Journal of Clinical Pharmacology最新文献_第4页

A Retrospective Analysis of PK and Response of Oral Ibuprofen in the Treatment of a Patent Ductus Arteriosus in Extremely Low Gestational Age Neonates. 口服布洛芬治疗极低胎龄新生儿动脉导管未闭的PK和疗效回顾性分析。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-16 DOI: 10.1002/jcph.70033

Mohd Asif, Katelyn Sushko, Abdul Razak, Sayem Borhan, Michael Rieder, John van den Anker, Samira Samiee-Zafarghandy

{"title":"A Retrospective Analysis of PK and Response of Oral Ibuprofen in the Treatment of a Patent Ductus Arteriosus in Extremely Low Gestational Age Neonates.","authors":"Mohd Asif, Katelyn Sushko, Abdul Razak, Sayem Borhan, Michael Rieder, John van den Anker, Samira Samiee-Zafarghandy","doi":"10.1002/jcph.70033","DOIUrl":"https://doi.org/10.1002/jcph.70033","url":null,"abstract":"Oral ibuprofen is the preferred pharmacotherapeutic option for treatment of a persistent patent ductus arteriosus (PDA), but evidence for its optimal use in extremely low gestational age newborns (ELGANs) remains limited. In the current study, we aimed to investigate the pharmacokinetics and exposure-response relationship of oral ibuprofen in ELGANs of ≤72 h postnatal age (PNA) on standard (SD) versus those >72 h PNA on high-dose (HD) regimen for closure of persistent PDA. This was a retrospective analysis of data from a previous population PK study of ELGANs with a persistent PDA treated with a SD (10-5-5 mg/kg/day, PNA <72 h) versus a HD (20-10-10 mg/kg/day, PNA >72 h) oral ibuprofen, with the primary aim of comparing degree of exposure, defined as AUC0-24 (AUC from time 0 to 24 h). Twelve ELGANs received SD versus 11 receiving HD oral ibuprofen. The mean (SD) of exposure at 24 h (AUC0-24 h) was 486 (128) and 509 (208) (P = .41) and at 72 h (AUC0-72 h) was 1529 (493) and 1510 (820) (P = .94). Two (16%) ELGANs in the HD group developed severe gastrointestinal (GI) AEs and 1 (9%) in the SD had severe intraventricular hemorrhage. The use of SD and HD oral ibuprofen in ELGANs with PNA of <72 h and those >72 h, respectively, resulted in comparable exposure. The PNA-dependent response to oral ibuprofen and exposure-response relationship in ELGANs of higher PNA needs further investigation.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pediatric Developmental Drug Toxicity: Description of Juvenile Animal Studies in US FDA Prescribing Information and Assessing the Need for New Approach Methodologies. 儿童发育药物毒性：美国FDA处方信息和评估新方法方法需求的幼年动物研究描述。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-16 DOI: 10.1002/jcph.70030

Gelareh Abulwerdi, Hillary Nguyen, Sherbet Samuels, Elizabeth Hahn, Nina Smikh, Robert Nadeau, Dionna J Green, Gilbert J Burckart

{"title":"Pediatric Developmental Drug Toxicity: Description of Juvenile Animal Studies in US FDA Prescribing Information and Assessing the Need for New Approach Methodologies.","authors":"Gelareh Abulwerdi, Hillary Nguyen, Sherbet Samuels, Elizabeth Hahn, Nina Smikh, Robert Nadeau, Dionna J Green, Gilbert J Burckart","doi":"10.1002/jcph.70030","DOIUrl":"https://doi.org/10.1002/jcph.70030","url":null,"abstract":"Currently juvenile animal studies (JAS) are the standardized way for pediatric preclinical developmental safety assessments. With advancement of new approach methodologies (NAMs) and reduced animal testing that can add to JAS findings, the assessment of the prior outcome of JAS in pediatric drug development is essential. The objectives of this study were to (a) identify, extract, and analyze JAS studies from the prescribing information (PIs) of approved pediatric products, and (b) assess the results which were obtained through those JAS studies in relation to the latest guidance. This study identified 74 approved pediatric drug products with JAS described on the PIs. For JAS, 83.8% included one species with rats being the most common. The weight of evidence approach, outlined in the S11 Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals Guidance, considers two objective criteria that can be easily assessed from PIs: youngest intended pediatric age and the clinical treatment duration. More than half of the products (64.9%) were intended for children and adolescents, and about half of the products (51.4%) were intended for acute or single use. JAS produced a warning added in the pediatric use section of the PIs in only 8.1% (6/74) of approved pediatric products. NAMs are being developed in areas such as secondary targets, developmental genetics, microphysiologic systems, and quantitative systems pharmacology modeling, all of which can compliment JAS for developmental safety assessments. So while JAS can contribute to pediatric preclinical safety assessment, the development of NAMs should be further explored.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical Pharmacology Guidances Advancing Drug Development and Regulatory Assessment: Role and Opportunities. 促进药物开发和监管评估的临床药理学指南：作用和机遇。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-16 DOI: 10.1002/jcph.70029

