and are used as maintenance therapy in localized and metastatic disease; however, dose reductions are frequently required due to myelosuppression. This study evaluated the safety, efficacy, and optimal dosing of VNR and CPM in pediatric patients with relapsed or refractory RMS. Pediatric patients treated with VNR and CPM at our institution between March 2014 and May 2024 were retrospectively reviewed. Dosing was based on the RMS 2005 protocol, with dose reductions implemented before or during treatment to minimize treatment interruptions. Eighteen patients received 139 cycles of therapy (median age at initiation, 15.6 years; range, 7-21 years), including 13 relapsed and 5 refractory cases. The median number of cycles administered was 5.5 (range, 1-26), with a median interval of 28 days. The median adjusted dose ratios over three cycles were 55% for VNR and 53.5% for CPM. Disease control lasting longer than 10 months was achieved in six patients (33%). Neutropenia occurred in 89% of patients, whereas anemia and thrombocytopenia requiring transfusion occurred in 28% and 22%, respectively. No grade 4 non-hematologic toxicities or treatment-related deaths were observed after dose adjustment. VNR and continuous low-dose CPM chemotherapy were safe and feasible with dose adjustments. In heavily pretreated patients, initiating therapy at approximately 80% of the standard dose may be appropriate.

Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxicities. Oxidative hepatic metabolism of zongertinib invitro is principally driven by cytochrome P450 (CYP) 3A. It is necessary, therefore, to assess the effect of a strong CYP3A inhibitor on the pharmacokinetics of zongertinib in humans. This study investigated the effect of multiple oral doses of the strong CYP3A inhibitor and regulatory-recommended probe inhibitor of P-glycoprotein (P-gp), itraconazole, on the pharmacokinetics of a single dose of zongertinib in healthy male participants. This open-label, two-period, fixed-sequence, clinical drug-drug interaction study assessed the pharmacokinetics of a 15 mg oral dose of zongertinib in the absence and presence of multiple oral doses of itraconazole. The extent of drug-drug interaction was estimated using the adjusted geometric mean (gMean) ratios (90% confidence intervals [CIs]) for the test (T) treatment (zongertinib and itraconazole) vs. the reference (R) treatment (zongertinib alone). Primary endpoints were the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and the maximum measured plasma concentration (Cmax) of zongertinib. The secondary pharmacokinetic endpoint was AUC for zongertinib from time 0 to the last quantifiable time point (AUC0-tz). Sixteen participants received zongertinib alone (Period 1, R), followed by co-administration with itraconazole (Period 2, T). In terms of zongertinib exposure, the gMean ratio of T to R was 141.2% (90% CI: 126.3-157.7%) for AUC0-∞, 142.8% (90% CI: 126.0-161.9%) for AUC0-tz, and 126.9% (90% CI: 106.6-151.0%) for Cmax. Co-administration with itraconazole resulted in a mild increase in total exposure to zongertinib that was not considered clinically relevant given its wide therapeutic window. These data indicate that the approved 120 mg dose of zongertinib can be administered without dose adjustment in combination with CYP3A/P-gp inhibitors.

Cystic fibrosis (CF) is a monogenic disorder leading to pulmonary disease, pancreatic insufficiency and cystic fibrosis-related diabetes (CFRD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now being investigated in people with cystic fibrosis (pwCF) and CFRD. To date, their therapeutic potential has been almost exclusively studied in case reports or case series. These agents improved glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) parameters. Benefits were also observed in weight reduction, particularly for subjects on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). However, discordant results have also been reported. Moreover, GLP-1RAs have improved pulmonary function, even following lung transplantation. Importantly, the dual glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has also yielded favourable outcomes. Finally, preliminary evidence suggests potential inhibition of bone resorption, pointing to a therapeutic perspective in cystic fibrosis-related bone disease (CFBD). However, potential adverse events should not be ignored. These include risk of acute pancreatitis, nausea/vomiting, nutritional depletion, bowel dysmotility and distal intestinal obstruction syndrome, as well as others. Adverse events should be addressed with caution, and dose adjustments may be useful. Large prospective multicentre studies are now required to validate these outcomes and to suggest implications for clinical practice.

