British Journal of Clinical Pharmacology

Aims This systematic review and meta‐analysis aimed to evaluate the association between β‐blocker use and neuropsychiatric adverse events, specifically focusing on short‐term outcomes. Methods A comprehensive literature search identified studies reporting neuropsychiatric outcomes in patients using β‐blockers, including randomized controlled trials and observational studies. Relative risks (RR) and 95% confidence intervals (CIs) were calculated for outcomes such as dizziness, insomnia, nightmares, drowsiness and delirium. Results Our analysis revealed that β‐blocker use was significantly associated with an increased risk of dizziness (RR 1.72, 95% CI [1.39–2.14]; I² = 1%, 14 studies) compared to placebo. Lipophilic β‐blockers, especially propranolol, showed an even greater risk of dizziness (RR 3.13, 95% CI [1.44–6.84]; I² = 0%, three studies). Propranolol was also associated with increased insomnia risk compared to placebo (RR 1.13, 95% CI [1.00–1.28]; I² = 0%, five studies). Our data did not show statistically significant increases in the reports of nightmares and somnolence. Other adverse effects, including drowsiness, sleep disturbances, hallucinations and delirium, were noted. Conclusions Our findings suggest a significant association between β‐blocker use and an increased risk of neuropsychiatric adverse events, particularly insomnia and dizziness with higher risks associated with lipophilic β‐blocker use. Given the ambiguity surrounding dizziness and its classification as a neuropsychiatric effect, our findings are exploratory, and we cannot exclude a potential cardiovascular origin for dizziness. Most studies (75%) were published before the CONSORT statement in 1996, indicating potential reporting limitations and a lack of recent research. Additionally, 60% of studies had a high risk of bias, underscoring the need for more rigorous and contemporary investigations into the neuropsychiatric implications of β‐blocker use.

Aims The aim of this study was to characterize the risk of death in older adults co‐prescribed low‐dose methotrexate and TMP‐SMX vs. low‐dose methotrexate and a cephalosporin. Methods We conducted a retrospective, population‐based, new‐user cohort study in Ontario, Canada (April 1, 2002–August 1, 2022) using linked administrative healthcare data. Older adults taking low‐dose methotrexate who were newly co‐prescribed TMP‐SMX (n = 1602) were matched 1:1 with those who were newly co‐prescribed a cephalosporin. The primary outcome was death within 30 days of the antibiotic dispensing date. Secondary outcomes included all‐cause hospitalization, a hospital visit with myelosuppression and a hospitalization with persistent infection defined as the main diagnosis. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RR) were obtained using modified Poisson regression. Results In a propensity‐score matched cohort of 3204 adults taking low‐dose methotrexate, the 30‐day risk of death was similar in adults co‐prescribed TMP‐SMX vs. a cephalosporin (14/1602 [0.87%] vs. 15/1602 [0.94%]; RR 0.93 [95% CI 0.45–1.93]). The risk of all‐cause hospitalization (RR 1.49 [95% CI 1.13–1.97]) and infection (RR 2.78 [95% CI 1.30–5.95]) was higher in adults treated with TMP‐SMX than those treated with cephalosporins. Conclusions In older adults taking low‐dose methotrexate, co‐prescription of TMP‐SMX vs. a cephalosporin was not associated with a higher 30‐day risk of death but was associated with a higher 30‐day risk of all‐cause hospitalization and hospital admission with persistent infection. If verified, these risks should be balanced against the benefits of co‐prescribing TMP‐SMX and low‐dose methotrexate.