Anuradha Ramamoorthy, Daphne Guinn, Elimika Pfuma Fletcher, Michael Pacanowski, Kellie Reynolds, James Polli, Rajanikanth Madabushi

引用次数: 0

Quantifying the Effect of Posaconazole on Venetoclax Metabolism in Chinese Patients with Hematologic Diseases. 泊沙康唑对中国血液病患者Venetoclax代谢的定量影响。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-12 DOI: 10.1002/jcph.70025

Wenli Sun, Lei Wang, Hai He, Gen Wang, Meng Li, Yang Xue, Jing Xing, Jian Cheng, Hongxing Liu

{"title":"Quantifying the Effect of Posaconazole on Venetoclax Metabolism in Chinese Patients with Hematologic Diseases.","authors":"Wenli Sun, Lei Wang, Hai He, Gen Wang, Meng Li, Yang Xue, Jing Xing, Jian Cheng, Hongxing Liu","doi":"10.1002/jcph.70025","DOIUrl":"https://doi.org/10.1002/jcph.70025","url":null,"abstract":"Venetoclax (Ven) and posaconazole (PSZ) are commonly co-administered in patients with hematological diseases, including acute myeloid leukemia, chronic lymphocytic leukemia, and other related conditions. Due to CYP3A inhibition by PSZ, Ven plasma concentrations (ConcVen) are elevated, necessitating dose adjustments. This study aimed to quantitatively characterize the relationship between PSZ exposure and Ven pharmacokinetics through retrospective analysis of data from hematological patients receiving concurrent therapy. We examined correlations between ConcVen (both absolute and normalized by daily dose [ConcVen/DD]) and PSZ exposure metrics (daily dose and plasma concentrations [ConcPSZ]) using Spearman's analysis. A population pharmacokinetic model incorporating an innovative rectified linear unit-like function was developed to quantify the nonlinear interaction between these drugs and characterize Ven disposition, providing a more precise mathematical description of their relationship. This was followed by Monte Carlo simulations to predict steady-state peak concentrations across various dosing scenarios and PSZ exposure concentrations. The analysis included 461 paired Ven-PSZ concentration measurements from 282 patients. Significant correlations were observed between both ConcVen and ConcVen/DD versus ConcPSZ (P < .01). Ven pharmacokinetics was best described by a two-compartment model, with clearance showing significant concentration-dependent reduction with increasing ConcPSZ. Simulations demonstrated that Ven doses of 70 and 100 mg daily maintained therapeutic steady-state concentrations. However, careful monitoring of Ven concentrations is warranted when ConcPSZ exceeds 2.5 µg/mL. Based on these findings, we recommend that Ven dose adjustments during concurrent PSZ therapy be guided by therapeutic drug monitoring of both agents, with dosing decisions informed by our population pharmacokinetic model incorporating measured ConcPSZ.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Current Evidence on SGLT-2 Inhibitors in Prediabetes: A Review of Preclinical and Clinical Data. SGLT-2抑制剂治疗前驱糖尿病的最新证据：临床前和临床数据综述

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-10 DOI: 10.1002/jcph.70026

Fariba Pourkarim, Taher Entezari-Maleki, Haleh Rezaee

引用次数: 0

Physiologically Based Pharmacokinetic (PBPK) Model to Predict the Magnitude of Drug-Drug Interaction Between Fezolinetant and CYP1A2 Inhibitors. 基于生理的药代动力学（PBPK）模型预测非唑啉坦和CYP1A2抑制剂之间药物相互作用的程度。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-08 DOI: 10.1002/jcph.70024

