British journal of clinical pharmacology最新文献

{"title":"Adverse events associated with monoclonal antibodies used for treatment of COVID-19: A systematic review and meta-analysis.","authors":"Htet Htet, Han You Kyung, Ismail Abdul Sattar Burud, Heethal Jaiprakash, Thiruselvi Subramaniam, Igor Iezhitsa, Renu Agarwal","doi":"10.1002/bcp.70025","DOIUrl":"https://doi.org/10.1002/bcp.70025","url":null,"abstract":"<p><strong>Aims: </strong>This review aimed to synthesise the evidence related to the incidence of serious and non-serious adverse events with the use of monoclonal antibodies (mAbs) among COVID-19 patients.</p><p><strong>Methods: </strong>Databases were searched from January 2020 to September 2023 for randomized clinical trials (RCTs) that used mAbs for the treatment of COVID-19 regardless of disease severity. Study screening, data extraction and data analysis were performed independently by two reviewers. The Cochrane risk of bias 1.0 tool was used for methodological quality assessment.</p><p><strong>Results: </strong>Sixteen studies were identified for analysis with 9682 participants in the intervention arm and 10 115 participants in the control arm. Seven trials reported hepatoxicity and there was a statistically significant increase in the chance of hepatoxicity among patients treated with mAbs compared to those given standard of care (SoC) or placebo with risk ratio (RR) = 1.70, 95% confidence interval (CI) 1.29-2.24. Five trials reported for neutropenia and there was a statistically significant association of neutropenia with the use of mAbs compared to SoC or placebo with RR = 4.03, 95% CI 1.74-9.34. Ten trials reported any disease-related serious adverse events related to the disease and there was a reduction of risk compared to SoC/placebo,  although this reduction was not statistically significant (RR = 0.88, 95% CI 0.70-1.11).</p><p><strong>Conclusions: </strong>The use of mAbs was found to be associated with an increased risk of hepatoxicity and neutropenia compared to SoC/placebo among COVID-19 patients with moderate certainty of evidence. Long-term observational studies are recommended to observe post-COVID adverse events related to the use of mAbs.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and effectiveness of the anti-amyloid monoclonal antibody (mAb) drug lecanemab for early Alzheimer's disease: The pharmacovigilance perspective.","authors":"Amy Bobbins, Miranda Davies, Elizabeth Lynn, Debabrata Roy, Alison Yeomans, Saad A W Shakir","doi":"10.1002/bcp.70021","DOIUrl":"https://doi.org/10.1002/bcp.70021","url":null,"abstract":"<p><p>The development of humanized IgG1 anti-amyloid monoclonal antibodies, such as lecanemab, provides a promising novel treatment pathway with potential disease-modifying effects for patients with early Alzheimer's disease (AD). Lecanemab, which gained marketing approval by the United States Food and Drug Administration (US FDA) in July 2023, has since been approved in multiple countries, including the United Kingdom (UK). The decision by the UK's Medicines and Healthcare products Regulatory Agency (MHRA) to approve lecanemab in August 2024 followed similar regulatory decisions in the US and Japan. However, at the time of approval, the decision contrasted with that of the European Medicine Agency (EMA) in July 2024. Subsequently, the EMA recommended the marketing approval of lecanemab in November 2024 following a re-examination of further data submitted by the Marketing Authorisation Holder. The UK's National Institute for Health and Care Excellence (NICE) has not recommended lecanemab for use in early AD amid concerns, including treatment cost and the translation of efficacy outcomes into clinically meaningful improvement. The risks of serious adverse events (SAEs), including amyloid-related imaging abnormalities (ARIA), have also emerged from clinical trial data with a concern for the potential for rare, life-threatening events. This narrative review discusses the requirement for a robust method of monitoring the safety and effectiveness of lecanemab in the real-world clinical setting considering recent regulatory decisions. Additionally, the need to evaluate proposed risk minimization measures (RMMs) is discussed considering the resource constraints of healthcare systems, such as those faced by the UK's National Health Service (NHS).