British journal of clinical pharmacology最新文献

Severe forms of vascular malformations (VM) can highly impact patients' quality of life and lead to life-threatening organ dysfunction. Numerous VM are caused by somatic activating mutations in the PI3K/AKT/mTOR signalling pathway. Alpelisib, a PIK3CA inhibitor was recently FDA-approved for paediatric PIK3CA-related overgrowth syndrome (PROS). However, an empiric and fixed dose of 50 mg was selected, irrespective of weight, in the absence of any pharmacokinetic (PK) data. We aim to report novel alpelisib PK data in children to support dosing decisions.

Nine patients with severe VM (PROS: n = 4, other VM: n = 5) were included. Mean age was 10.5 years (SD = 5.2 years), and mean weight was 43 kg (SD = 24 kg). AUC on the fixed dose of 50 mg/day was highly variable (mean = 7035 ng*h/mL, SD = 4057, CV = 58%). AUC was correlated with weight.

As short- and long-term adverse effects to alpelisib in children are unknown, a dosing based on PK data is urgently needed.

Aims: For new medicines, drug companies obtain regulatory approval on the strategy to generate evidence in the paediatric population, which can be supported by extrapolation of evidence obtained in a reference population. This study investigated whether paediatric marketing authorization applications (PMAAs) supported by extrapolation based on exposure-matching were more successful-i.e. approval of the targeted paediatric population-and efficient-i.e. duration of the drug development-compared to PMAAs not supported by extrapolation.

Methods: Data was extracted from completed paediatric investigation plans (PIPs), associated drug labels and public assessment reports published on the European Medicines Agency website. Assessment reports were evaluated to assess whether PMAAs were supported by extrapolation based on exposure-matching. Wilcoxon rank-sum tests were used to compare PMAAs supported and not supported by extrapolation based on exposure-matching for outcomes of interest.

Results: Exposure-matching supported the benefit/risk assessment of 39.6% of the PMAAs. Targeted and approved minimum age of the paediatric population were comparable for PMAAs where extrapolation based on exposure-matching supported the benefit/risk assessment (2.0 vs. 2.0 years, P-value = .72), but not for PMAAs not supported by extrapolation (0.2 years vs. 0.5 years, P-value = .05). Completion of drug development was 5.4 years vs. 4.3 years (P = .04) in PMAAs supported by extrapolation based on exposure-matching compared to those not supported by extrapolation, respectively.

Conclusions: PMAAs supported by extrapolation based on exposure-matching succeeded more often in obtaining marketing approval in the targeted paediatric population than PMAAs not supported by exposure-matching, but were also less efficient.

Aims: 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.

Methods: 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.

Results: 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 2 g 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 8 mg/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).

Conclusions: Our study underscores the significant variation in temocillin clearance and unbound fractions among different participant groups, challenging the efficacy of traditional 2 g q12h dosing. For patients with enhanced renal function and lower inflammation, continuous infusion emerges as a more effective strategy to achieve optimal target attainment.

Aims: The suitability of the DOAC score for assessing bleeding risk in Chinese patients with atrial fibrillation (AF) who are receiving non-vitamin K antagonist oral anticoagulants (NOACs) remains unclear. We compared the DOAC score to the HAS-BLED and ORBIT scores in Chinese patients in a real-world retrospective study.

Methods: The efficacy of these scores was assessed by a comparison study that measured their discrimination, calibration, net reclassification index (NRI), and decision curve analysis (DCA) over a 1-year follow-up period.

Results: Among 2532 patients with non-valvular AF (mean age, 71.7 ± 11.3 years, 58.5% men), major bleeding (MB) occurred in 91 patients (3.59%/year): 44 intracranial haemorrhage (ICH) events (1.74%/year) and 49 gastrointestinal bleeding (GB) events (1.94%/year). The best predictor for MB was the HAS-BLED score (area under the receiver operating characteristic curve [AUC], 0.674). HAS-BLED score ≥3 provided the best prediction for MB (AUC, 0.642), followed by DOAC score ≥8 and ORBIT score ≥4 (AUCs of 0.615 and 0.583, respectively). The DOAC and HAS-BLED scores did not differ significantly in discriminating MB events and risk reclassification. The calibration performance of the HAS-BLED score was superior to that of the other two scores. Decision curve analysis showed that using the HAS-BLED score to predict MB and ICH is clinically beneficial. However, there were no significant distinctions among the three models in forecasting GB.

Conclusions: In a non-valvular AF Chinese patients receiving NOACs, the HAS-BLED score showed an ability to predict MB comparable to that of the DOAC score and superior to that of the ORBIT score. The DOAC score does not seem to be more suitable for Chinese patients than the HAS-BLED score.

Aims: An unbiased means of documenting medication-taking is important to ensure quality evidence about adherence research and to accurately identify individuals at risk of suboptimal adherence for the development of targeted and effective interventions. Guidance to assist researchers in the understanding of risk of bias when conducting or reviewing adherence research is currently not available. To address this gap, tools to identify and gauge the magnitude of important biases that may impact adherence research have been developed.

Methods: The Risk of Bias tool for Interventional Adherence Studies (RoBIAS) and the Risk of Bias tool for Observational Adherence Studies (RoBOAS) were constructed from a literature review of key adherence guidelines/frameworks, drafted initially through author consensus. The draft bias tools were piloted and evaluated with expert adherence researchers through an online survey platform to assess the internal consistency and agreement in responses, including gather "free text" feedback to improve the tool's utility.