Aims Evidence on the optimal targets of vancomycin for treating other Gram‐positive infections apart from methicillin‐resistant Staphylococcus aureus (MRSA) is lacking. This review aims to identify the recommended vancomycin therapeutic level for favourable clinical outcomes among patients infected with vancomycin‐sensitive enterococcal infections. Methods Analytical studies describing the vancomycin levels of vancomycin‐sensitive enterococcal infections among adult population were searched. The primary outcome was 30‐day all‐cause mortality, and the secondary outcomes were clinical failure and nephrotoxicity. Study characteristics were extracted and pooled using random‐effects meta‐analysis. The study quality was assessed using the Joanna Briggs Institute critical appraisal tool. Results A total of nine retrospective cohorts studies involving 1013 patients with vancomycin‐sensitive enterococci were included. The meta‐analysis found that high area under the curve to minimum inhibitory concentration ratio (AUC/MIC) of vancomycin ≥ 389 mg*h/L significantly lowered the 30‐day mortality (odds ratio [OR], 0.44, 95% confidence interval [CI], 0.26–0.75). Analysis of the target AUC/MIC showed that high vancomycin AUC/MIC (≥ 389–400 mg*h/L) significantly reduced clinical failure rate (OR 0.59, 95% CI 0.37–0.94). The mortality and treatment failure rates did not differ significantly between those with high or low trough levels. Higher vancomycin AUC/MIC and trough levels were significantly associated with increased nephrotoxicity (OR 3.11, 95% CI 1.65–5.89; OR 2.95, 95% CI 1.60–5.44, respectively). Conclusions The use of a higher vancomycin AUC/MIC concentration can be effective to reduce 30‐day mortality and clinical failure but this needs to take into consideration the risk of nephrotoxicity. Well‐conducted prospective studies are warranted due to the scarcity of evidence.

Aims The Drug Utilization 90% Index (DU90%), the number of medicines making up 90% of a doctor's prescribing, is a simple tool that can be used to describe core prescribing patterns. This research aimed to pilot the application of the DU90% in the Irish context, to investigate the relationship between the DU90% and prescriber and practice characteristics and prescribing quality. Methods Retrospective observational study using anonymous prescription data from a sample of Irish general practitioners (GPs). Participating GPs provided demographic details and extracted prescription data for 2018–2022 using their existing software systems. The DU90% was calculated annually at both the practice and prescriber level. Prescribing quality indicators included antibiotic, benzodiazepine prescribing rates and high‐risk nonsteroidal anti‐inflammatory drug prescribing. The association of the DU90% with prescriber and practice characteristics and prescribing quality indicators was explored with multilevel modelling. Results Thirty‐eight prescribers from 22 different practices were included. The mean DU90% for prescribers was 141.5 (standard deviation 12.9) and for practices was 145.62 (standard deviation 11.87). Practices in receipt of the rural deprivation grant had a significantly lower DU90% (incidence rate ratio 0.94, 95% confidence interval 0.88–0.98). There was no evidence of an association between prescriber‐level characteristics and the DU90% (sex, years qualified, number of sessions worked). There was a small positive relationship between the prescriber DU90% and total prescriptions, antibiotic and benzodiazepine prescribing rates, and higher rates of high‐risk nonsteroidal anti‐inflammatory drug prescriptions. Conclusion Applying the DU90% to Irish general practice prescriptions is feasible, revealing that GPs typically use 140 medicines in the bulk of their prescribing.

Aims A 42‐year‐old male developed chronic primary hypoparathyroidism after total thyroidectomy. Conventional therapy led to recurrent nephrolithiasis and therefore rhPTH(1‐84) (parathyroid hormone [PTH]) treatment was considered. According to the dosing guideline for PTH, calcium plasma levels are adequately controlled with once‐daily administration. However, the effect on urinary calcium excretion is only transient and hence does not lower the risk of nephrolithiasis. This raises the question of whether multiple‐daily or continuous administration of PTH is more effective in lowering urinary calcium excretion. We aimed to construct a pharmacokinetic‐pharmacodynamic (PKPD) model to answer this question. Methods A single patient was treated with intermittent PTH followed by off‐label continuous infusion of PTH. PTH was measured in plasma, calcium and phosphate in plasma and urine. A one‐compartment PKPD model for PTH was developed with Edsim++. The effect of PTH was described by the relative clearance of calcium and phosphate. Results The PKPD model for PTH showed visually a marked effect on phosphate clearance, but less on calcium clearance. During the study, the patient also received medication that influenced calcium homeostasis but to a lesser extent phosphate homeostasis. Therefore, phosphate was chosen as the effect parameter, resulting in an EC50 of 6.3 pmol/L PTH. Conclusions The PKPD model for PTH was completed with the unique data of a single patient who received PTH according to various dosing regimens, including continuous infusion. Continuous administration of PTH is favoured because it permanently increases the phosphate clearance and therefore needs to be further investigated.