Aumolertinib with or without chemotherapy in EGFR-mutated advanced non-small-cell lung cancer (AENEAS2): an open-label, multicentre, randomised, controlled, phase 3 trial.

Developmental and epileptic encephalopathies (DEEs) are severe, drug-resistant epilepsies associated with major developmental, cognitive, and behavioral burden. Although pharmaceutical-grade cannabidiol (CBD) has shown efficacy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), evidence across the broader DEE spectrum remains fragmented. The aim of this systematic review was to quantify seizure and safety outcomes with pharmaceutical-grade CBD in DEE and explore whether effectiveness differs by syndrome type, age band, dose, clobazam co-medication, or follow-up duration. We conducted a systematic review and meta-analysis of PubMed, Embase, and CENTRAL from inception to 12 October 2025. Eligible studies enrolled individuals of any age with DEE treated with pharmaceutical-grade CBD, as add-on therapy or monotherapy. Mixed-etiology reports were eligible when DEE-specific data could be isolated or obtained from authors. Main outcomes were proportions achieving ≥50% or ≥75% seizure reduction, and seizure freedom; key safety outcomes were also collected. Random-effects generalized linear mixed models were used; small-study effects were explored with funnel plots and Egger's test. Prespecified subgroup analyses were performed by age (pediatric, adult, mixed) and syndrome (DS, LGS, Doose syndrome, CDKL5-related DEE, unspecified DEE, and other defined DEEs); post-hoc exploratory subgroup analyses examined CBD dose, concomitant clobazam use, and follow-up duration. Effect modification was tested using interaction p-values and interpreted with guidance from the Cochrane Handbook and the Instrument to assess the Credibility of Effect Modification in Analyses (ICEMAN). Forty-six studies (5 randomized controlled trials [RCTs] and 41 non-randomized studies; 2592 patients) met the inclusion criteria. The pooled ≥50% responder rate was 49.9% (95%CI 44.9-55.0); ≥75% responders comprised 26.7% (95%CI 22.0-32.0), and seizure freedom was achieved in 5.7% (95%CI 4.0-8.0). Age, syndrome type, dose, concomitant clobazam use, and follow-up duration did not demonstrate a robust or consistent pattern of effect modification across efficacy outcomes. Although some subgroup analyses reached statistical significance, these findings were often imprecise, based on small subgroups with wide confidence intervals, and did not meet ICEMAN credibility criteria. Adverse-event profiles were consistent across studies: somnolence, decreased appetite, diarrhea, fatigue, and behavioral changes predominated, mostly mild to moderate and manageable with dose adjustment. Transaminase elevations occurred mainly with valproate co-therapy and were reversible upon dose reduction or discontinuation. Serious adverse events were uncommon, and withdrawals due to adverse events were infrequent. Pharmaceutical-grade CBD is associated with clinically meaningful seizure reduction in roughly half of patients with DEE, mirroring pivotal RCT results in DS and LGS. Nevertheless, substantial between-study heterogeneity and low-credibility subgroup signals preclude confident attribution of superior efficacy to any specific subgroup. These findings should be interpreted cautiously given the imprecision and heterogeneity of the available evidence. Future research should prioritize well-powered, prospectively phenotyped, and syndromically defined cohorts with standardized outcome measures and individual participant data sharing to elucidate true effect modifiers and optimize patient selection. CRD420251186064.

Community-acquired pneumonia (CAP) remains a major global health burden, with antibacterial therapy as the primary treatment strategy. In clinical practice, plasma drug concentrations are often used to guide therapy, yet they may not reliably reflect effective pulmonary exposure, which is particularly critical for older adults, patients with comorbidities, and critically ill populations. In recent years, targeted pulmonary pharmacokinetics/pharmacodynamics (PK/PD) studies have gained increasing attention and have become an important reference for guiding precision antimicrobial therapy in clinical settings. This review provides a comprehensive overview of the pulmonary PK characteristics of key antibiotics commonly used for CAP, including macrolides, fluoroquinolones, β-lactams, tetracyclines, and the pleuromutilin agent lefamulin. Major factors influencing drug distribution in the lung are summarized. The significance of pulmonary PK/PD targets in antibiotic selection, dose adjustment, and individualized treatment is discussed, aiming to support improved clinical outcomes, rational antibiotic use, and resistance management. A deeper understanding of pulmonary PK/PD properties is essential to advance evidence-based and optimized treatment for CAP.

