British journal of clinical pharmacology最新文献

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.

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.

Prescribing cascades occur when medication is prescribed to prevent/treat the adverse effects of another medication and may be intentional/unintentional. This study examines the prevalence of nine prescribing cascades (ThinkCascades) in The Irish Longitudinal StuDy on Ageing (TILDA). A prospective cohort study examined those aged ≥50 years with three consecutive data collection waves (N = 6118) recorded between Wave 1 (2009/2011) and Wave 5 (2018). Nine separate analysis sets were created, representing each ThinkCascade. Exposure was the incident use of Drug A at wave x. A prescribing cascade was defined as the incident use of Drug B at wave x + 1, with continued use of Drug A. Five out of nine ThinkCascades were identified over 9 years of follow-up. Overall, 24 participants experienced at least one ThinkCascade, representing a 2.1% prevalence (n = 1153 eligible). This low prevalence may indicate prescribers' awareness of prescribing cascades. Higher event rates are required to examine any association with adverse health outcomes.

This review focuses on the development of radiopharmaceutical imaging agents and radioligand therapeutics for paediatric use. Nuclear medicine plays an important role in the diagnosis and treatment of various childhood conditions, including cancers, infections and brain disorders. It assesses organ function alongside structure, allowing for earlier and more specific diagnoses, crucial in children where symptoms can be nonspecific. This review discusses the current landscape of paediatric radiopharmaceuticals, including commonly used diagnostic imaging agents and radioligand therapies, as well as drug candidates in clinical development. However, developing radiopharmaceuticals for children presents several challenges. These include ethical considerations, the need for tailored dosing and formulations due to physiological differences between children and adults, limited availability of paediatric-specific data and regulatory hurdles. The article provides an overview of current approaches for paediatric dose determination, including the use of consensus guidelines and ongoing efforts to refine dosimetry models. The review further addresses clinical considerations and regulatory pathways for paediatric radiopharmaceuticals, including the roles of the Food and Drug Administration (FDA) and European Medicines Agency (EMA), as well as specific legislation like the RACE Act in the United States. Finally, regulatory pathways for paediatric radiopharmaceuticals, including the role of paediatric investigation plans (PIPs) and initial paediatric study plans (iPSPs), are discussed. The importance of dose optimization and innovative clinical trial designs to advance the development of safe and effective radiopharmaceuticals for children is highlighted.

Aims: To characterize psychotropic medicine utilization and identify its correlates in injured Australian workers with back and neck-related conditions following a workers' compensation claim.

Methods: Psychotropic medicine utilization (antidepressants, gabapentinoids, anxiolytics, hypnotics/sedatives and antipsychotics) was examined among 22 595 injured workers with accepted claims (2010-2016) in Victoria, Australia, over three years post-claim. The defined daily dose (DDD) per 1000 workers per day was used to describe utilization and temporal trends. Zero-inflated negative binomial regression was employed to identify its determinants.

Results: The overall utilization (DDD/1000/day) of psychotropics for all-injured workers was 135.4 (CI: 128.8-142.1), highest for antidepressants (74.2, CI: 70-78.5), followed by gabapentinoids (31.6, CI: 29.7-33.5), anxiolytics (16.1, CI: 14.7-17.6), hypnotics/sedatives (10.6, CI: 9.4-11.8) and antipsychotics (2.9, CI: 2.3-3.4). Workers with longer periods of disability showed increasing utilization across each medicine group and for psychotropic medications overall. Middle age was associated with higher utilization while higher socioeconomic status and living regionally were associated with lower psychotropic utilization. Gabapentinoid utilization (more than doubled (109.2%) from 20.7 in 2010 to 43.3 in 2016. Conversely, anxiolytics and hypnotics/sedatives utilization showed a relative decrease over the study period. The utilization of psychotropics increased among injured workers across the course of their claim.

Conclusions: Psychotropic medicine utilization in compensated Australian workers with back or neck conditions was high, particularly in those with longer disability duration. Psychotropic prescribing has changed over time, with a notable increase in gabapentinoid utilization. Furthermore, a trend indicating long-term or higher-dose use of psychotropics was observed, raising concerns of potential overuse.

Purpose: The aim of this is to test the feasibility of identifying unsuspected, previously unknown drug-outcome associations, that is, collateral drug benefits (CDBs), through a systematic screening analysis of real-world health-care databases. Ultimately, such screening could lead to drug repurposing.

Methods: We analysed data from the Danish National Prescription Registry and the Danish Patient Registry, covering 1996-2022. The study employed the sequence symmetry analysis (SSA), an exposure-anchored self-controlled design that compares the number of clinical outcomes in symmetrical windows before and after the exposure drug initiation. To verify the directionality and robustness of these associations, we incorporated the case-crossover (CCO) design, another self-controlled design. The obtained associations were ranked according to the hypothetical number of averted outcomes, if a causal effect could be assumed.

Results: The analysis included 1.3 billion prescriptions and 260 million diagnosis records, resulting in 27 820 976 drug-diagnosis combinations and 7 920 323 drug-drug combinations. Preventive associations in both the SSA and CCO were found in 7795 drug-diagnosis and 5088 drug-drug combinations. A manual review of the highest ranked 100 associations resulted in 11 drug-diagnosis and 2 drug-drug associations as potential unknown CDBs. Notable findings included selective serotonin reuptake inhibitors linked to a lower risk of certain cardiovascular outcomes, anticholinesterases associated with fewer delirium diagnoses and progestogens associated with a reduced risk of obesity.

Conclusions: The study confirms that hypothesis-free screening is feasible and that combining sequence symmetry analysis and case-crossover designs can identify potential collateral drug benefits. Further validation studies are required to confirm these findings and explore their clinical implications.