Aims The accuracy of model‐informed precision dosing largely depends on selecting the most appropriate population pharmacokinetic (popPK) model from many available options. This study aims to evaluate the concordance of optimal initial simulated doses among various vancomycin popPK models developed in neonates and to explore the role of predictive performance in explaining the variability in probability of target attainment (PTA). Methods A virtual neonatal patient population was created and 26 previously externally evaluated vancomycin popPK models were used to simulate 5 different dosing regimens. For each simulated scenario, the area under the concentration–time curve and PTA were calculated to assess the agreement on optimal initial doses across the 26 models. A multiple regression was performed to explore the impact of the models' predictive performance on PTA. Results For most models (15/26), there was an agreement on the optimal dosing regimen. The highest PTA being achieved by the model with the best a priori predictive performance. The multiple regression model significantly predicted mean ln‐transformed PTA, with F(2, 23) = 5.406 and P = .010, yielding an adjusted R² of .21. PTA was significantly influenced by imprecision (P = .048) but not bias (P = .469). Conclusion In conclusion, our study demonstrated that, despite the variability in bias and imprecision, there was a consensus on the initial optimal doses for the majority of models; however, models with superior a priori predictive performance yielded higher PTA values. Bias and imprecision alone only seem to predict a small proportion of the variability in PTA, with imprecision having a more pronounced effect.

Aims Paclitaxel and nanoparticle albumin‐bound (nab)‐paclitaxel can cause early, extremely severe neutropenia, occasionally leading to fatal outcomes. As paclitaxel is a substrate of P‐glycoprotein, this study aimed to investigate the impact of ABCB1 single‐nucleotide variants, which encode P‐glycoprotein, on early, extremely severe neutropenia in patients receiving paclitaxel/nab‐paclitaxel plus ramucirumab as second‐line therapy for unresectable advanced/recurrent gastric cancer. Methods We analysed patients treated at Aichi Cancer Center Hospital from January 2018 to August 2023, with DNA samples stored in the Cancer BioBank Aichi. The impact of ABCB1 variants T1236C (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642) on early, extremely severe neutropenia was examined. Neutropenia was defined as a decline in neutrophil count to <100/μL within 28 days of therapy initiation. Firth's logistic regression evaluated the association between the ABCB1 C3435T (rs1045642) TT genotype and early, extremely severe neutropenia, adjusted for age, sex, baseline neutrophil count, and serum albumin and aspartate aminotransferase levels. Results Of the 203 eligible patients, 5 (2%) experienced neutropenia with neutrophil counts of <100/μL. The odds ratio for neutrophil counts of <100/μL was 28.1 (95% confidence interval 2.8–283.3) in patients with the ABCB1 C3435T (rs1045642) TT genotype. Conclusion The ABCB1 C3435T (rs1045642) TT genotype was significantly associated with early, extremely severe neutropenia in patients receiving paclitaxel/nab‐paclitaxel. Evaluating this genotype status may help predict those at increased risk for early, extremely severe neutropenia.

Aims This study evaluates how changes in intestinal bile acid composition, induced by cholestyramine, a bile acid sequestrant, affect metformin's pharmacodynamics (PD). Methods An open‐label, 2‐period 1‐sequence crossover study was conducted with healthy male adults. Each period consisted of both before and after metformin treatments. Cholestyramine was administered during the second period to change the bile acid pool. For, PD assessment, an oral glucose tolerance test was conducted at each treatment in both periods. Metformin was administered 3 times during each period, and cholestyramine was administered 3 times per day for 7 days during the second period. Maximum serum glucose concentration, area under the glucose concentration curve and homeostatic model assessment of insulin resistance were calculated. Baseline‐corrected PD parameters were derived by subtracting pre‐metformin values from post‐metformin values. Lipid and panels and bile acid profiles in stool were measured. Adverse events were monitored throughout the study. Results Fourteen subjects completed the study. The mean values of 3 PD parameters were all decreased after metformin administration in both periods. Cholestyramine administration led to a further decrease in baseline‐corrected PD parameters, significantly reducing the area under the glucose concentration curve by 44.7%. Diarrhoea, the most common adverse event, was reported in 10 subjects during the metformin alone treatment and in 1 subject during the cholestyramine combined treatment (P < .01). Conclusion Cholestyramine affected the glucose‐lowering effect of metformin by the possible change in the bile acid pool in the gut, and metformin‐associated diarrhoea was improved by cholestyramine.

