British journal of clinical pharmacology最新文献

{"title":"The tacrolimus concentration-to-dose ratio is associated with kidney function in heart transplant recipients.","authors":"Maaike R Schagen, Teun B Petersen, Boris C A Seijkens, Jasper J Brugts, Kadir Caliskan, Alina A Constantinescu, Brenda C M de Winter, Isabella Kardys, Dennis A Hesselink, Olivier Manintveld","doi":"10.1002/bcp.70041","DOIUrl":"https://doi.org/10.1002/bcp.70041","url":null,"abstract":"<p><strong>Aim: </strong>Heart transplantation (HT) is frequently complicated by chronic kidney disease, of which tacrolimus-related nephrotoxicity is an important cause. In kidney and liver transplant recipients, fast tacrolimus metabolism (defined as a low concentration-to-dose [C₀/D] ratio), negatively affects kidney function. Here, the association between the C₀/D ratio and kidney function in HT recipients was investigated.</p><p><strong>Methods: </strong>This was a retrospective study including 209 HT recipients who received an immediate-release tacrolimus formulation. The C₀/D ratio and kidney function (estimated glomerular filtration rate [eGFR]) were assessed at 3, 6, 12, 36 and 60 months post-HT. Patients were categorized as fast, intermediate and slow metabolisers, depending on their individual median C₀/D ratio as calculated over the follow-up period. A linear mixed-effects model analysis was performed, in which the time-varying eGFR was the dependent variable.</p><p><strong>Results: </strong>The distribution of the individual median C₀/D ratios ranged from 0.41 to 8.9 ng/mL/mg. At baseline, patients' kidney function was comparable. In the multivariable linear mixed-effects model, fast metabolisers (C₀/D ratio ≤1.53) had a significantly lower eGFR compared to slow metabolisers (C₀/D ratio >2.27) (-6.8 mL/min/1.73 m², 95% CI -11.2, -2.4, p = 0.002). This association was confirmed when utilizing the individual median C₀/D ratio as a continuous variable: for each 1 unit increase in the C₀/D ratio there was a 2.8 mL/min/1.73 m² (95% CI 1.0, 4.5) increase in eGFR (P = 0.002).</p><p><strong>Conclusion: </strong>Fast tacrolimus metabolism is significantly associated with worse kidney function in HT recipients in the first 5 years post-HT when compared to recipients with intermediate and slow tacrolimus metabolism.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656075","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":"Severe myelosuppression and alopecia after thiopurine initiation in a patient with NUDT15 deficiency","authors":"Annie Siyu Wu,&nbsp;Lee Mozessohn,&nbsp;Richard B. Kim,&nbsp;Jonathan S. Zipursky","doi":"10.1002/bcp.70047","DOIUrl":"10.1002/bcp.70047","url":null,"abstract":"<p>Thiopurines are a class of immunosuppressant and antineoplastic agents. They are widely used in the treatment of inflammatory bowel disease, haematological malignancies and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at 10-fold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the <i>NUDT15</i> gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 5","pages":"1511-1515"},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656134","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":"Assessing the environmental impact of medicines in Italy using data from the Italian Medicines Agency","authors":"Valentina Giunchi,&nbsp;Michele Fusaroli,&nbsp;Agnese Cangini,&nbsp;Filomena Fortinguerra,&nbsp;Simona Zito,&nbsp;Andrea Pierantozzi,&nbsp;Carlotta Lunghi,&nbsp;Elisabetta Poluzzi,&nbsp;Francesco Trotta","doi":"10.1002/bcp.70046","DOIUrl":"10.1002/bcp.70046","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study builds on the environmental risk analysis presented in the 2022 National Report on Medicines Use in Italy by the Italian Medicines Agency and aims to assess the environmental risk posed by medicines in Italy and its regions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The analysis selected 90 medicines based on three criteria: high utilization, low predicted no effect concentration (PNEC), and inclusion or candidacy for the European Watch List. For each medicine, the environmental risk was computed as the ratio between the predicted environmental concentration (PEC) and the PNEC. The PEC was derived following the approach of the Swedish Association of Pharmaceutical Industries and Italian drug utilization data. The risk was classified high if the ratio was greater than 10 and moderate if greater than 1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 13 medicines were identified as posing a high risk, including cardiovascular agents, antibiotics, analgesics, antidepressants and antiparasitic agents. The high risk was driven by either a very low PNEC (eg, estradiol and lacidipine) or high utilization (eg, amoxicillin, ibuprofen and diclofenac). Regional analysis showed higher risk due to high consumption for azithromycin and ofloxacin in central and southern Italy, and for levonorgestrel in northern Italy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study points to the need for prioritizing targeted sampling in surface waters for medicines estimated at high risk. To prevent and mitigate the risk, a more conscious clinical practice coupled with appropriate waste management are required.