Mary P Choules, Yukio Otsuka, Jace C Nielsen, Megumi Iwai, Peter L Bonate

{"title":"Physiologically Based Pharmacokinetic (PBPK) Model to Predict the Magnitude of Drug-Drug Interaction Between Fezolinetant and CYP1A2 Inhibitors.","authors":"Mary P Choules, Yukio Otsuka, Jace C Nielsen, Megumi Iwai, Peter L Bonate","doi":"10.1002/jcph.70024","DOIUrl":"https://doi.org/10.1002/jcph.70024","url":null,"abstract":"Fezolinetant is a non-hormonal, selective neurokinin 3 receptor antagonist approved in multiple countries including the United States, in Europe, and in Asia for the treatment of moderate to severe vasomotor symptoms in menopausal women. Fezolinetant is primarily metabolized by CYP1A2 and was found to be a sensitive substrate for CYP1A2 metabolism based on a clinical DDI study with strong CYP1A2 inhibitor, fluvoxamine. Therefore, coadministration with CYP1A2 inhibitors or inducers (such as smoking) could lead to changes in fezolinetant exposure. A physiological-based pharmacokinetic (PBPK) model was built for fezolinetant using the Simcyp simulator software with in vitro and in vivo data. The final verified model was used to predict fezolinetant exposure following coadministration with mexiletine (moderate CYP1A2 inhibitor), ciprofloxacin (moderate CYP1A2 inhibitor), and cimetidine (weak CYP1A2 inhibitor). Depending on the dosing regimen of the inhibitor and the meal status, coadministration with a weak CYP1A2 inhibitor, such as cimetidine, was predicted to increase fezolinetant Cmax by 1.30 to 1.36 and AUCinf by 1.61 to 2.01 fold. A moderate CYP1A2 inhibitor, such as mexiletine, was predicted to increase fezolinetant Cmax by 1.36 to 1.59 fold and AUCinf by 3.38 to 4.61 fold. Another moderate CYP1A2 inhibitor, ciprofloxacin, was predicted to increase fezolinetant Cmax by 1.39 to 1.49 fold and AUCinf by and 1.99 to 2.33 fold. The results of the PBPK analysis supported global labeling language statements for fezolinetant.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of Risk Factors for Supratherapeutic Anti-Xa Levels with Treatment-Dose Enoxaparin in Hospitalized Patients Without Severe Renal Impairment. 无严重肾功能损害的住院患者应用依诺肝素治疗超抗xa水平的危险因素评价

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-01 DOI: 10.1002/jcph.70023

Donna Barakeh, Michael Sirimaturos, Elsie Rizk, Hangil Seo, Mahmoud Sabawi

{"title":"Evaluation of Risk Factors for Supratherapeutic Anti-Xa Levels with Treatment-Dose Enoxaparin in Hospitalized Patients Without Severe Renal Impairment.","authors":"Donna Barakeh, Michael Sirimaturos, Elsie Rizk, Hangil Seo, Mahmoud Sabawi","doi":"10.1002/jcph.70023","DOIUrl":"https://doi.org/10.1002/jcph.70023","url":null,"abstract":"The standard dose of enoxaparin for therapeutic anticoagulation is 1 mg/kg every 12 h in patients with a creatinine clearance (CrCl) greater than 30 mL/min. Besides pregnancy, obesity, and renal impairment, literature on other risk factors for supratherapeutic anti-Xa levels is sparse. The objective of this retrospective study was to determine novel risk factors for supratherapeutic anti-Xa levels and further inform empiric enoxaparin dosing. We included adult patients with CrCl greater than 30 mL/min that received 1 ± 0.09 mg/kg of enoxaparin every 12 h. The primary outcome was the correlation between blood urea nitrogen (BUN) and anti-Xa levels. The associations between other clinical factors and supratherapeutic anti-Xa levels were also evaluated. Secondary outcomes included the incidence of major bleeding and breakthrough thrombosis in patients who had supratherapeutic levels versus those who did not. A total of 732 patients were included in the final analysis. A small correlation was detected between BUN and anti-Xa levels (Pearson correlation coefficient 0.25, P <. 001). However, multivariate analyses revealed that only female sex, body mass index, number of enoxaparin doses prior to the initial anti-Xa level, concomitant corticosteroid administration, and lower CrCl were associated with an increased risk of supratherapeutic levels (P <. 05) when controlling for other factors. There were no significant differences in the incidence of major bleeding or breakthrough thrombosis in patients with supratherapeutic, therapeutic, or subtherapeutic levels. In this study, we identified potential risk factors for supratherapeutic anti-Xa levels in patients without severe renal impairment that may be clinically relevant when empirically dosing therapeutic enoxaparin.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Phenome-Wide Association Study of Marijuana Use and Circulating Biomarkers in the United States: National Health and Nutrition Examination Survey 2009-2018. 美国大麻使用和循环生物标志物的全现象关联研究：2009-2018年国家健康和营养检查调查。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-01 DOI: 10.1002/jcph.70022