</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral paltusotine, a nonpeptide selective somatostatin receptor 2 agonist: Mass balance, absolute bioavailability and metabolism in healthy participants.","authors":"Rosa Luo, Ajay Madan, Christine T Ferrara-Cook, Deepak Dalvie, Lance Goulet, R Scott Struthers, Alan S Krasner","doi":"10.1002/bcp.70020","DOIUrl":"https://doi.org/10.1002/bcp.70020","url":null,"abstract":"<p><strong>Aims: </strong>Paltusotine is a novel, nonpeptide, selective somatostatin receptor 2 agonist in development for the treatment of acromegaly and carcinoid syndrome. This study investigated the mass balance, routes of excretion, absolute bioavailability and metabolite profile of orally administered paltusotine.</p><p><strong>Methods: </strong>In Part A of the two-part, phase 1 study, a single dose (oral solution) of 20 mg paltusotine containing approximately 3.0 MBq (80 μCi) of ¹⁴C-labelled paltusotine was administered to six healthy male participants to evaluate the mass balance and metabolite profile of paltusotine. In Part B, a single dose (oral solution) of paltusotine 20 mg followed approximately 90 min later by a single microtracer intravenous bolus injection of approximately 50 μg paltusotine containing 0.0185 MBq (0.5 μCi) of ¹⁴C-labelled paltusotine was administered to five healthy male participants to assess absolute bioavailability of paltusotine.</p><p><strong>Results: </strong>The mean absolute bioavailability of paltusotine 20 mg was 69% (90% CI 59-82%). The mean recovery of total radioactivity was 94% (90% in faeces and 3.9% in urine), with excretion primarily via the biliary route. The exposure (AUC_0-inf) ratio of unchanged paltusotine to total reactivity in plasma was 0.75, indicating that there were no abundant circulating metabolites. The geometric mean half-life (t_1/2) for paltusotine in plasma was 26-28 h. Treatment-emergent adverse events associated with paltusotine were mild and transient.</p><p><strong>Conclusions: </strong>Oral dosing with paltusotine is associated with efficient absorption from the gastrointestinal tract. Most of the administered dose is excreted unchanged. Pharmacokinetic properties of paltusotine are supportive of once-daily dosing.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virtual twin approach using physiologically based pharmacokinetic modelling in hospitalized patients treated with apixaban or rivaroxaban.","authors":"Frédéric Gaspar, Jean Terrier, Celestin Jacot-Descombes, Pauline Gosselin, Valentine Ardoino, Camille Lenoir, Victoria Rollason, Chantal Csajka, Caroline F Samer, Pierre Fontana, Youssef Daali, Jean-Luc Reny","doi":"10.1002/bcp.70032","DOIUrl":"https://doi.org/10.1002/bcp.70032","url":null,"abstract":"<p><strong>Aims: </strong>In a large cohort of hospitalized patients, previously validated physiologically based pharmacokinetic (PBPK)-based models for apixaban and rivaroxaban are being assessed for their performance in predicting individual pharmacokinetics, aiming to identify patients at high risk of under- or overdosing based on demographic, physiological and CYP-related phenotypic characteristics.</p><p><strong>Methods: </strong>Clinical data were collected from hospitalized patients treated with apixaban (n = 100) or rivaroxaban (n = 100) at the Geneva University Hospitals (HUG). These patients were recruited in the OptimAT trial (NCT03477331). PBPK modelling created virtual twins for each patient, integrating demographic, kidney function, P-glycoprotein (Pgp) and cytochrome P450 (CYP450) 3A phenotyping. Individual PK profiles were simulated for every patient and compared to actual drug exposure, as assessed with LC/MS-MS.</p><p><strong>Results: </strong>Mean fold error (MFE) (95% CI) for the apixaban and rivaroxaban models integrating demographic and kidney function was within the pre-required bioequivalency criteria with 1.10 (1.04-1.16) and 0.97 (0.93-1.02), respectively. Adding individual Pgp and CYP3A phenotypes led to a slight overprediction 1.25 (1.17-1.33) and 1.30 (1.21-1.39), but patients at risk for bleeding were correctly predicted with MFEs of 0.90 (0.76-1.04) and 1.15 (1.11-1.20).</p><p><strong>Conclusions: </strong>In a large cohort of hospitalized patients, a PBPK model incorporating demographic characteristics and kidney function can accurately predict, within bioequivalency criteria, an individual's apixaban and rivaroxaban plasma exposure. The added value of individual Pgp and 3A phenotypes on the predictive performance need to be further explored, although patients at higher risk for bleeding may benefit. This innovative approach represents an important step towards the application of PBPK at bedside.