The Screening Tool of Older Person's Prescriptions (STOPP) is used to detect potentially inappropriate medication. Version 2 includes 80 criteria, whereof two can be considered implicit as their detection primarily relies on the assessor's expertise: (A1) drugs without indication and (A2) drug treatment beyond recommended duration. To explore the inter‐rater agreement for detection of explicit and implicit criteria, data on consecutive primary care patients from a previous study (n = 302, 65–99 years of age) were used, including independent assessments of the 78 explicit criteria (23 556 assessments) and the two implicit criteria (604 assessments) by two specialist physicians. Overall, 123 (0.5%) explicit and 10 (2%) implicit criteria were fulfilled according to both physicians. The positive agreement for a criterion being fulfilled was 56% for explicit and 16% for implicit criteria, with kappa values of 0.56 and 0.09. Discordant detection of furosemide and proton pump inhibitors was common using explicit and implicit criteria.

Exploring factors related to difficulties in extracting tablets or capsules from press‐through‐packages is essential for optimizing the dosage form. To achieve this, the involvement of patient insight is important. In the present study, the preferences of patients regarding drugs that are difficult to extract from their packaging were collected using an electronic medication notebook (‘harmo®’) based on dispensing data. We found that approximately 30% of respondents had difficulty removing tablets or capsules from their packaging, with 125 specific drugs identified as ‘hard to push out’. Independent factors related to ‘hard‐to‐push‐out’ drugs were female sex and feeling of weakness in the hands or fingers. Furthermore, several ‘hard‐to‐push‐out’ drugs had characteristics such as a spherical shape or small major axis or small major axis drug‐to‐pocket size ratio. The findings of this study may help improve the quality of drug packaging, thus enhancing the patients' medication experience.

Aims Psychedelics, including mescaline, may serve as novel treatments for depression and anxiety. However, data is scarce on the safety of mescaline. Methods The present pooled analysis included two double‐blind, randomized, placebo‐controlled studies with a total of 48 participants and 96 mescaline administrations. Single oral‐dose administrations (n = 16/dose) of mescaline at doses of 100–800 mg were used. Acute subjective and autonomic effects and acute and subacute adverse effects were recorded. Liver and kidney function, blood cell counts, and “flashbacks” were documented at the end of the studies. Results Positive subjective effects dose‐dependently increased and were higher than negative subjective effects for all mescaline doses. Autonomic effects increased moderately. Systolic blood pressure remained < 180 mmHg in all participants. Of all mescaline administrations, diastolic blood pressure > 100 mmHg was measured in 6%, heart rate > 100 beats/min was measured in 3% and body temperature > 38 °C was measured in 5%. The total number of acute adverse effects was 51, 12, 179, 143, 165 and 180 at 100, 200, 300, 400, 500 and 800 mg doses of mescaline, respectively. Nausea was dose‐limiting. Kidney and liver function and blood cell counts remained normal. “Flashbacks” were reported after 2% of all mescaline administrations. Conclusions These findings suggest that the administration of single mescaline doses up to 800 mg are safe in a controlled clinical setting with regard to acute psychological and physical harm in healthy participants.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use has published an addendum on estimands and sensitivity analysis in clinical trials along with related training materials. These define an estimand as a precise description of the treatment effect that reflects the scientific question of interest. In December 2022, the US Food and Drug Administration released draft guidance recommending estimands of interest be specified in bioequivalence trial protocols. However, experience in implementing estimands in clinical pharmacology trials is limited and so we introduce estimands and provide step‐by‐step considerations about the estimand thinking process in this setting. We also describe a particular case study, a bioequivalence trial, illustrating how the estimand framework can provide transparency and alignment throughout the design, conduct and analysis of the trial. This involves discussion of how to identify and handle intercurrent events, which are events that can affect interpretation of the drug or metabolite endpoints. Furthermore, we discuss the broader applicability of the estimand framework to other clinical pharmacology trials. Finally, we encourage further discussion between industry, academia, regulators and the International Council for Harmonisation on whether the estimand framework should be considered in all clinical pharmacology regulatory guidance documents.