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 5","pages":"1297-1305"},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647107","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":"General practitioner consultation for postmenopausal bleeding after COVID-19 vaccination-a self-controlled cohort study.","authors":"Rana Jajou, Eugène P van Puijenbroek, Renee Veldkamp, Jetty A Overbeek, Florence P A M van Hunsel, Agnes C Kant","doi":"10.1002/bcp.70045","DOIUrl":"https://doi.org/10.1002/bcp.70045","url":null,"abstract":"<p><strong>Aims: </strong>The incidence of postmenopausal bleeding (PMB) has been increasing over the past years. Little is known about the risk of PMB after COVID-19 vaccination. Our study aimed to investigate this based on routine general practitioner (GP) healthcare data from the Netherlands.</p><p><strong>Methods: </strong>A retrospective self-controlled cohort study was performed, which included women aged ≥50 years who received at least 1 COVID-19 vaccination in 2021 and were registered in the GP databases of Nivel (the Nivel Primary Care Database, Nivel-PCD) or PHARMO by 1 January 2021. GP consultations for PMB in the exposed period (28 days after each COVID-19 vaccination) were compared with the nonexposed period (all-time outside the exposed period). Incidence rate ratios (IRRs) were calculated using Poisson regression, adjusting for SARS-CoV-2 infection during the study follow-up period.</p><p><strong>Results: </strong>A total of 692 760 COVID-19 vaccinated women aged ≥50 years were included. No increased GP consultations for PMB was observed for all COVID-19 vaccines together, as well as when stratifying the results by vaccine type (mRNA vs. vector) and vaccine brand (Pfizer/BioNTech, Moderna, AstraZeneca, Johnson & Johnson). After the second Moderna dose an adjusted IRR of 1.47 (95% confidence interval: 0.93-2.32) was observed and after the third Pfizer/BioNTech dose an adjusted IRR of 1.33 (95% confidence interval: 0.92-1.93); however, these results were not statistically significant.</p><p><strong>Conclusion: </strong>No increased number of GP consultations for PMB in primary care was observed after COVID-19 vaccination in general, nor for any of the COVID-19 vaccine brands, vaccine doses or potential risk groups.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656125","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":"Janus kinase inhibitors for the treatment of lichen Sclerosus: A systematic review","authors":"Chin-Hsuan Shen,&nbsp;Tzu-Yu Wang,&nbsp;Ching-Chi Chi","doi":"10.1002/bcp.70042","DOIUrl":"10.1002/bcp.70042","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The current treatment options for lichen sclerosus (LS) remain limited. We aimed to systematically assess the evidence on the effects of Janus kinase (JAK) inhibitors in treating LS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a systematic review and searched PubMed, Cochrane, Embase and the Airiti Library from inception to 16 January 2025. As we expected a lack of relevant randomized trials, we also included relevant single-arm trials, case reports and case series. The risk of bias of included case reports and case series was evaluated using Murad's tool, while single-arm trials were assessed using Alsinbili's tool.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This systematic review included a total of nine studies, with one single-arm trial and three case reports on baricitinib, one single-arm trial and one case report on abrocitinib, two case reports on topical ruxolitinib and one case report on tofacitinib. A total of 43 LS patients (31 females and 12 males) were included, with four presenting with extragenital LS and one with bullous type affecting both genital and extragenital areas. The overall risk of bias of the included studies was low to unclear. Improvements in clinical symptoms, lesion characteristics and quality of life were observed for both genital and extragenital LS, with adverse events being tolerable.