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor-Response to the article \"Drug-induced liver injury associated with pretomanid, bedaquiline, and linezolid: Insights from FAERS database analysis\".","authors":"Jaya Ranjalkar, Premila M Wilfred, Raja Priya","doi":"10.1002/bcp.70038","DOIUrl":"https://doi.org/10.1002/bcp.70038","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paracetamol and its metabolites in children and adults with spinal muscular atrophy - a population pharmacokinetic model.","authors":"Qiaolin Zhao, Marie Mostue Naume, Brenda C M de Winter, Thomas Krag, Sissel Sundell Haslund-Krog, Karoline Lolk Revsbech, John Vissing, Helle Holst, Morten Hylander Møller, Tessa Munkeboe Hornsyld, Morten Dunø, Christina Engel Hoei-Hansen, Alfred Peter Born, Per Bo Jensen, Mette Cathrine Ørngreen","doi":"10.1002/bcp.70028","DOIUrl":"https://doi.org/10.1002/bcp.70028","url":null,"abstract":"<p><strong>Aims: </strong>The aim of the study was to investigate whether differences in paracetamol pharmacokinetics (PK) between spinal muscular atrophy (SMA) patients and healthy controls (HC) could be attributed to specific clinical covariates.</p><p><strong>Methods: </strong>Nonlinear mixed-effects modelling (NONMEM 7.4) was used to develop a population PK model, explore covariates for paracetamol and its metabolites and perform simulations.</p><p><strong>Results: </strong>With body weight as allometric scaling in the model, SMA disease resulted in a 58% (95% confidence interval [CI]: 20%-130%) increase in the volume of distribution for paracetamol and its metabolites compared to healthy controls. Decreased plasma myoglobin and plasma bilirubin concentrations, seen in SMA patients, resulted in a higher paracetamol leftover clearance (SMA, median: 13.30 L/h/70 kg, 95% CI: 9.14-18.29%; HC, median: 4.05 L/h/70 kg, 95% CI: 3.38-8.83%) and a shift from slower sulfate formation clearance (SMA, median: 8.78 L/h/70 kg, 95% CI: 7.22-9.61%; HC, median: 9.30 L/h/70 kg, 95% CI: 8.42-10.15%) and faster oxidative metabolites elimination clearance (SMA, median: 3.74 L/h/70 kg, 95% CI: 3.31-4.72%; HC, median: 3.25 L/h/70 kg, 95% CI: 2.87-3.92%). Simulations revealed that in SMA patients, higher bodyweight was associated with increased exposure to paracetamol and its metabolites.</p><p><strong>Conclusions: </strong>The differences in PK between SMA patients and healthy controls could be explained by body weight and the disease itself. SMA patients should be dosed cautiously, ensuring doses do not exceed the recommended body weight adjusted limit.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variability in intestinal drug metabolizing enzymes and transporters in Crohn's disease and potential impact on oral drug absorption.","authors":"Sarah Alrubia, Brahim Achour, Zubida M Al-Majdoub, Amin Rostami-Hodjegan, Jill Barber","doi":"10.1002/bcp.70019","DOIUrl":"https://doi.org/10.1002/bcp.70019","url":null,"abstract":"<p><strong>Aims: </strong>The aim of study was to generate quantitative data on the abundance of drug-metabolizing enzymes and transporters (DMETs) in inflamed and non-inflamed Crohn's disease (CD) ileum and colon, for incorporation into physiologically based pharmacokinetic (PBPK) models, enabling prediction of oral drugs' pharmacokinetics (PK) perturbation in CD patients.</p><p><strong>Methods: </strong>Homogenate fractions were processed from 13 inflamed (six ileum and seven colon) and seven non-inflamed (two ileum and five colon) CD and 10 healthy (five ileum and five colon) tissues from deceased subjects by calcium chelation elution, and protein abundances determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics and compared with healthy values. PBPK simulation was applied to predict the potential effect of altered DMET profiles on the PK of oral drugs.</p><p><strong>Results: </strong>All investigated proteins showed trends for reduced expression in inflamed and non-inflamed CD samples relative to healthy individuals. Significant downregulation (P < 0.05) was observed for CYP3A4, AOX1, NAT1 and several SULTs in inflamed ileum as well as UGT1A10, NAT1, BCRP and several SULTs in inflamed and non-inflamed colon. Inter-individual variability was generally higher in CD, with exceptions, for most targets (up to 146%CV in inflamed ileum and up to 169% in histologically normal colon tissues). Integration of abundance data into a verified PBPK model of CD showed a considerable (≥2-fold; CD predicted relative to healthy predicted) change in systemic drug exposure for 10 drugs examined.