British journal of clinical pharmacology最新文献

{"title":"Utilization and expenditure on medicines for the management of osteoporosis in Ireland: A repeated cross-sectional study.","authors":"Amelia Smith, Lisa Kelly, Claire Gorry, Bernard Duggan, Michael Barry","doi":"10.1002/bcp.70008","DOIUrl":"https://doi.org/10.1002/bcp.70008","url":null,"abstract":"<p><strong>Aim: </strong>Osteoporosis is a prevalent skeletal disease characterized by low bone mass and increased fracture risk. Management of osteoporosis typically involves antiresorptive and anabolic therapies, which are reimbursed in Ireland through various drug schemes. This study aims to summarize the utilization patterns associated with medicines used in the management of osteoporosis in Ireland.</p><p><strong>Methods: </strong>This study is a repeated cross-sectional analysis of the overall utilization of and expenditure on medicines used in the management of osteoporosis in Ireland. A number of additional drug utilization metrics are investigated: the rate of osteoporosis medication prescribing per 1000 General Medical Services eligible population, adherence to bisphosphonates, denosumab and teriparatide, and the proportion of patients initiating denosumab as first-line treatment.</p><p><strong>Results: </strong>There has been a significant change in the utilization of medicines used for the treatment of osteoporosis in Ireland over the last 13 years. The associated total annual expenditure was €28.7 million in 2011, increasing to €33.8 million in 2023. The most commonly used medicines have changed significantly over the period analysed; in 2011 the majority of patients were treated with bisphosphonates, whereas from 2019, the majority of patients were treated with denosumab. Poor patterns of treatment adherence were observed in this study.</p><p><strong>Conclusion: </strong>The findings suggest evolving patterns in osteoporosis management in the Irish context. The study highlights the need for ongoing monitoring of medication use to ensure safe, effective and cost-effective care in the context of an aging population at increasing risk for osteoporosis.</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":"143596232","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":"Anticoagulation intensity and outcomes among southeast-Asians with moderate-to-severe mitral valve stenosis.","authors":"Punyawee Puchsaka, Wipharak Rattanavipanon, Sararat Phetroong, Rudeekorn Ue-Sethasakdhi, Suparat Wattanasombat, Wattana Wongtheptien, Surakit Nathisuwan","doi":"10.1002/bcp.70034","DOIUrl":"https://doi.org/10.1002/bcp.70034","url":null,"abstract":"<p><strong>Objective: </strong>To determine the optimal anticoagulation intensity of warfarin in a South-East Asian population with moderate-to-severe rheumatic mitral stenosis.</p><p><strong>Methods: </strong>A multicentre, retrospective study examined patients with rheumatic mitral stenosis who had not undergone valve replacement or repair and required long-term warfarin therapy at two hospitals in Thailand from 2013 to 2018. The main outcomes were thromboembolism and major bleeding. Incidence rate ratios for these events at each level of anticoagulation intensity (international normalized ratio [INR]) were compared.</p><p><strong>Results: </strong>The study included 933 patients with 3538 patient-years of follow-up, a mean follow-up of 3.8 years and 23 700 INR values. Mean age was 56.1 ± 11.8 years. During follow-up, there were 149 thromboembolic events (4.2 per 100 patient-years) and 132 major bleeding events (3.7 per 100 patient-years). Net adverse clinical events were lowest at INR 2.50-2.99, with no significant difference between INR 2.00-2.49 and 3.00-3.50. Standard INR (2.0-3.0) and high-intensity INR (2.5-3.5) had comparable net adverse clinical event rates (incidence rate ratio 0.99, 95% confidence interval [CI] 0.66-1.54, P = .99). However, thromboembolism incidence was higher with standard INR (incidence rate ratio 2.49, 95% CI 1.13-6.23, P = .013), while major bleeding was lower (incidence rate ratio 0.57, 95% CI 0.35-0.98, P = .045). No significant difference in intracranial haemorrhage rates was observed between the two INR intensities.</p><p><strong>Conclusion: </strong>The standard anticoagulation intensity is an optimal range for Asian population with moderate-to-severe rheumatic mitral stenosis. High intensity anticoagulation (INR of 2.50-3.50) further reduces thromboembolism but increases major bleeding but not intracranial haemorrhage.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596159","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":"Exposure-tumour growth inhibition modelling of brigimadlin using phase I solid tumour data to support phase II dose selection.","authors":"Ida Neldemo, Kamunkhwala Gausi, Céline Sarr, Lena E Friberg, Reinhard Sailer, Mehdi Lahmar, Girish Jayadeva, Alejandro Pérez-Pitarch, Ulrike Schmid, David Busse","doi":"10.1002/bcp.70031","DOIUrl":"https://doi.org/10.1002/bcp.70031","url":null,"abstract":"<p><strong>Aims: </strong>Brigimadlin (BI 907828) is a potent, oral MDM2-p53 antagonist under clinical investigation for the treatment of advanced solid tumours. A brigimadlin exposure-tumour growth inhibition (E-TGI) model was developed to support the recommended phase II dose (RP2D) selection of brigimadlin in future clinical trials.</p><p><strong>Methods: </strong>Population modelling was applied to analyse longitudinal tumour size (sum of longest diameters, SLD) data of 151 patients from a phase I trial treated with 5-80 mg brigimadlin every third or fourth week (q3w/q4w). The impact of brigimadlin exposure on tumour shrinkage was assessed and the effects of patient- and tumour-related covariates on model parameters were explored. The final E-TGI model was used to simulate the effect of brigimadlin treatment on longitudinal SLD. The probability of dropout from tumour assessments were characterized via logistic regression and included in simulations to allow for realistic predictions of tumour shrinkage over time.</p><p><strong>Results: </strong>The E-TGI model adequately characterized the observed SLD data over time. Simulations demonstrated a substantially stronger tumour shrinkage with higher dose, based on the identified exposure-response relationship. For patients with the most common tumour (dedifferentiated liposarcoma) and standard body weight (70 kg) and remaining in the study for 1 year, the median relative change from baseline in tumour size was 0.141%, -4.48%, -10.8% and -17.4%, for treatment with 20, 30, 45 and 60 mg brigimadlin q3w doses, respectively.</p><p><strong>Conclusions: </strong>The developed E-TGI model predicted that higher doses of brigimadlin resulted in a substantially stronger tumour shrinkage. These results contributed to selecting 45 mg brigimadlin q3w dose as RP2D in subsequent clinical trials.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596226","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":"Adverse events associated with monoclonal antibodies used for treatment of COVID-19: A systematic review and meta-analysis","authors":"Htet Htet,&nbsp;Han You Kyung,&nbsp;Ismail Abdul Sattar Burud,&nbsp;Heethal Jaiprakash,&nbsp;Thiruselvi Subramaniam,&nbsp;Igor Iezhitsa,&nbsp;Renu Agarwal","doi":"10.1002/bcp.70025","DOIUrl":"10.1002/bcp.70025","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 </div>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 5","pages":"1306-1321"},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70025","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":"OA","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,&nbsp;Miranda Davies,&nbsp;Elizabeth Lynn,&nbsp;Debabrata Roy,&nbsp;Alison Yeomans,&nbsp;Saad A. W. Shakir","doi":"10.1002/bcp.70021","DOIUrl":"10.1002/bcp.70021","url":null,"abstract":"<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":"91 5","pages":"1352-1360"},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70021","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":"OA","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":"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":"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,&nbsp;Premila M. Wilfred,&nbsp;Raja Priya","doi":"10.1002/bcp.70038","DOIUrl":"10.1002/bcp.70038","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 5","pages":"1518-1519"},"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":"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}