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Single-arm trials with baricitinib and abrocitinib provide the highest current evidence for JAK inhibitors in treating genital LS. While evidence for extragenital LS remains limited to case reports, baricitinib shows therapeutic potential. These findings support baricitinib and abrocitinib as potential candidates for future randomized controlled trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 5","pages":"1322-1329"},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656126","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":"Pharmacology and safety of TAS5315, a Bruton tyrosine kinase inhibitor, in healthy volunteers: First-in-human, randomized, ascending-dose studies.","authors":"Yuji Kumagai, Tomoe Fujita, Mika Maeda, Akiko Yamamoto, Hideki Amano","doi":"10.1002/bcp.70039","DOIUrl":"https://doi.org/10.1002/bcp.70039","url":null,"abstract":"<p><strong>Aim: </strong>TAS5315 is a Bruton tyrosine kinase (Btk) inhibitor in development for autoimmune and allergic diseases, including rheumatoid arthritis (RA) and chronic spontaneous urticaria (CSU). Two clinical studies evaluated the pharmacology and safety of single and multiple oral doses of TAS5315.</p><p><strong>Methods: </strong>Two phase 1 studies (single ascending-dose [SAD] and multiple ascending-dose [MAD]) assessed the pharmacokinetics (including effect of food), pharmacodynamics (Btk occupancy, inhibition of basophil activation) and safety of TAS5315 (up to 8 mg/day) in healthy males.</p><p><strong>Results: </strong>TAS5315 showed linear pharmacokinetics over a 0.01-8 mg dose range; maximum plasma concentration and area under the plasma concentration-time curve were reduced by ~40% by food. TAS5315 had dose dependent effects on Btk and basophil activation. In the SAD study, doses ≥2 mg resulted in mean Btk occupancy of almost 100% at 2 and 6 h, and >80% at 24 h, post-administration. TAS5315 1-8 mg/day inhibited basophil activation (mean change from baseline -55% to -89%). TAS5315 was generally tolerable. Although it dose-dependently reduced platelet aggregation (over 2-8 mg in both studies) and prolonged bleeding time (1-8 mg in the MAD study), no relationship between these effects and clinical symptoms was observed. All adverse drug reactions were mild and resolved without treatment; no noteworthy safety concerns were observed in either study.</p><p><strong>Conclusion: </strong>These data indicate TAS5315 has potential as a novel therapeutic for immunological diseases associated with aberrant Btk signalling, including RA and CSU. Further evaluation of TAS5315 is warranted.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633654","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":"Pharmacokinetics of betamethasone in pre-eclampsia: An in vivo and ex vivo study.","authors":"Sam Schoenmakers, Letao Li, Anna C M Kluivers, Michelle Broekhuizen, Madhavi S Harhangi, A H Jan Danser, Irwin Reiss, Karel Allegaert, Sjoerd A A van den Berg, Bertrand D van Zelst, Ron H N van Schaik, Philip L J DeKoninck, Emma Ronde, Sebastiaan D T Sassen, Sinno H P Simons, Birgit C P Koch","doi":"10.1002/bcp.70035","DOIUrl":"https://doi.org/10.1002/bcp.70035","url":null,"abstract":"<p><strong>Aims: </strong>To enhance understanding of betamethasone and its metabolites' pharmacokinetics in pregnancy, specifically early-onset pre-eclampsia, through a population pharmacokinetic model. Additionally, to investigate the placental metabolism and transfer of betamethasone and its main metabolites.</p><p><strong>Methods: </strong>A prospective, single-centre pharmacokinetic study was conducted in pregnant women (n = 28) with imminent preterm birth treated with intramuscular betamethasone. Betamethasone serum concentrations were determined from serial venous blood samples (n = 194). Placental transfer and metabolism were studied using ex vivo human placental perfusion (healthy term; n = 3) and placental explant experiments (healthy term, n = 4; early-onset pre-eclampsia, n = 4). Additionally, placental mRNA expression of CYP3A4, CYP3A7, 11β-hydroxysteroid dehydrogenase (HSD) 1 and 11β-HSD2 were quantified in healthy and early-onset pre-eclampsia placentas.</p><p><strong>Results: </strong>The population pharmacokinetic model was best described by a 2-compartment nonlinear mixed effects model. Betamethasone clearance in early-onset pre-eclamptic women was 60% lower of that observed in women without pre-eclampsia (9.35 vs. 15.78 L/h), resulting in a 40% median increase in maternal betamethasone exposure (1567 vs. 1114 ng h/mL). Ex vivo experiments showed placental transfer of betamethasone to the foetal circulation (foetal-to-maternal ratio 0.76 ± 0.05 [in a perfused placental cotyledon]). The placenta only converted betamethasone into 11-ketobetamethasone, with similar ratios in early-onset pre-eclampsia and healthy placental explants (3.0 ± 2.2 vs. 1.4 ± 0.4 per mg tissue, P = .27). The expression of 11β-HSD1 mRNA was lower in early-onset pre-eclampsia placentas (P = .015), while placental CYP3A7 and 11β-HSD2 mRNA expression were similar.