Cancan Zhang, Elizabeth Mostofsky, Hui Zhang, Bo Zhang, Julia Lindenberg, Maelys J Amat, Kenneth J Mukamal

{"title":"A Phenome-Wide Association Study of Marijuana Use and Circulating Biomarkers in the United States: National Health and Nutrition Examination Survey 2009-2018.","authors":"Cancan Zhang, Elizabeth Mostofsky, Hui Zhang, Bo Zhang, Julia Lindenberg, Maelys J Amat, Kenneth J Mukamal","doi":"10.1002/jcph.70022","DOIUrl":"https://doi.org/10.1002/jcph.70022","url":null,"abstract":"This study aimed to assess the associations between recent cannabis use and 49 biochemical biomarkers in a representative sample of American adults, using data from the 2009-2018 National Health and Nutrition Examination Survey. A phenotype-wide association study (PheWAS) was conducted to uncover new biomarkers linked to cannabis use. The analysis included 19,926 adults aged 18-59, with a mean age of 38.93 years (50.8% women), and 36.7% reporting recent cannabis use. Metabolic associations included higher high-density lipoprotein (HDL) cholesterol (3.51 mg/dL, 95% CI [2.50, 4.62]) and lower glycohemoglobin (-0.09%, 95% CI [-0.15, -0.04]) and glucose (-2.39 mg/dL, 95% CI [-4.07, -0.70]). Hematological findings included higher hemoglobin (0.09 g/dL, 95% CI [0.02, 0.16]), mean erythrocyte volume (1.46 fL, 95% CI [1.12, 1.80]), mean erythrocyte hemoglobin (0.46 pg, 95% CI [0.32, 0.60]), erythrocyte volume fraction (0.31%, 95% CI [0.11%, 0.50%]), and lower erythrocyte counts (-0.04 million cells/µL, 95% CI [-0.07, -0.02]). Serum chemistry associations included higher bicarbonate (0.20 mmol/L, 95% CI [0.06, 0.35]) and lower chloride (-0.47 mmol/L, 95% CI [-0.69, -0.24]). Associations were also observed with 25 hydroxyvitamin-3 (OHD3) (2.38 nmol/L, 95% CI [0.55, 4.22]) and epi-25OHD3 (0.40 nmol/L, 95% CI [0.15, 0.65]), and an inverse association with globulin (-0.03 g/dL, 95% CI [-0.06, -0.01]). Sensitivity analyses confirmed the robustness of these associations. Recent marijuana use is associated with diverse and complex phenotypes, several of which have not been previously evaluated. Further validation studies are warranted, this approach offers an opportunity to understand a comprehensive range of potential effects of marijuana use.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In Vitro and Clinical Evaluations of UGT1A1-, P-gp-, OATP1B1-, and BCRP-Mediated Drug-Drug Interactions of Belumosudil, a Potent ROCK2 Inhibitor. 有效的ROCK2抑制剂Belumosudil的UGT1A1-、P-gp-、OATP1B1-和bcrp介导的药物-药物相互作用的体外和临床评价

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-03-27 DOI: 10.1002/jcph.70018