</p><p><strong>Conclusions: </strong>CD inflammation significantly suppresses the expression of intestinal DMETs, which, together with changes in other system parameters, can alter the fate of drugs taken orally in these patients. Virtual patients within a PBPK framework, informed by the measured DMET ranges in the intestine, may serve as a guide for dose adjustment in the absence of dedicated clinical studies.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative splicing with CYP3A4*22: Implications for the steroid-tacrolimus drug interaction","authors":"Jana Stojanova,&nbsp;Nuala Ann Helsby,&nbsp;Daniel F. B. Wright,&nbsp;Bridin Murnion,&nbsp;Richard O. Day","doi":"10.1002/bcp.70029","DOIUrl":"10.1002/bcp.70029","url":null,"abstract":"&lt;p&gt;We read with interest the recent study by Saqr et al. (2024) examining steroid-tacrolimus drug interactions in 2462 kidney transplant recipients.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Their findings provide important insights into the complex interplay between &lt;i&gt;CYP3A4&lt;/i&gt; and &lt;i&gt;CYP3A5&lt;/i&gt; genotypes and drug–drug interactions involving enzyme induction in the setting of immunosuppressive therapy. An unexpected finding was that patients with three or four loss of function (LOF) alleles in these genes showed a similar proportional increase in tacrolimus clearance with steroids relative to no LOF alleles (10.3% &lt;i&gt;vs&lt;/i&gt;. 11.8%), whereas those with 1- and 2-LOF alleles showed a minor increase (2.6% and 5%, respectively). Consideration of the genetic groupings, and the functional consequences of the alleles, may provide mechanistic insight into this observation.&lt;/p&gt;&lt;p&gt;Due to the prevalence of LOF alleles in &lt;i&gt;CYP3A5&lt;/i&gt;, the 2-LOF group in Saqr et al. represents 67.5% of participants, 99% of whom have two LOF alleles in this gene (assigned as 2-LOFa, Table 1). The 3/4-LOF group represents people that additionally carry &lt;i&gt;CYP3A4*22&lt;/i&gt;, predominantly as a single copy (3-LOF group, Table 1; 98%). The subgroups with less frequent &lt;i&gt;CYP3A5&lt;/i&gt; and &lt;i&gt;CYP3A4&lt;/i&gt; genotypes (2-LOFb and 4-LOF in Table 1) account for a small proportion of participants that are unlikely to impact the median clearance estimates for the larger groups.&lt;/p&gt;&lt;p&gt;The unexpected clearance patterns with steroid induction may be explained by examining how &lt;i&gt;CYP3A4*22&lt;/i&gt; differs mechanistically from other LOF alleles. &lt;i&gt;CYP3A5&lt;/i&gt;&lt;i&gt;*6&lt;/i&gt; and &lt;i&gt;*7&lt;/i&gt; prevent production of functional protein through coding region changes that eliminate enzyme activity, while &lt;i&gt;*3&lt;/i&gt; occurs in an intronic splice site, which causes premature termination.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In contrast, &lt;i&gt;CYP3A4&lt;/i&gt;&lt;i&gt;*22&lt;/i&gt; occurs in intron 6 and influences the proportion of a nonfunctional alternatively spliced transcript, which retains the intron; however, this is tissue specific, occurring in the liver but not the small intestine.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Wang and Sadee quantified both this transcript and functional CYP3A4 mRNA in tissue samples.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Only 5% of the alternatively spliced transcript was present in liver samples from people with the &lt;i&gt;CYP3A4*1/*1&lt;/i&gt; genotype, while those with at least one &lt;i&gt;*22&lt;/i&gt; allele showed approximately 19%.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Notably, in small intestine samples, there was no difference in the spliced transcript proportions between genotype groups. This suggests &lt;i&gt;*22&lt;/i&gt; might exclusively impact the clearance of drugs metabolized by CYP3A4, possibly without impacting intestinal absorption.&lt;/p&gt;&lt;p&gt;The functional consequences of &lt;i&gt;CYP3A4*22&lt;/i&gt; may involve additional mechanisms. Recent work identified rs62471956, a variant in complete linkage disequilibrium with &lt;i&gt;*22&lt;/i&gt;, which affects CYP3A4 expression through altered enhancer interactions.&lt;s","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 4","pages":"1283-1284"},"PeriodicalIF":3.