British journal of clinical pharmacology最新文献

Aims: Liver cytochromes (CYPs) play an important role in drug metabolism but display a large interindividual variability resulting both from genetic and environmental factors. Most drug dose adjustment guidelines are based on genetics performed in healthy volunteers. However, hospitalized patients are not only more likely to be the target of new prescriptions and drug treatment modifications than healthy volunteers, but will also be more subject to polypharmacy, drug-drug interactions, or to suffer from disease or inflammation affecting CYP activities.

Methods: We compared predicted phenotype based on genetic data and measured phenotype using the Geneva cocktail to determine the extent of drug metabolizing enzyme variability in a large population of hospitalized patients (>500) and healthy young volunteers (>300). We aimed to assess the correlation between predicted and measured phenotype in the two populations.

Results: We found that, even in cases where the genetically predicted metabolizer group correlates well with measured CYP activity at group level, this prediction lacks accuracy for the determination of individual metabolizer capacities. Drugs can have a profound impact on CYP activity, but even after combining genetic and drug treatment information, the activity of a significant proportion of extreme metabolizers could not be explained.

Conclusions: Our results support the use of measured metabolic ratios in addition to genotyping for accurate determination of individual metabolic capacities to guide personalized drug prescription.

Aims: To examine the cost-effectiveness of first-line systemic therapies recommended by the National Comprehensive Cancer Network guidelines for Unresectable Hepatocellular Carcinoma (uHCC) from the US social and payer's perspective.

Methods: A cost-effectiveness analysis was conducted using a three-state partitioned survival model to assess the cost-effectiveness of atezolizumab plus bevacizumab, tremelimumab plus durvalumab, durvalumab, lenvatinib and sorafenib as first-line treatments for uHCC. Clinical efficacy was derived from a published network meta-analysis. Cost and utility inputs were collected from literature. Main outcomes measured were quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). Univariate and probabilistic sensitivity analyses, as well as scenario analyses were performed.

Results: Over a 10-year time horizon, atezolizumab plus bevacizumab yielded the highest QALYs. Compared to sorafenib, atezolizumab plus bevacizumab, tremelimumab plus durvalumab and lenvatinib had ICERs of $196 704/QALY, $800 755/QALY and $2 032 756/QALY, respectively. Sorafenib was dominated by durvalumab due to lower QALYs and higher costs. At a willingness-to-pay threshold of $150 000/QALY, probabilistic sensitivity analysis revealed that durvalumab had a 99.96% probability of providing the highest net monetary benefit.

Conclusions: At a willingness-to-pay threshold of $150 000/QALY, durvalumab is likely the most cost-effective first-line systemic therapy for uHCC compared to sorafenib. Although atezolizumab plus bevacizumab yielded the highest QALYs, their ICERs exceeded the commonly accepted cost-effectiveness threshold ($150 000$ per QALY gained). These findings can inform clinical decision-making, resource allocation and future research priorities in managing uHCC.

Aims: Recording the indication for a medicine in the prescription supports communication. In May 2023, our district hospitals made the free-text indication field in prescriptions compulsory for all medicines in the inpatient prescribing system. This study aimed to evaluate the effect of introducing a compulsory indication field in an inpatient prescribing system.

Methods: Text in the indication field was manually classified as an indication, 'other text', 'rubbish text', 'to be determined' and 'blank'. Prescribing data were extracted from the district data warehouse. The change in proportion of prescriptions with an indication was compared for 8 weeks after introduction of a compulsory indication field to an equivalent 8 weeks in 2022. Secondary outcomes included medication cessation and indication recording before discharge.

Results: We analysed 81 634 prescriptions before and 82 726 after indications were made compulsory. The proportion of prescriptions with an indication increased from 29.2% to 75.6%. 'Rubbish text' increased from 0% to 2.3%, 'other text' from 2.5% to 14.7%, and 'to be determined' from 0.0% to 6.6%. Of 5557 prescriptions with 'to be determined' initially, 18.1% were ceased and 2.7% had an indication before discharge.

Conclusions: After making the prescription indication field compulsory, the proportion of medicines with an indication increased from 29% to 76%, with only a small increase in 'rubbish text'. Following the system change, the quality of information recording improved but there was no change in medicine use. Compulsory fields should be combined with improvements in other components of care to improve medicine use.

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: 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.