Aim Brensocatib is an oral, selective, competitive and reversible dipeptidyl peptidase 1 inhibitor in development for the treatment of bronchiectasis. This study evaluated the pharmacokinetics (PKs), safety and tolerability of brensocatib in participants with varying degrees of renal impairment and normal renal function. Methods In this phase 1, multicentre, open‐label study, 28 participants with mild, moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] 60 to <90, 30 to <60 and 15 to <30 mL/min/1.73 m², respectively) or normal renal function (≥90 mL/min/1.73 m²) received a single oral 25‐mg dose of brensocatib. Blood samples were collected to measure brensocatib PKs at predetermined time points over the 14‐day study period. PK parameters were derived using noncompartmental methods. Results Demographic and baseline characteristics were similar across groups. There were no significant differences between groups in brensocatib PK parameters. The mean coefficient of variation (CV) of elimination half‐life of brensocatib was 37.0 (15.3), 42.8 (21.7), 36.3 (22.9) and 39.1 (17.8) h for mild, moderate, severe and normal renal function groups, respectively. Single‐dose brensocatib was quickly absorbed; all groups had a median time to maximum observed plasma concentration of 1 h. Regression model analyses indicated no significant relationships between selected brensocatib PK parameters and eGFR. No treatment‐emergent adverse events were reported during the study. Conclusion Single‐dose brensocatib was well tolerated. The study data do not indicate a significant effect of renal impairment on brensocatib elimination and systemic exposure, suggesting that dose adjustment of brensocatib is not necessary in participants with renal impairment. Clinical Trial Registration Number NCT05673603.

Aims The present study aimed to quantitatively investigate the potential drug–drug interaction (DDI) mechanism between meropenem (MEPM) and valproic acid (VPA). Methods In the present study, we firstly developed a physiologically based pharmacokinetic (PBPK) model of MEPM and VPA. The verified PBPK model was then used to quantitatively investigate the potential DDI between MEPM and VPA. The effect of genetic polymorphisms of acylpeptide hydrolase (APEH) on DDI was also evaluated. Results In our simulation, the plasma concentration of hydrolysate of VPAG decreased to 63% when combined with MEPM. Total plasma concentration of VPA before carbapenem use was 53.61 mg/L, whereas it was 45.42 mg/L during carbapenem use. The inhibition of hydrolysis of VPAG by MEPM alone could not result in a rapid and substantial decrease in the plasma concentration of VPA. Parameter sensitivity analysis showed that the changes of absorption played an important role in the maximum plasma concentration (Cmax) of VPA, whereas area under the plasma concentration–time profile (AUC) was more susceptible to elimination changes. In addition, a decrease in APEH activity had little impact on the plasma pharmacokinetics of VPA. Conclusions The DDI between MEPM and VPA might be a comprehensive result of multiple factors. On the basis of our simulation, interval medication of MEPM injection and VPA immediate release tablet at 4–6 h timed interval was recommended, or intravenous administration of VPA solution was preferred when combination regimen was necessary in a clinical setting.

Aims Since their emergence on the drug market, synthetic cannabinoids (SC) are still gaining increasing importance in forensic toxicology. The representatives of the so‐called new psychoactive substances have in common that they have not undergone preclinical safety studies. Hence, knowledge on toxicokinetic (TK) data is sparse. As an alternative to human studies not being allowed for ethical reasons, a sophisticated pig model was applied in the present study to assess the TK of the SC 5F‐MDMB‐P7AICA. Methods Pigs pulmonarily received 5F‐MDMB‐P7AICA via an ultrasonic nebulizer. The parent compound and its main metabolite 5F‐MDMB‐P7AICA dimethyl butanoic acid were determined in serum and whole blood using liquid chromatography–tandem mass spectrometry. Obtained data was analysed by population (pop) TK modelling. The final pop TK model parameters for pigs were upscaled via allometric scaling techniques for the prediction of human exposure. Results The serum concentration–time profiles of the parent and the pop TK analysis revealed that a 4‐compartment model best describes the TK data. The administration of the aerosol into the lung compartment follows zero‐order kinetics. A transit compartment was further included to accurately describe the time delay between detection of the parent and the metabolite. Despite the different structure, TK parameters were found to be comparable to other examined SC. Conclusion The predictions of human SC exposure suggest that multiple administration of 5F‐MDMB‐P7AICA substantially enhances the window of detection. The simulations pose extrapolation of the data used for model development with respect to dose linearity and allometric scaling to humans.