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of factors influencing the relationship between voriconazole plasma concentrations and adverse effects in a paediatric population.","authors":"Keiko Hikino, Kensuke Shoji, Jumpei Saito, Koya Fukunaga, Xiaoxi Liu, Toshihiro Matsui, Tomoyuki Utano, Akira Takebayashi, Daisuke Tomizawa, Motohiro Kato, Kimikazu Matsumoto, Takashi Ishikawa, Toshinao Kawai, Hidefumi Nakamura, Isao Miyairi, Chikashi Terao, Taisei Mushiroda","doi":"10.1002/bcp.70026","DOIUrl":"https://doi.org/10.1002/bcp.70026","url":null,"abstract":"<p><strong>Aims: </strong>The influence of CYP2C19 polymorphisms on voriconazole plasma concentrations is recognized, but its extent, other contributing factors and risks for adverse reactions remain under-explored.</p><p><strong>Methods: </strong>This study focused on Japanese paediatric patients recruited between 2020 and 2022 treated with voriconazole. We specifically investigated the occurrence of cholestasis and thrombocytopenia as adverse reactions of voriconazole. Voriconazole plasma levels were modelled in a previous study using a population pharmacokinetics approach. Missing values were estimated with a Bayesian method in Phoenix NLME. We analysed CYP2C19*2, CYP2C19*3 and CYP2C19*17. Clinical and laboratory data were collected before and after voriconazole treatment.</p><p><strong>Results: </strong>Among the 60 patients (mean age: 6.5 years; 53.3% male), 38 had haematological malignancies, 18 inborn errors of immunity, 2 solid tumours and 2 other diseases. Adverse reactions occurred in 12 patients. The voriconazole plasma concentrations were significantly higher in those experiencing these adverse reactions (mean normalized concentrations: 0.66 in cases vs. -0.16 in controls, P = .025), with a trend towards higher concentrations in carriers of the CYP2C19*2 or *3 alleles (mean normalized concentrations: 0.98 in carrier cases vs. 0.016 in noncarrier cases, P = .14). A predictive model for voriconazole concentrations, incorporating carriership of CYP2C19*2 or *3, C-reactive protein levels, and platelet counts, showed a summed variance explained of 23.6% with the variance attributable to CYP2C19*2 or *3 carrier status alone was 2.6%. Including carrier status improved the area under the receiver operating characteristic curve for predicting adverse reactions to 0.70.</p><p><strong>Conclusions: </strong>Our findings underscore the role of the CYP2C19 polymorphism in voriconazole-induced thrombocytopenia and cholestasis.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding factors that influence the drug choice of prescribers: A Q-methodology study.","authors":"Mariëlle G Hartjes, Annelot E F Elsevier, Jan Willem Grijpma, Milan C Richir, Michiel A van Agtmael, Jelle Tichelaar","doi":"10.1002/bcp.70009","DOIUrl":"https://doi.org/10.1002/bcp.70009","url":null,"abstract":"<p><strong>Introduction: </strong>Therapeutic decision-making often involves weighing several treatment options on the basis of, among other things, the disease profile, patient characteristics but also prescriber-specific factors. This study investigated the factors influencing therapeutic decision-making among prescribers and explores how these factors differ between healthcare professionals.</p><p><strong>Methods: </strong>This Q-methodology study involved 37 participants from different medical backgrounds, including physicians, dentists, midwives, physician assistants and advanced nurse practitioners from various intra- and extramural settings in the Netherlands. Participants ranked 55 factors on their importance for medication prescribing, and factor analysis was used to identify distinct prescriber profiles. These profiles were subsequently enriched using qualitative data derived from post-sorting interviews.</p><p><strong>Results: </strong>Four prescriber profiles were identified that explained 59% of the study variance: pragmatic contextual, guideline oriented, experience driven and vulnerability focused. Several factors were ranked differently in each profile. The pragmatic contextual profile emphasized patient context and risk prevention, the guideline-oriented profile adhered to clinical guidelines, the experience-driven profile relied on clinical experience and patient-centred communication, and the vulnerability-focused profile prioritized personalized care for specific patient groups.</p><p><strong>Conclusion: </strong>This study sheds light on the diverse factors influencing prescriber decision-making in medical practice. By identifying four prescriber profiles, it reveals the complexity and diversity in how prescribers balance guidelines, clinical experience and patient-specific considerations in their practice. These findings offer direction for developing educational and policy initiatives to enhance the quality of prescribing, ultimately improving patient outcomes.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}