British journal of clinical pharmacology最新文献

Serenoa repens is widely used for benign prostatic hyperplasia and androgenetic alopecia due to its 5alpha-reductase inhibitory activity. However, emerging reports describe sexual, psychiatric and somatic adverse effects resembling a post-finasteride syndrome. Cases were identified from self-reports submitted to an Italian online forum dedicated to post-finasteride syndrome. All individuals underwent structured clinical evaluation at the CERFIT centre, including medical and psychiatric history, symptom assessment and available laboratory data. Reports were documented using the official Italian pharmacovigilance forms (www.vigierbe.it), and causality was independently assessed by two clinicians using the Naranjo Scale. Reported doses ranged from 120-900 mg/day, with adverse effects emerging within 1 month in 61% of cases. Symptoms were severe and persistent (mean duration 4.7 years), with complete remission in only three patients. According to the Naranjo Scale, causality was deemed 'probable' in 54% of reports; combined therapies (e.g., S. repens plus finasteride) were associated with increased severity and persistence. A possible post-Serenoa syndrome marked by persistent sexual and neuropsychiatric symptoms may represent an underestimated issue. Misbelief in the absolute safety of S. repens likely hinders reporting. Given its widespread, unsupervised use, further pharmacovigilance and clinical studies are warranted.

Aim: Interleukin 5 is an important target for the treatment of eosinophil-associated diseases including eosinophilic asthma. SHR-1703 is an innovative humanized anti-interleukin-5 monoclonal antibody designed to improve asthma control. This study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SHR-1703 in asthma patients.

Methods: In the single ascending dose study, eligible patients were randomized to receive SHR-1703 (400 or 600 mg) or placebo and followed up to Day 281. Primary endpoints were safety and tolerability.

Results: Most treatment-emergent adverse events (TEAEs) were mild or moderate. The incidence of TEAEs was comparable between the SHR-1703 and placebo groups. The median (range) T_max was 13.9 (7.0-14.1) and 10.3 (10.0-14.0) days for SHR-1703 400 and 600 mg, respectively. SHR-1703 at 400 and 600 mg has an extended mean (standard deviation) half-life of 75.1 (11.1) and 72.6 (12.7) days. Meanwhile, SHR-1703 markedly and rapidly reduced peripheral blood eosinophils by over 50% in 1 day. The largest mean (standard deviation) decline of eosinophils from baseline reached 87.7 (5.8)% for 400 mg and 91.1 (4.7)% for 600 mg, with the effect sustained over 100 days. The eosinophil levels remained below the baseline up to the end of follow-up.

Conclusion: SHR-1703 was well-tolerated and showed promising efficacy in eosinophilic asthma patients.

Aim: The impact of antibiotics allergy labels (AALs) on intensive care unit (ICU) patients remains unclear. This study aimed to evaluate the effect of AALs on clinical outcomes in ICU patients.

Methods: A retrospective cohort study was conducted on ICU patients in Huashan Hospital, Shanghai, China, between January 2005 and December 2019. AALs were identified from electronic health records. Clinical characteristics and outcomes were compared between patients with and without AALs before and after propensity score matching (PSM). Multivariable logistic regression analysis was conducted to identify risk factors for carbapenem-resistant Enterobacterales (CRE) acquisition.

Results: Among 1514 patients, 183 (12%) had AALs, with penicillin being the most frequently reported (78%). After PSM, patients with AALs received fosfomycin more frequently (23% vs. 10%, p = .001) and had lower use of third-/fourth-generation cephalosporins and β-lactam/β-lactamase inhibitor combinations (BLBLIs) (46% vs. 70%, p = .000). Median antibiotic duration was slightly shorter in the AAL group (10 vs. 11 days, p = .023). Mortality and 30-day readmission rates did not differ significantly. However, extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) acquisition was lower in the AAL group (3% vs. 8%, p = .043). Patients with AALs had a shorter hospital stays (12 vs. 14 days, p = .002) and reduced hospitalization costs (44 954 vs. 59 279 Yuan, p = .001).

Conclusion: AALs significantly altered antibiotic prescribing but were not associated with worse outcomes. Unexpectedly, AALs correlated with lower ESBL-E acquisition, shorter hospitalization and reduced costs, suggesting complex effects that warrant further prospective investigation.

Aim: Sunitinib has marked pharmacokinetic (PK) and pharmacodynamic (PD) interpatient variability. This study evaluated the utility of extensive excretory/metabolic/PD pharmacogenomics (PGx) with hepatic functional imaging (HNI) to explore their associations with sunitinib PK/PD (toxicity/response) and progression-free survival (PFS), respectively.

Methods: Eligible patients (pts) suitable for sunitinib therapy. At baseline: (i) PGx: blood analysed by the Affymetrix DMET™ Plus Array (1936 variants/225 genes) and Sanger sequencing (HNF1A, FLT3, VEGFR2, VEGFR3, RET, PDGFRα, TNFα). (ii) HNI: pts given IV 800 MBq ^99mTc-MIBI, imaging data analysed for hepatic extraction/excretion parameters (CL_HNI, T_1/2-HNI, 1hRET, HEF, T_d1/2). In cycles 1 and 2, bloods taken for sunitinib parent (SU), metabolite (SU12662) and total SU (metabolite + parent) PK. Associations evaluated between (i) HNI parameters and (2) PGx, with sunitinib PK, toxicity/response and PFS.