Predictors of early discontinuation of clozapine under rapid titration in a Turkish tertiary inpatient setting.

To investigate antidepressant treatment changes following transitioning to secondary care for depression in older adults and examine their associations with social determinants. This Danish register-based cross-sectional study included all older adults with a first outpatient visit to psychiatric hospitals (referred by general practitioners or private psychiatrists) for depression within the first year after initiating antidepressant treatment during 2006 and 2016. Treatment changes were assessed using three outcomes based on antidepressant prescriptions redeemed before and within 90days after the outpatient visit: (i) antidepressant switching, (ii) discontinuation, and (iii) dose changes. Social determinants included education, occupation, income, marital status, household type, urbanicity, and ethnicity. Multiple logistic regression and generalized linear regression were employed for association analyses. Of 792 individuals referred to outpatient care after starting antidepressants (61% female; mean age 79), 25% discontinued treatment. Among those who continued (n=594), 47% switched antidepressants. Of those who stayed on the same antidepressant (n=315), only 46% had recorded dose information, and 38% of these had dose adjustments. Among social determinants, low income was associated with a higher likelihood of discontinuation compared to higher income (odds ratio: 2.10; 95% confidence interval: 1.14-3.87). Short education was associated with an average dose reduction of 15units (beta-coefficient, 95% CI: -15, -25 to -4.4) compared to long education. Prescribers' information was not available and >50% of prescriptions had missing dose information. Noticeable changes in antidepressant treatment occurred after secondary care contact, with some differences across social determinants, mainly related to income and education.

Cabozantinib is a multi-targeted tyrosine kinase inhibitor that targets Vascular Endothelial Growth Factor Receptor (VEGFR) 2, c-MET, and RET. It exhibits antiangiogenic and antitumorigenic effects and has the potential to treat a variety of malignancies. Palmar-Plantar Erythrodysesthesia (PPE), one of the most common side-effects of tyrosine kinase inhibitors, can have a considerable impact on patients’ quality of life and medication adherence, making it a key therapeutic obstacle in maximising the efficacy of targeted cancer therapy. We describe a rare early-onset bullous type of PPE that developed within 15 days of starting cabozantinib in a 32-year-old woman with papillary renal cell carcinoma. The patient developed severe bullous and hyperpigmented acral lesions, which hampered everyday activities. The response followed a dosage-dependent pattern, with partial improvement and relapse after dose adjustment and full resolution after additional dose reduction and topical treatment. This case emphasises the need to identify unusual and early signs of PPE to provide prompt care while maintaining oncologic therapy

Entrectinib, a multi-target tyrosine kinase inhibitor (TKI) against TRK, ROS1, and ALK, is clinically approved for genetically-defined solid tumors. The prevalence of drug-drug interactions (DDIs) with increased use indicates the need for further research. This present study aimed to screen 32 cardiovascular drugs for inhibitory effects on entrectinib metabolism and to elucidate the pharmacokinetic interaction with nicardipine. We utilized rat liver microsomes to screen cardiovascular drugs and identify potent inhibitors. The inhibition kinetics of nicardipine were determined in vitro, and molecular docking to the primary entrectinib-metabolizing cytochrome P450 isoform was performed to investigate a potential mechanism for the observed interaction. Furthermore, in vivo pharmacokinetic studies were conducted in rats to evaluate the impact of nicardipine on entrectinib exposure. In rat liver microsomes, nicardipine was identified as a moderately potent inhibitor with a half-maximal inhibitory concentration (IC50) of 1.43µM, inhibiting entrectinib metabolism through dual competitive and noncompetitive mechanisms (inhibition constants: Ki=1.28µM; αKi=1.92µM). In vivo studies showed that nicardipine significantly increased the area under the curve (AUC) and maximum plasma concentration (Cmax) of entrectinib by ~1.5-fold, while reducing clearance (CLz/F) and volume of distribution (Vz/F) (p<0.05). These findings in rat models and in silico docking indicate that nicardipine increases entrectinib exposure. While these results underscore the risk of significant DDIs, further clinical studies in humans are required to confirm this interaction and determine if entrectinib dose adjustments are necessary to mitigate adverse events.