</p><p><strong>Conclusion: </strong>Women with early-onset pre-eclampsia have elevated betamethasone exposure. Betamethasone transfers freely into the foetal circulation, with placental metabolism resulting only in 11-ketobetamethasone. Decreased placental 11β-HSD1 expression may play a role in increased betamethasone exposure in early-onset pre-eclampsia.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623667","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":"Methotrexate toxicity and glucarpidase: A call for dose optimization","authors":"Arjen Koppen,&nbsp;Maaike A. Sikma,&nbsp;Frederike K. Engels,&nbsp;Marise R. Heerma van Voss,&nbsp;Martine E. D. Chamuleau,&nbsp;Imke H. Bartelink,&nbsp;Marieke A. Dijkman","doi":"10.1002/bcp.70044","DOIUrl":"10.1002/bcp.70044","url":null,"abstract":"&lt;p&gt;High-dose methotrexate (HDMTX) is a folic acid antagonist that is used to treat acute lymphoblastic leukaemia, lymphoma and osteosarcoma in adult and paediatric patients. HDMTX cytotoxicity is concentration and time-dependent. Due to intracellular accumulation, prolonged exposure to relatively low MTX levels can lead to myelosuppression, mucositis, nephro-, hepato- and neurotoxicity and can ultimately result in multi-organ failure. HDMTX can be safely administered to patients with normal renal function provided that the necessary measures are taken to prevent side effects. These measures include urine alkalinization, hydration and pharmacokinetically guided leucovorin (folinic acid) rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 2%–12% of patients with these diseases.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; As 80%–90% of MTX elimination is via renal clearance, a vicious cycle may occur in which delayed renal clearance increases nephrotoxicity and vice versa, ultimately resulting in prolonged exposure to high MTX blood concentrations.&lt;/p&gt;&lt;p&gt;Glucarpidase (brand name Voraxaze®) is used to rapidly reduce high MTX blood concentrations observed in HDMTX treated patients with (potentially) impaired renal function.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Rapid reduction of methotrexate concentration is considered to prevent further serious methotrexate (nephro)toxicity.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Timely administration of glucarpidase (within 48–60 h from the start of HDMTX infusion) is important to break the cycle of reduced MTX clearance, prolonged half-life and increased nephrotoxicity.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Recently, the appropriate dose of glucarpidase has become a topic of debate, as the current recommended dose does not appear to be well established. Doses other than the recommended dose have not been systematically investigated due to a lack of dose-finding studies.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; This raises the question of whether regulatory authorities should require more rigorous clinical pharmacological investigation of the optimal dose when approving antidotes.&lt;/p&gt;&lt;p&gt;Glucarpidase is a recombinant carboxypeptidase that catalyses the conversion of methotrexate to the inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate in the blood. Glucarpidase is mainly found in plasma (volume of distribution in adults = 3.55 L), where the enzyme activity persists for hours (plasma concentration half-life: 9 h, activity half-life: 5.6 h).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; One unit of glucarpidase cleaves 1 μmol of methotrexate in 1 min at 37°C.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The current-approved dose of glucarpidase is 50 units/kg of body weight (U/kg), irrespective of plasma methotrexate concentration. This clinically recommended dose is based on calculations derived from in vitro studies. According to the manufacturer, 50 U/kg glucarpidase theoretically reduces a plasma methotrexate concentration of 1000 μmol/L to 10 μmol/","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 5","pages":"1289-1292"},"PeriodicalIF":3.