Aims The ideal dosing weight metric for enoxaparin remains elusive. Dosing remains focused on actual body weight, which may inadvertently increase the risk of bleeding in those with obesity, or ideal weight, which may underdose those with obesity. Our aim was to determine the optimal obesity‐adjusted enoxaparin dosing weight. Methods Multisite retrospective data were collected over a 2.0‐year period for those with minimum 48 h of in‐hospital twice‐daily enoxaparin and factor anti‐Xa level 3–5 h postdose (n = 220). Multiple linear regression calculated the associated variance between a range of nominal dosing weights and factor anti‐Xa levels, adjusted for renal function. Dosing weights were calculated as ideal body weight (IBW) and then adjusted for increasing percentages of weight above IBW, i.e. IBW + 10% above IBW, IBW + 20% etc. up to actual body weight. A similar approach was used for lean body weight (LBW). Results For body mass index ≥30 kg/m² optimal variance explained by dosing weight metrics was at IBW + 40% (23%) and similarly for LBW + 40% (23%). Using actual body weight (ABW) had lowest associated variance with factor anti‐Xa levels (18%) followed by unadjusted IBW (13%) or unadjusted LBW (19%). In those with body mass index <30 kg/m² there was similar associated variance in the ranges of IBW + 20–50% and LBW 10–40% (21%). Conclusion Compared to IBW + 40% or LBW + 40% use of ABW to calculate dose was poorly associated with factor anti‐Xa levels, as was IBW or LBW. IBW + 40% and LBW + 40% require further study as a dosing weight metric and may provide a more consistent factor anti‐Xa response in those with obesity.

Current methods of dose determination have contributed to suboptimal and inequitable health outcomes in underrepresented patient populations. The persistent demand to individualise patient treatment, alongside increasing technological feasibility, is leading to a growing adoption of model‐informed precision dosing (MIPD) at point of care. Population pharmacokinetic (popPK) modelling is a technique that supports treatment personalisation by characterising drug exposure in diverse patient groups. This publication addresses this important shift in clinical approach, by collating and summarising recommendations from literature. It seeks to provide standardised guidelines on best practices for the development of popPK models and their use in MIPD software tools, ensuring the safeguarding and optimisation of patient outcomes. Moreover, it consolidates guidance from key regulatory and advisory bodies on MIPD software deployment, as well as technical requirements for electronic health record integration. It also considers the future application and clinical impact of machine learning algorithms in popPK and MIPD. Ultimately, this publication aims to facilitate the incorporation of high‐quality precision‐dosing solutions into standard clinical workflows, thereby enhancing the effectiveness of individualised dose selection at point of care.

Aim To evaluate the effectiveness of a Bayesian adaptive dosing strategy in achieving target busulfan exposure in adult patients undergoing haematopoietic cell transplantation (HCT). Methods This study included 71 adult patients scheduled to receive high‐dose busulfan. Busulfan was administered to achieve a cumulative area under the curve (AUC) of 66.0 mg/L/h (16 000 μM/min), 82.60 mg/L/h (20 000 μM/min) or 87.6 mg/L/h (21 200 μM/min) depending on the regimen. Individual pharmacokinetic (PK) parameters of busulfan were estimated from three blood samples using a one‐compartment model and Bayesian estimation after the first standard dose. Individual PK parameters were used to adjust subsequent doses to achieve the target exposure. Results All patients had their dose adjusted after the first dose administration. The final deviation from the target AUC was significantly improved compared to the initial deviation after standard mg/kg dosing (mean absolute deviation 19.5% vs 11.7%, P < .01). In addition, the proportion of patients with marked deviation from target exposure (ie, >25%) decreased significantly from 31% after standard dosing to 10% after PK‐guided dosing (P < .01). Canonical busulfan‐related toxicity, specifically veno‐occlusive disease, was observed in 5% of patients who achieved successful PK‐guided dosing. In contrast, one‐third of patients with off‐target exposure with poor dosing experienced toxicity. Conclusion The Bayesian adaptive dosing strategy significantly improves the accuracy of achieving the target busulfan AUC in patients undergoing HCT. This approach not only reduces marked deviations from target exposure, but also reduces the incidence of busulfan‐related toxicity, thereby maintaining a favourable toxicity/efficacy ratio.

