British journal of clinical pharmacology最新文献

Aims: Mycophenolic acid (MPA), the active component of enteric-coated mycophenolate sodium (EC-MPS), exhibits highly variable pharmacokinetics. Only a few population pharmacokinetic (popPK) models and Bayesian estimators (MAP-BE) exist for estimating MPA AUC and all in renal transplantation. This study aimed to develop a popPK model and MAP-BE for MPA AUC estimation using a limited sampling strategy (LSS) in solid organ transplant (SOT), haematopoietic stem cell (HSC) recipients and patients with autoimmune diseases (AID) on EC-MPS.

Methods: Full and sparse MPA pharmacokinetic profiles were extracted from our ISBA system, split into development (75%) and validation (25%) sets. An additional extraction was performed after the modelling process for external validation. Pharmacokinetic parameters were estimated using Monolix® (SAEM algorithm). Several absorption models (first order, transit, gamma) were compared. AUC_predicted by MAP-BE and LSS was compared to the all-sample MAP-BE AUC_reference using Simulx®.

Results: We included 153 PK profiles (863 concentration) from 129 patients (116 SOT and HSC, 13 AID), median [min-max] age 45 years [6-80]. A one-compartment model with double-gamma absorption and first-order elimination best fitted the data. The final model included the EC-MPS indication and inter-occasion variability on gamma rate constants. Main PK parameters (mean ± SD) were Cl/F = 4.99 ± 2.22 L/h and Vd/F = 12.60 ± 0.08 L. The optimal LSS at 20 min, 2 h and 4 h post-dose showed good performance in both validation sets (rMPE -2.67% and -4.91%; RMSE 13.55% and 13.47%).

Conclusions: The double-gamma absorption model provided an accurate fit. The MAP-BE offers a tool for EC-MPS dose individualization in SOT, HSC and AID patients.

Continuation of opioids at transitions of care increases the risk of long-term opioid use and related harm. To our knowledge, no study has examined the implementability of opioid deprescribing interventions at transitions of care. Our scoping review aimed to identify the type of opioid deprescribing interventions employed at transitions of care and assess the implementability of tested interventions. Nine electronic databases were searched on 15 May 2023 for English-language studies of adults transitioning between care settings, where opioid deprescribing interventions targeting patients, clinicians or health systems were implemented. Implementability was assessed using the Cochrane Intervention Complexity Assessment Tool for Systematic Reviews to determine intervention complexity, and mapped to the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to understand the process evaluation. A total of 79 studies were identified, with 94.0% (n = 74) examining hospital-to-home transitions. Mixed interventions (combination of pharmacological and nonpharmacological) were tested in 49.0% (n = 39) of studies. Pharmacological interventions were identified in 31.0% (n = 24) of studies, and the remaining 20.0% (n = 16) applied nonpharmacological interventions. Mixed interventions comprising multiple components were the most complex and resulted in reduced opioid use across transitions of care in 28.0% (n = 22) of studies. Few studies reported on RE-AIM dimensions including implementation (5.0% of studies), reach (4.0%), adoption (4.0%) and maintenance (0%). Most opioid deprescribing interventions targeted hospital to home care transition with mixed results in opioid deprescribing. Further research should consider the implementability of interventions during transitions of care to elucidate the impact of opioid deprescribing interventions across care settings.

Evidence indicates a lack of clarity regarding the contributions of interventions aimed at optimizing pharmacotherapy, primarily guided by pharmaceutical care, for clinically significant improvements in older individuals. Thus, there is a need to deepen the understanding of this scenario and the factors involved. Therefore, this study aims to map and summarize scientific evidence regarding experiences and strategies employed in providing pharmaceutical services and interventions in geriatric wards. A scoping review was conducted based on 3 electronic databases (PubMed, EMBASE and Web of Science). Studies meeting the inclusion criteria, published up to September 2024, and in English, Spanish or Portuguese were selected. Experimental and observational studies were eligible for inclusion. Screening, eligibility, extraction and assessment of the studies were carried out by 2 independent researchers. The exploration of bibliographic databases yielded 3,976 references, and 40 studies were deemed suitable for inclusion. Predominantly conducted in countries with high human development, these studies categorized services and interventions as: (i) medication review; (ii) medication reconciliation; and (iii) pharmaceutical counselling. Highlighted tools included STOPP and START criteria, Beers criteria, and the Medication Appropriateness Index, facilitating identification of issues such as potentially inappropriate medications (27.6-90.8% of older individuals using at least 1 potentially inappropriate medication), drug-related problems (34.5-98.2% of patients with at least 1 drug-related problem) and adverse drug events (58-88.4% of patients with at least 1 adverse drug event). The acceptance rate of interventions exhibited considerable variation (13-95.3%). Only 10 studies evaluated clinical outcomes in patients. Barriers included the need for additional training for pharmacists in geriatrics, significant time investment, lack of continuity in assessments and a lack of recognition of interventions by other members of the multiprofessional team. There is a clear trend towards improving medication prescription adequacy and contributing to the quality of pharmacotherapy through pharmaceutical services and interventions in geriatric wards. However, several gaps still need to be addressed, and this review emphasizes identifying obstacles to be overcome, providing guidance for future investigations.

Aims: Sex and gender may influence penicillin allergy label (PAL) prevalence and outcomes. This review evaluates the effectiveness and safety of direct delabelling (DD) and oral challenge (OC) for low-risk patients and examines sex and gender differences in reporting and outcomes.

Methods: We searched PubMed, Database of Abstracts of Reviews and Effects, ClinicalTrials.gov, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, medRxiv, Ovid MEDLINE, and Ovid EMBASE until February 2024 for studies including DD or OC compared to no intervention, skin testing or other methods. Two reviewers assessed quality. Meta-analyses were conducted, and subgroup analyses were carried out if I² >   75%. Descriptive data was analysed using NVivo 14 and reported narratively.

Results: From 1046 screened studies, 28 met inclusion criteria (two RCTs, 26 quasi-experimental studies). Sex at baseline was reported in 86% of studies, with 61% females: 18% disaggregated outcomes by sex with a female mean delabelling rate of 66%. Gender variables were not reported. OC was not found to be more or less as effective comparaed to skin testing in RCTs (risk ratio [RR] 1.04; 95% confidence interval [CI] 0.95, 1.13, I² = 74%). DD interventions had a 27% delabelling rate (95% CI 10%, 50%, I² = 96%), with nursing staff achieving 29% (95% CI 15%, 47%, I² = 63%) and allergists/immunologists 6% (95% CI 0.00, 0.00, I² = 20%). Quasi-experimental studies reported 90% delabelling for OC, with 59% by allergists/immunologists and 90% by pharmacists. Adverse events averaged 4% and were non-severe.

Conclusions: DD and OC are effective for delabelling low-risk penicillin allergies. Comprehensive data is lacking on sex and gender differences, indicating a need for further research.

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.