Results: N = 15 pts. The two most significant associations in either direction between PGx variants or HNI parameters (p < .05) for: (i) PK included: (a) SU logAUC_0-14days with HEF, ATP7B (rs1801246) and UGT8 (rs4148254); (b) SU logAUC_0-28days, with T_d1/2, SLC15A1 (rs8187832) and SLC10A2 (rs188096); (c) SU12662 logAUC_0-14days with HEF, ABCC3 (rs11568591), PPARD (rs1003973) and SLC15A1 (rs8187840); and (d) SU12662 logAUC_0-28days with SULT1A2 (rs1059491) and SLC10A2 (rs188096). (ii) Toxicity: (a) Diarrhoea grade 1+ with HEF, VEFGR3 (rs307826) and AKAP9 (rs7785971); (b) ≥grade 3 AEs with CBR1 (rs998383); (iii) overall response rate with SULT1E1 (rs1881668) and GSTA2 (rs2180314); and (iv) PFS with CYP4Z1 (rs4926802) and CYP2A6 (rs28399442).

Conclusions: Exploratory associations were observed between sunitinib PK/PD with hepatic functional imaging with extensive pharmacogenomics. Further validation is required.

Background and aim: Mineralocorticoid receptor antagonists (MRAs) effects on glucose metabolism and diabetes risk are inconsistently reported. We conducted a meta-analysis to evaluate the association between MRA use and glycaemic profile change as well as the risk of diabetes occurrence and progression.

Methods: Eligible studies enrolling adult patients receiving spironolactone, eplerenone or finerenone for any clinical indication were included. The primary outcomes were new-onset diabetes mellitus and change in HbA1c (%) levels. A secondary outcome was alterations in glucose levels.

Results: This meta-analysis of 20 studies evaluated the effects of MRAs on glycaemic parameters. Spironolactone significantly reduced endpoint HbA1c (%) compared to placebo  (mean difference -0.27%, 95% CI: -0.38 to -0.15; P < 0.00001; I² = 31%) and in change-from-baseline fasting glucose (-0.24 mmol/L, 95% CI: -0.27 to -0.21; P < 0.00001; I² = 0%) over 4-24 weeks. Similarly, change-from-baseline HbA1c (%) was significantly lowered (-0.19%, 95% CI: -0.29 to -0.08; P = 0.0004; I² = 33%). In a head-to-head comparison, spironolactone and eplerenone showed no significant difference in HbA1c (%) change (-0.03%, 95% CI: -0.50 to 0.43; P = 0.89; I² = 88%). In the FINEARTS-HF trial, finerenone significantly reduced the risk of developing new-onset diabetes by 24%. Lastly, finerenone was associated with slightly lower rates of insulin initiation (8.1% vs. 9.0%) and escalation in glucose-lowering medication classes (32.1% vs. 34.0%) compared to placebo.

Conclusions: Spironolactone use is associated with modest but statistically significant improvements in HbA1c and glucose levels compared to placebo, suggesting a potential glycaemic benefit.

Herpes simplex virus (HSV) may cause recurring oral or genital ulcers. We report a series of patients nonresponsive to suppressive valacyclovir therapy, explained by subtherapeutic acyclovir plasma levels. After a dose increase, or in some patients only after concomitant prescription of cimetidine, adequate levels were reached associated with significant clinical improvement.

Aim: The purpose of this study is to estimate the risk of gastrointestinal bleeding (GIB) by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) individual agents.

Methods: A systematic review was conducted for each unique antidepressant (i.e. SSRI: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and SNRIs: desvenlafaxine, venlafaxine, and duloxetine) combined with search terms for GIB in PubMed and EMBASE from inception to October 2025. Articles including results on specific antidepressants and GIB risk were included.

Results: From a total of 1218 identified publications, 20 studies were included and analysed using a random-effect meta-analysis. Twelve studies (60%) used a case-control design, three (15%) a cohort study design, one (5%) a case cross-over, one (5%) used both case-control and cross-over designs and three (15%) were randomized control trials (RCTs). Studies sample sizes ranged from 666 235 from a Medicaid population to 1280 from 43 hospitals participating in a RCT. Fluoxetine had the most studies providing evidence (19 studies) and fluvoxamine and duloxetine had the least (five studies). Each antidepressant showed an increased risk of GIB. Venlafaxine had the highest estimated risk (OR 1.50, 95% CI 1.32-1.70), followed by citalopram (OR 1.38, 95% CI 1.17-1.62) and fluoxetine (OR 1.38, 95% CI 1.26-1.51). Paroxetine had the lowest GIB risk (OR 1.31, 95% CI 1.07-1.62).