Interpretation of urine buprenorphine and norbuprenorphine concentrations is widely used to assess adherence during treatment for opioid use disorder. However, the relationships between dose, timing of sample collection, and metabolite ratios remain unclear, leading to potential misinterpretation in clinical practice. Data were collected from patients on a psychiatry unit who were either inducted on or continued buprenorphine therapy and underwent urine testing for buprenorphine and its metabolite, norbuprenorphine. Urine samples were collected 16 to 786 min after the last buprenorphine dose. Norbuprenorphine-to-buprenorphine ratios were calculated. Data analysis using Python included polynomial regression and random forest models. Daily buprenorphine doses ranged from 2 to 24 mg. A polynomial regression model predicting time since last dose, using urine buprenorphine concentration, norbuprenorphine-to-buprenorphine (NB/B) ratio, cumulative dose, daily dose, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), resulted in an R2 of 0.620 (P = 0.00006). A random forest model using time since last dose, daily dose of buprenorphine, and cumulative dose of buprenorphine to predict the NB/B ratio achieved an R2 of 0.762. No significant relationship was found between daily dose and urinary concentrations of buprenorphine, norbuprenorphine, or the NB/B ratio. Patient-specific variables like age and body mass index (BMI) were not significant predictors. The NB/B ratio alone was inadequate for estimating adherence, cumulative exposure, or recent dose. Urine buprenorphine metabolite concentrations and NB/B ratios alone are insufficient for assessing adherence or guiding dose adjustments. Effective monitoring requires integrating metabolite data with clinical context, dosing history, and precise sample timing to inform treatment personalization and avoid misinterpretation.

In a drug landscape dominated by the highly potent synthetic opioid fentanyl, traditional methadone initiation protocols increasingly fail people with opioid use disorder (OUD). While "low" initial dose selection and "slow" dose adjustment rates reduce risk for methadone-associated toxicity, they also result in weeks to months of unrelieved withdrawal symptoms and cravings, especially for people with high opioid tolerance from routine fentanyl use. For this growing population, "low-and-slow" forces a choice between 3 poor options: suffer weeks to months of withdrawal, self-manage withdrawal through non-prescribed substance use, or give up on treatment. Our commentary combines a Peer Support Specialist's lived experiences with methadone initiation and evidence from the peer-reviewed literature to illustrate this problem and the role of one potential solution: rapid methadone initiation (RMI), defined here as reaching a methadone dose of 80 mg or more within the first 7 days of treatment. For appropriately selected patients, RMI is associated with positive outcomes, including improved patient satisfaction, reduced readmission rates, and increased retention in care. Though regulations permit and growing evidence supports RMI, adoption remains limited. Our commentary, therefore, concludes by sharing frameworks to support providers in implementing RMI as a potential treatment option for people with OUD across applicable care settings. Methadone's life-saving potential depends on dosing that matches the physiological reality of fentanyl use. Collectively, addiction clinicians define the community standard of care. In the face of a transformed drug landscape, it is time for that standard to evolve to ensure that the option for rapid and effective relief becomes the rule, rather than the exception.