Results: Of the 121 approached reviewers, only 20 out of the 30 reviewers who consented to participate completed the piloting of the tools. Both tools are structured around four domains relating to: (i) study design, (ii) randomization (RoBIAS tool) and confounding factors (RoBOAS tool), (iii) adherence outcome measurement, and (iv) data analysis. Each domain consists of items/statements, mapped to specific biases relevant to adherence research and study designs, including a domain-based ranking scale to determine the appropriate risk of bias judgement.

Conclusions: The tools are intended to have utility when systematically reviewing adherence research and to inform the design of future adherence studies.

Aims: We aimed to examine the recent trends in the use of acid suppression therapies, including proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs) and potassium-competitive acid blockers (P-CABs), in patients undergoing dual antiplatelet therapy (DAPT) as aspirin-clopidogrel following coronary stent implantation in South Korea between 2018 and 2022.

Methods: This observational study analysed data from the Health Insurance Review and Assessment Service (HIRA) on patients who underwent coronary stent implantation and received aspirin-clopidogrel DAPT. Patients who received acid suppression therapy for >60 days during DAPT were included in the analysis. Trends in the use of PPIs, H2RAs and P-CABs were assessed at 6-month intervals using the Cochran-Armitage trend test.

Results: Of the 128 121 patients studied who received DAPT, 61 731 (48.2%) were prescribed acid suppression therapy. The proportion of patients receiving concomitant acid suppressants with DAPT increased from 42.8% in 2018 to 53.8% in 2022. PPIs were the most commonly used therapies (78.9%), followed by H2RAs (14.6%) and P-CABs (6.5%). PPI use peaked in 2020 and declined thereafter, whereas P-CAB use steadily increased, surpassing that of H2RA by 2021.

Conclusions: The landscape of acid suppression therapy for patients undergoing DAPT has evolved with a growing preference for P-CABs. This shift highlights the need for further research comparing the efficacy and safety of acid suppressants to guide clinical decision making.

Aims: Crovalimab is a novel C5 inhibitor administered first intravenously and then subcutaneously in patients with paroxysmal nocturnal haemoglobinuria (PNH) naive to complement inhibition or switching from eculizumab or ravulizumab. Crovalimab showed efficacy and safety comparable to eculizumab in the pivotal COMMODORE 2 and supporting studies.

Methods: We characterized crovalimab pharmacokinetics and the relationship between exposure pharmacokinetic parameters and pharmacodynamic biomarkers, efficacy and safety endpoints using pooled data (healthy volunteers [n = 9], naive [n = 210] and switched [n = 211] patients). Pharmacodynamic biomarkers included 50% complement activity and free C5; normalized lactate dehydrogenase was a marker of haemolysis. Adverse events (AEs) of special interest, related serious AEs, related Grade ≥3 AEs and infections were assessed.

Results: There was no clinically relevant difference in crovalimab concentrations between naive and switch patients. Bodyweight had a statistically significant impact on crovalimab clearances and volumes of distribution. Thus, the recommended dosing regimen used weight-based, two-tiered dosing (100 kg cutoff). Age did not have a clinically meaningful impact on crovalimab exposure. In COMMODORE 2, and the supporting COMMODORE 1 and 3 studies, complete terminal complement activity inhibition was achieved immediately at the end of the initial intravenous infusion and sustained throughout the treatment period in ≥97% of patients. Crovalimab concentrations above ≈100 μg/mL achieved complete inhibition of terminal complement activity, resulting in disease control with normalized lactate dehydrogenase ≤1.5 × upper limit of normal (ULN). There was no increased risk of AEs at higher exposure.

Conclusions: These data confirm an effective crovalimab-dosing regimen that achieves complete terminal complement activity inhibition and disease control in patients with PNH.

The use of tramadol and other opioids for pain management has been accompanied by a multitude of challenges and concerns worldwide. The use of tramadol saw a decline in Denmark during 2017–2019 accompanied by a slight increase in the use of morphine and oxycodone. Using the Danish National Prescription Registry and utilizing data until and including 2023, we aimed to provide updated data on the utilization patterns of tramadol and other opioids in Denmark. We found a 35% decline in the use of tramadol from 2017 to 2023 most likely due to media attention, regulatory actions, health campaigns and targeted education of physicians and patients by the Danish health authorities. This decline was accompanied by an increase in the number of new (+90%) and current users of morphine (+57%), which surpassed those of tramadol, oxycodone and other opioids in 2023.

Poisoning management includes gastrointestinal decontamination strategies to decrease the burden of poison entering the body and change the expected severe toxicity expected to a less toxic, more favourable outcome. Common modalities are orogastric lavage, oral-activated charcoal and whole-bowel irrigation. Endoscopic retrieval and laparotomy are rare options reserved for severe ingestions and body packers. Although supporting data are generally of low quality, gastrointestinal decontamination is likely to improve patient outcome in many situations. Unfortunately, technical limitations and contraindications can explain their infrequent use. Orogastric lavage can be useful for early lethal ingestions, albeit with significant complications such as aspiration and perforation. Activated charcoal cannot adsorb every substance. Usual dosing is 1 g/kg per dose. Whole-bowel irrigation is reserved for charged molecules or substances not adsorbed to activated charcoal but requires intact gut motility. Indications depend on several factors inherent to the ingestion (dose, time, poison) and patient's characteristics. During recent decades, studies of newer pharmaceuticals or modified-release formulations showed that significant amounts of poison, especially pharmacobezoars, persist in the gut hours postingestion, thus are amenable to gastrointestinal decontamination. Improved understanding of gut motility in volunteer studies and overdose showed clinically significant reduction in drug exposure with activated charcoal. The 1-h dogma for gastrointestinal decontamination, especially activated charcoal, is now obsolete. Clinicians must perform a risk assessment for each ingestion to determine the expected benefit at the time of decision-making, choosing the modality to achieve reduction in the toxicity burden while planning for complications or contraindications.