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603948","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":"Factors influencing physicians’ antimicrobial prescribing decisions: A systematic review of qualitative studies","authors":"Savannah Reali,&nbsp;Yee Chin Kwang,&nbsp;Jin-Gun Cho,&nbsp;Jan-Willem Alffenaar,&nbsp;Parisa Aslani","doi":"10.1002/bcp.70011","DOIUrl":"10.1002/bcp.70011","url":null,"abstract":"<p>Inappropriate and overuse of antimicrobials is increasing antimicrobial resistance. Understanding physicians' antimicrobial decision-making is essential for developing interventions to optimize prescribing. The aim of this review was to identify the factors that influence physicians' antimicrobial prescribing decisions. A systematic literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline and Scopus were searched from 2014 onwards using three key concepts: antimicrobial, prescribing and attitude. The search identified 11 038 articles for review. Studies were included if they used qualitative methods and obtained data directly from physicians. Factors influencing antimicrobial prescribing were extracted and categorized into physician-related, patient-related, medication- and condition-related, and external factors. A model of the antimicrobial prescribing process was created to illustrate how these factors influence decision-making. Fifty-three articles from 23 countries met the inclusion criteria. Forty factors influencing antimicrobial prescribing were identified, with the most common being time pressures, patient/carer demand for antimicrobials, diagnostic uncertainty, clinical experience, and the use of evidence-based guidelines and diagnostic tests. The harm to the patient and the physician of underprescribing were considered to outweigh the potential population harm of antimicrobial resistance due to overprescribing. Antimicrobial decision making is a complex process influenced by many different types of factors at each point in the prescribing journey. Awareness of these factors is vital for the success of interventions aiming to optimize antimicrobial prescribing. Future interventions should investigate how to balance individual and population harm whilst considering the individual factors that influence prescribing decisions.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 5","pages":"1330-1351"},"PeriodicalIF":3.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603947","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":"Drug-drug interaction study with itraconazole supplemented with physiologically based pharmacokinetic modelling to characterize the effect of CYP3A inhibitors on venglustat pharmacokinetics.","authors":"Li Li, Yan-Yan Zhang, Jyoti Sharma, Sylvaine Cartot-Cotton, Nigel Crawford, Sreeraj Macha, Yi Li, Jasminder Sahi","doi":"10.1002/bcp.70037","DOIUrl":"https://doi.org/10.1002/bcp.70037","url":null,"abstract":"<p><strong>Aims: </strong>Venglustat is an oral glucosylceramide synthase inhibitor under clinical investigation to treat various lysosomal storage diseases. Metabolism is a main pathway for its elimination in humans with CYP3A being the major contributor. This study aims to evaluate effect of CYP3A inhibition (using itraconazole) on venglustat exposure and to develop and validate a physiologically based pharmacokinetic (PBPK) model to assess effects of additional CYP3A inhibitors of varying potencies on venglustat pharmacokinetics.</p><p><strong>Methods: </strong>An open-label, single-sequence, 2-period drug-drug interaction (DDI) study was conducted in healthy subjects with coadministration of multiple twice daily oral doses of 100 mg itraconazole against a single dose of 15 mg venglustat. A minimal PBPK model was developed using available physicochemical, in vitro and in vivo pharmacokinetic data and validated using data from relevant venglustat clinical studies including the itraconazole DDI study. Effects of additional CYP3A inhibitors on venglustat exposure were predicted.</p><p><strong>Results: </strong>Coadministration with itraconazole increased venglustat area under the concentration-time curve by 2.03-fold (90% confidence interval [90%CI]: 1.81-2.27). Venglustat steady-state area under the concentration-time curve during a dosing interval following coadministration with strong (clarithromycin), moderate (fluconazole) and weak (fluvoxamine and cimetidine; with CYP2D6 inhibition turned off) CYP3A inhibitors is predicted to increase by 1.74- (5th-95th centile, 1.30-2.49), 1.52- (1.23-1.88), 1.08- (1.03-1.15) and 1.08-fold (1.04-1.12), respectively.</p><p><strong>Conclusion: </strong>The effect of itraconazole on venglustat exposure was quantified clinically, and a minimal PBPK model was successfully developed, validated and applied to assess DDI effect of additional CYP3A inhibitors on venglustat. The results help to further understand the DDI potential with venglustat and will inform dose recommendations with comedications.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603946","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}