Olivier Schueller, Lauren Lohmer, Felix Beck, Jeegar Patel, Jasminder Sahi

{"title":"In Vitro and Clinical Evaluations of UGT1A1-, P-gp-, OATP1B1-, and BCRP-Mediated Drug-Drug Interactions of Belumosudil, a Potent ROCK2 Inhibitor.","authors":"Olivier Schueller, Lauren Lohmer, Felix Beck, Jeegar Patel, Jasminder Sahi","doi":"10.1002/jcph.70018","DOIUrl":"https://doi.org/10.1002/jcph.70018","url":null,"abstract":"Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase 2 inhibitor, approved as a treatment for chronic graft-versus-host disease. Prior clinical studies demonstrated that coadministration with strong CYP3A4 inducers or proton pump inhibitors requires dose modification of belumosudil. In vitro assessments suggested that belumosudil may inhibit uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B1 (OATP1B1), and breast cancer resistance protein (BCRP), resulting in drug-drug interactions (DDIs). This three-part clinical DDI study (NCT05806567) was conducted to assess the effect of multiple doses of belumosudil (200 mg daily) on the single-dose pharmacokinetics of raltegravir (UGT1A1-sensitive substrate), dabigatran etexilate (P-gp-sensitive substrate), and rosuvastatin calcium (OATP1B1/BCRP-sensitive substrate). Although there was no marked change in raltegravir exposure after coadministration with belumosudil, exposure to the glucuronide metabolite was decreased by 39.6% (area under the curve from time 0 to the time of last measurable concentration [AUC0-last]) and 42.4% (maximum observed concentration [Cmax]), suggesting that belumosudil is an in vivo inhibitor of UGT1A1. There was an approximate 2-fold increase in Cmax, AUC0-last, and AUC from time 0 extrapolated to infinity (AUC0-inf) for dabigatran etexilate, suggesting a potential and clinically relevant DDI for belumosudil and sensitive P-gp substrates. Cmax and AUC0-last for rosuvastatin calcium increased by 3.6-fold and 4.6-fold, respectively, suggesting a clinically relevant interaction with drugs that are substrates of OATP1B1 or BCRP. There was no impact of coadministration with raltegravir, dabigatran etexilate, or rosuvastatin calcium on belumosudil pharmacokinetics, and belumosudil was well tolerated.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Once- Versus Twice-Daily Tacrolimus Therapy: Does Improved Adherence Lead to Better Efficacy?-A Pharmacokinetic Perspective. 他克莫司每日一次与每日两次治疗：依从性的提高是否会带来更好的疗效？-药代动力学观点。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-03-27 DOI: 10.1002/jcph.70021

Zi-Yan Dai, Lu Han, Juan Wang, Xiao-Qin Liu, Rui Chen, Zheng Jiao

{"title":"Once- Versus Twice-Daily Tacrolimus Therapy: Does Improved Adherence Lead to Better Efficacy?-A Pharmacokinetic Perspective.","authors":"Zi-Yan Dai, Lu Han, Juan Wang, Xiao-Qin Liu, Rui Chen, Zheng Jiao","doi":"10.1002/jcph.70021","DOIUrl":"https://doi.org/10.1002/jcph.70021","url":null,"abstract":"Tacrolimus, a critical immunosuppressant in organ transplantation, is available in immediate-release (IR-T) and extended-release (ER-T) formulations. While ER-T improves patient adherence, clinical studies have not demonstrated superior outcomes compared to IR-T. However, the underlying reasons for this discrepancy remain unclear. This study aimed to evaluate tacrolimus exposure under non-adherent dosing behaviors with IR-T and ER-T and to provide insights for selecting the optimal tacrolimus formulation. Monte Carlo simulations were conducted to assess the proportion of target attainment (%PTA) and deviation time (DT) from the therapeutic range in scenarios involving delayed or missed doses, based on published population pharmacokinetic models. The influence of renal function, the post-transplantation period, and hematocrit levels on %PTA and DT were also analyzed. Our findings revealed that patients on ER-T exhibited lower %PTA and longer DT than those on IR-T when doses were delayed or missed, reflecting poorer \"forgiveness.\" This observation elucidates the lack of clinical superiority observed for ER-T in previous studies. Furthermore, fast metabolizers experienced worse forgiveness with ER-T, exacerbating the challenge of maintaining therapeutic levels. Additionally, a web-based dashboard was developed to calculate the %PTA and DT for individual patients and to provide formulation recommendations tailored to their dosing behaviors and clinical characteristics. In conclusion, adherence and forgiveness play a crucial role in the success of pharmacotherapy. This study highlights the significance of pharmacokinetic modeling and simulation in providing evidence-based recommendations for selecting the optimal tacrolimus formulation.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0