Conclusion: GIB is an uncommon adverse event, but this analysis demonstrates that the risk of GIB is elevated for commonly used SSRI/SNRI products, highlighting the relevance for those patients with an increased risk of GIB.

Aims: Children with primary immunodeficiency (PID) and secondary antibody deficiency (SAD) often require immunoglobulin replacement therapy due to low plasma immunoglobulin G (IgG) levels and recurrent infections. Existing pharmacokinetic models for immunoglobulin in PID patients predominantly focus on adults, with limited attention to secondary antibody deficiencies and a lesser emphasis on paediatric populations. This study aims to investigate the pharmacokinetic properties of IgG in paediatric patients with PID and SAD.

Methods: Population pharmacokinetic analysis for PID and SAD children treated with intravenous immunoglobulin at a tertiary paediatric centre was conducted using NONMEM® (7.5.1). Dosing simulations to achieve therapeutic levels of 6 and 8 gL^-1 were performed.

Results: A population pharmacokinetic analysis of 64 patients (median age 4.08 years, range 0.06-16.8) was performed. A two-compartment model with first-order elimination, incorporating both additive and proportional residual error, adequately described the data. Interindividual variability was modelled on clearance, volume of distribution and baseline IgG levels, with allometric scaling to a 70-kg body weight applied a priori. The estimated clearance was 0.308 L^-1 day^-1 70 kg^-1 (95% CI 0.23, 0.67), and the volume of distribution was 10.96 L^-1 70 kg^-1 (95% CI 5.97, 15.79). Patients with SAD exhibited a lower clearance rate of 54% compared with PID patients. Dosing simulations indicated that the recommended SAD dosing regimen maintained therapeutic IgG levels in the simulated population. However, only 44.8% to 51.9% of patients with PID achieved target IgG levels with the standard regimen.

Conclusions: This study provides insights into immunoglobulin pharmacokinetics in paediatric PID and SAD patients, guiding optimised dosing strategies. Administering a loading dose would improve the probability of maintaining therapeutic IgG levels during the 4-week dosing interval.

Aims: This study aimed to develop and validate a population pharmacokinetic-pharmacodynamic (pop-PK-PD) model to describe carboplatin-induced myelosuppression in cancer patients and support dose individualization.

Methods: Data from 580 cancer patients treated with carboplatin at Amsterdam UMC between 2019 and 2022 were used for model development, focusing on lung, gynaecological and gastric/oesophageal cancers. Platelet (PLT) and neutrophil (NT) counts, along with patient-specific covariates (e.g., age, serum albumin, eGFR), were extracted from Electronic Health Records and used in the analysis. Given the absence of pharmacokinetic (PK) samples, PK parameters were derived from a literature carboplatin pop-PK model. Model applicability to inform personalized carboplatin dosing was evaluated on a separate cohort of 210 patients treated between 2022 and 2024 in the same centre.

Results: Two joint Friberg models effectively described carboplatin-induced myelosuppression. Serum albumin, eGFR and paclitaxel and pemetrexed co-medications were included in the final model. On the test cohort, >85% of NT and >87% of PLT observations fell within the 90% confidence interval of Bayesian model predictions, confirming that the model can support dose adjustments for subsequent treatment cycles. An example of model-based dose adjustments is also presented with a simulation study.

Conclusions: The pop-PK-PD model demonstrated strong performance in describing and predicting carboplatin-induced myelosuppression, thus providing a valuable strategy for dose personalization. Further refinements and validation steps are needed before integrating such an approach into clinical workflows.

Aims: A plasma clozapine concentration below 350 ng/mL may result in treatment failure; however, a rapid method for predicting whether a patient's plasma concentration meets this threshold is lacking. This study aimed to develop a nomogram to predict the risk of subtherapeutic clozapine concentrations in treated patients.

Methods: Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with subtherapeutic clozapine concentrations. A predictive nomogram prediction model was then constructed based on these factors. The ethics committee of the Xi'an Mental Health Center approved the study (XAJWKY-2024034).

Results: Multivariate logistic regression analysis identified daily dose (OR = 0.987, 95% CI: 0.984-0.990, P < 0.001) and sex (OR = 3.863, 95% CI: 2.597-5.746, P < 0.001) as independent factors influencing the subtherapeutic concentrations of clozapine. A predictive nomogram was constructed based on a multivariable prediction model, which demonstrated good accuracy and discriminative ability, with an area under the curve of 0.760. Validation of the model's calibration curve resulted in a concordance index of 0.764. A decision curve analysis revealed that the nomogram predicting the risk of subtherapeutic plasma clozapine concentrations exhibited a greater net benefit value, ranging from 10% to 62%. Additionally, our research indicated that the daily dosage of clozapine required for male patients to achieve a plasma concentration of 350-600 ng/mL ranges from 228.8 to 392.2 mg, whereas it ranges from 154.2 to 264.3 mg for female patients.

Conclusions: The constructed nomogram was effective at predicting the risk level associated with subtherapeutic clozapine plasma concentrations.