Aims Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). LEN therapy for HCC is associated with a high incidence of adverse events, including hypertension (HTN). However, the risk factors associated with LEN therapy remain unclear. This study investigated the incidence of LEN‐induced HTN (LENiHTN), and the relationship between HTN incidence and patient demographics in patients with HCC receiving LEN therapy. Methods This was a single‐centre, retrospective study of patients with HCC who received LEN therapy between 19 April 2018 and 30 September 2020. The observation period was from 1 week before the start to 1 month after the end of LEN administration. Results Seventy‐five patients with HCC were enrolled. Any grade LENiHTN was found in 74.7% of patients. Among patients with LENiHTN, the use of 2 or more antihypertensive agents before starting LEN was less common (P = .007); serum potassium (K) and albumin–bilirubin score (ALBI) were lower (P = .013 and 0.038, respectively); and albumin (Alb) was higher (P = .025). The cut‐off values of K, Alb and ALBI for HTN were estimated at 4.1 mEq L⁻¹, 3.1 g dL⁻¹ and −1.736, respectively. In the multivariable analysis, low K (adjusted HR: 2.078) and low ALBI (adjusted HR: 2.845) were independent risk factors for LENiHTN. Conclusion Low K, high Alb and low ALBI were independent risk factors for LENiHTN. Systematic evaluation of HTN risk and early intervention for HTN prevention among high‐risk patients can markedly enhance LEN therapy efficacy and use.

Aims Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is a vital treatment for various paediatric malignant and nonmalignant diseases. The conditioning treatment before allo‐HSCT is crucial for successful engraftment. Treosulfan, a cytotoxic prodrug, has gained popularity due to its lower toxicity compared to traditional alkylating agents used for conditioning treatment. Methods We investigated the relationship between pharmacokinetics and pharmacodynamics of treosulfan in paediatric patients, in a substudy pooling from 2 multicentre phase 2 clinical trials. A total of 83 children with malignant and nonmalignant diseases received treosulfan‐based conditioning. Treosulfan exposure and its relationship with clinical outcomes, including survival, graft failure and graft‐vs.‐host disease, were investigated. Results Our findings reveal no significant association between treosulfan exposure and the key clinical outcomes or toxicity (P‐values between .22 and .99), if the dosing is based on the approved product information. Conclusion These findings suggest that treosulfan exposure after standardized body surface area‐based dosing is appropriate in paediatric allo‐HSCT.

Sulphonamides and trimethoprim, although generally well‐tolerated, have been temporally associated with aseptic meningitis. To address its presentation and outcome, a literature search was performed. We retained articles reporting patients with features of acute aseptic meningitis following intake of trimethoprim, sulfamethoxazole or sulfisoxazole. A cerebrospinal fluid investigation in ≥1 episode was a prerequisite for inclusion. Sixty articles reporting on 74 patients experiencing a total of 155 episodes were retained. Forty‐five (61%) patients had one or more recurrences. Median age at first episode was 43 (interquartile range [IQR] 23–61) years. Symptoms presented within 48 (IQR 6–168) hours of intake at the first episode and within 1.3 (IQR 1–5) hours at recurrences (p < .0001). Cerebrospinal fluid analysis revealed a predominantly neutrophilic (82%, IQR 65%–94%) pleocytosis (180, IQR 38–507 10⁶ cells/L), without low glucose or high proteins. Recovery took place within 2 (IQR 1–3) days after stopping the suspected agent. All but one patient completely recovered.

Aims This study evaluated the 10‐year consumption and economic patterns of classical analgesics, adjuvants and opioids in Portugal (2012‐2022), and conducted a comparative analysis between Portugal, Spain and Denmark to explore the consumption patterns among these countries for 2022. Methods Data on sales and national health service (NHS) costs were obtained from the Portuguese National Authority of Medicines and Health Products. Sales data were converted to defined daily dose (DDD) per 1000 inhabitants per day according to the Anatomical Therapeutic Chemical (ATC) classification/DDD methodology, while comparisons between Spain and Denmark were evaluated with the chi‐square test, when appropriate. Results The findings reveal that classical analgesics use in Portugal remained stable during the period 2012‐2022, with ibuprofen being the most consumed. Adjuvants, specifically gabapentinoids, experienced an 84% increase in use, primarily attributed to pregabalin. Weak opioids, led by tramadol, witnessed a 117% rise in use, while strong opioid use, led by tapentadol, increased by 618%. Portugal presented the lowest overall opioid consumption when compared to Denmark and Spain in 2022. Economic trends indicated a heightened NHS expenditure on analgesics, primarily driven by increased opioid use. Notwithstanding, there was no significant burden on relative expenditure over the 10‐year period. Conclusions Portugal presented a major increase in both weak and strong opioid prescriptions, aligning with the trends for Spain and Denmark. The development and approval of generic medicines and vigilant market monitoring are imperative strategies for managing the escalated costs resulting from heightened consumption, particularly concerning opioids.