TRANSFORM-1 Phase 3 study: Efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm) have altered the landscape of pregnancy and parenthood in cystic fibrosis (CF). As pregnant and breastfeeding females with CF (FwCF) were excluded from pivotal CFTRm trials, evidence to guide management and counsel families on maternal and child outcomes is limited. While CFTRm are unlicensed for use in pregnancy, substantial clinical benefit means most continue therapy. Early studies indicate that CFTRm cross the placenta and are detectable in breastmilk; reported associations include infant liver dysfunction and cataracts but risks remain poorly characterised. We describe the protocol for the first UK-based prospective study evaluating pregnancy and parenthood in FwCF and health outcomes in their children in the CFTRm era. A single protocol underpins three linked prospective observational substudies in the MATRIARCH_CF research programme. The 'Mama' cohort recruits FwCF planning pregnancy or pregnant, with follow-up from preconception to 24 months postpartum, assessing physical and psychological health, lung function and CF-related complications. 'Mini' recruits children aged 0-24 months born to a parent with CF and compares offspring exposed and unexposed to CFTRm in utero and/or through breastfeeding; measures include birth outcomes, congenital anomalies, liver biochemistry, growth and neurodevelopment. 'Midi' recruits children aged 3-6 years from the same exposure groups and assesses neurodevelopment and lung function. Longitudinal data across cohorts will strengthen the evidence base, support risk-benefit discussions and inform clinical guidance. The protocol was approved by NHS ethics HSC REC A committee (25/NI/0027 19 March 2025). Assessments align with routine care where possible. Visit windows are flexible and participants may decline individual assessments. The research team does not influence CFTRm initiation, cessation or dose adjustment. People with CF contributed throughout study design to ensure acceptability. Findings will be disseminated through PhD theses, conference presentations and peer-reviewed publications. NCT06797206.

Weight loss and clinical decongestion across heart failure phenotypes: a post-hoc analysis of a multicentre randomised trial (duel-hf)

Self-management and patient education are cornerstones in managing adrenal insufficiency (AI), to prevent adrenal crisis (AC). Glucocorticoid (GC) education group meetings are increasingly being incorporated into regular healthcare. However, few studies have evaluated its effectiveness. Multicentre pre-post intervention study conducted at four university hospitals in Sweden between 2015 and 2019. A total of 254 patients with AI along with 138 relatives were included. Participants attended a GC education group meeting led by an endocrinologist. Detailed guidance was provided on when and how to adjust GC doses to prevent AC together with instructions and supervised practice of hydrocortisone injections. Questionnaires on self-management were completed by both patients and relatives before the session and again six months later. In addition, patients also completed two HRQoL instruments. Patients with AI felt relatively safe and informed about their GC treatment at baseline. However, many lacked adequate knowledge on dose adjustments, including high-risk situations for AC. At follow up, 194 patients (76.4%) and 94 relatives (68.1%) completed the questionnaires. Both patients and relatives showed significant improvements in perceived safety and management of high-risk scenarios for AC. However, some knowledge gaps persisted. The education effort did not result in significant changes in HRQoL. Structured GC education group meetings enhance the knowledge of patients and their relatives to manage AI safely. We consider this a valuable component of AI care.

Objective Azvudine (FNC), an antiviral drug approved in China for the treatment of Coronavirus disease 2019 (COVID-19) infection, has not yet established a well-defined safety profile in patients with renal impairment. This study aimed to evaluate the safety of using FNC in patients with renal impairment. Methods We conducted a retrospective analysis of clinical data from 328 COVID-19 patients to assess FNC-related adverse drug events (ADEs). Patients were stratified into two cohorts: a control group with an estimated glomerular filtration rate (eGFR) &amp;gt; 70 mL/min/1.73 m 2 and a study group with eGFR ≤70 mL/min/1.73 m 2 . Our main objective was to assess whether there were any differences in the incidence of ADEs between the two groups. Secondly, we attempted to develop predictive models for ADEs that were frequent and closely related to the eGFR grade. Results Over half of the cohort (51.8%) experienced FNC-associated ADEs, predominantly hepatic function abnormalities (36.6%) and renal function abnormalities (18.9%). The incidence of acute kidney injury (AKI) was 8.8%. Patients with renal impairment exhibited a higher risk of ADEs, particularly among elderly individuals and patients with a high neutrophil count. No differences in hepatic function abnormalities were found between the two groups. Patients with renal impairment had a higher risk of renal function abnormalities and AKI, with decreased eGFR identified as an independent risk factor for these ADEs. The predictors included in the nomogram model for AKI were neutrophil count and eGFR grade. The nomogram model demonstrated predictive performance and calibration, with an area under the curve of 0.812. Conclusion These findings highlight the need for enhanced safety monitoring and potential dose adjustments when administering FNC to COVID-19 patients with renal impairment.