British journal of clinical pharmacology最新文献

Aims: The potential of mechanistic biomarkers to improve prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration, as well as to characterize their natural variability and impact of diurnal variation.

Methods: Serum samples from 227 healthy volunteers were recruited as part of a cross-sectional study; of these, 25 subjects had weekly serial sampling over 3 weeks, while 23 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), High Mobility Group Box-1 (HMGB1), total Keratin-18 (K18), caspase-cleaved Keratin-18 (ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage Colony-Stimulating Factor-1 (CSF-1) were assayed.

Results: Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models. Intra-individual variability was found to be non-significant, and there was no significant impact of diurnal variation.

Conclusion: Reference intervals for novel DILI biomarkers have been described. An upper limit of a reference range might represent the most appropriate mechanism to utilize these data. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification as required by regulatory authorities.

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 use of (GLP-1 RAs) among pregnant women is escalating, yet safety data remain insufficient. This study aims to comprehensively assess adverse drug reactions (ADRs) associated with GLP-1 RAs in pregnant women using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods: FAERS data from 2004 to 2023 were analysed, focusing on pregnant women aged 15-55 years exposed to GLP-1 RAs. Descriptive analysis covered patient demographics, clinical aspects and annual trends. Disproportionality analysis used reporting odds ratio and Bayesian confidence propagation neural network to detect ADR signals.

Results: Among 354 cases with 1671 ADR reports, an exponential rise in reported cases since 2012 was observed. The median age of the affected women was 36 years, with 50.56% classified as advanced age pregnant. The disproportionality analysis revealed significant ADR signals in the reproductive (n = 199) and gastrointestinal systems (n = 155), with spontaneous abortion and pre-eclampsia being the most concerning. Additionally, while no significant dose-related differences were found, the age subgroup analysis indicated heightened risk across most age groups, except for those aged 20-24 years, highlighting the need for careful monitoring of GLP-1 RAs used during pregnancy.

Conclusion: This study highlights increasing GLP-1 RA use in pregnant women and identifies potential pregnant ADRs. GLP-1 RAs are not recommended for use during pregnancy. In cases of unintentional exposure, close monitoring is advised to ensure maternal and foetal safety. These findings provide valuable insights for clinicians making informed decisions and regulators considering using GLP-1 RA in pregnancy.

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: 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 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: 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.

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.

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.