European Journal of Pharmaceutical Sciences最新文献

{"title":"pH-stat versus pH-shift lipolysis model: Exploring in vitro-in vivo relationships for lipid-based formulations of nilotinib","authors":"Hannah S. Kirschbaum ,&nbsp;Niklas J. Koehl ,&nbsp;Johannes A. Blechar ,&nbsp;Christina Wiesinger ,&nbsp;Laura J. Koehl ,&nbsp;Patrick J. O´Dwyer ,&nbsp;Martin Kuentz ,&nbsp;René Holm ,&nbsp;Christian Jede ,&nbsp;Brendan T. Griffin","doi":"10.1016/j.ejps.2025.107250","DOIUrl":"10.1016/j.ejps.2025.107250","url":null,"abstract":"<div><div>The pH-stat <em>in vitro</em> lipolysis method is well established for evaluating lipid-based formulations (LBFs), however the absence of a simulated gastrointestinal transition may lead to an overestimation of drug precipitation particularly in the case of weakly basic drugs. This study aimed to compare the conventional pH-stat method with a pH-shift lipolysis approach by evaluating a diverse set of LBFs using nilotinib, a weakly basic model drug. Additionally, the study sought to assess <em>in vitro–in vivo</em> relationships (IVIVRs) and enhance understanding of the predictive capabilities of these models. Four nilotinib-containing LBFs were tested <em>in vitro</em>, and pharmacokinetic profiles were evaluated in Sprague Dawley rats. The formulations included a supersaturated Peceol® solution (sLBF), a Peceol® lipid suspension (type I according to the Lipid Formulation Classification System (LFCS)), a type III LFCS medium-chain suspension, and a type IV LFCS suspension. The highest bioavailability was achieved with the Peceol® sLBF and the type III LFCS formulation. Strong IVIVRs were established for both <em>in vitro</em> lipolysis models. In conclusion, utilizing both <em>in vitro</em> models offered distinct advantages depending on the stage of development and the specific questions being addressed. This approach contributes to more efficient formulation development and a reduced reliance on animal studies in early-stage drug development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107250"},"PeriodicalIF":4.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947809","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":"Intranasal empagliflozin modulates synaptic plasticity in migraine: Insights into calcium signaling and epigenetic regulation","authors":"Nesrine S. El-Mezayen ,&nbsp;Ashraf A. Noah ,&nbsp;Samar O. El-Ganainy","doi":"10.1016/j.ejps.2025.107251","DOIUrl":"10.1016/j.ejps.2025.107251","url":null,"abstract":"<div><div>Migraine is a primary headache disorder without a definite pathophysiology or satisfactory managing strategies. Recently, migraine is primarily a disorder of brain plasticity coupled with altered Ca²⁺ dynamics regulating gene activity and protein expression. Further, epigenetics provided new insight into migraine pathogenesis and therapeutic response elucidation. Sodium-glucose co-transporter-2-inhibitors (e.g., empagliflozin (EMPA)), are a class of antihyperglycemic agents that can cross the blood-brain-barrier to maintain glucose homeostasis. EMPA possesses myriad pharmacological actions with potential beneficial effects for migraine management. Thus, the current study aimed at exploring EMPA efficacy and mechanisms for treating migraine headache, emphasizing its role in synaptic plasticity and epigenetic mechanisms.</div><div>Using an animal model of chronic migraine headache, the effect of oral (PO)/intranasal (IN) (brain-targeted)-EMPA versus Zolmitriptan (ZOL) on serum pain marker; Substance-P and migraine symptoms; pain, and photophobia were assessed biochemically and behaviorally. The influence on synaptic plasticity was evaluated by quantifying immunohistochemically stained synaptophysin in brain tissues and assessing calcium/calmodulin-activated-kinases (CaMKIIa)/ Camp-response-element-binding-protein (CREB)/calcitonin-gene-related-peptide (CGRP) or brain-derived-neurotrophic-factor (BDNF) pathways. Further, epigenetic modulation of migraine key genes was evaluated by determining HDAC6, CALCR, and MiR155–5p Moreover, serum glucose and amylin levels were appraised.</div><div>Both EMPA-PO/IN significantly decreased serum levels of substance-P and pain symptoms, increased brain serotonin levels, synaptophysin expression, and modulated the CaMKIIa/CREB/CGRP/or BDNF pathway. In addition, EMPA-IN, but not ZOL, down-regulated HDAC6, CALCR, and MiR155–5p expressions. Further, unlike EMPA-IN, ZOL, and EMPA-PO demonstrated significant hypoglycemic effects.</div><div>In conclusion, EMPA-IN shows potential as a novel therapeutic approach for managing migraine headaches by enhancing synaptic plasticity and modulating altered migraine-related epigenetic mechanisms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107251"},"PeriodicalIF":4.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931602","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":"Designing fluorescent estrogen mimetic 7-hydroxycoumarin probe substrates for human sulfotransferase enzymes","authors":"Risto O. Juvonen ,&nbsp;Pekka A. Postila ,&nbsp;Pankaj Kumar Singh ,&nbsp;Juhani Huuskonen ,&nbsp;Juri Timonen ,&nbsp;Muluneh Fashe ,&nbsp;Rasikh Hussain ,&nbsp;Zaeema Aqip ,&nbsp;Olli Kärkkäinen ,&nbsp;Hannu Raunio ,&nbsp;Olli T. Pentikäinen","doi":"10.1016/j.ejps.2025.107249","DOIUrl":"10.1016/j.ejps.2025.107249","url":null,"abstract":"<div><div>Sulfonation is one of drug metabolism reactions affecting homeostasis of estrogens. C-3 aryl substituted 7-hydroxycoumarins are fluorescent estrogen mimetics; i.e., the hydroxyl groups of both estrogens and 7-hydroxycoumarins are conjugated by human sulfotransferases (SULTs). Sulfonation of the 7‑hydroxyl group by SULTs decreases the fluorescence of 7-hydroxycoumarins. Sulfonation of a series of 7-hydroxycoumarins by human SULTs was determined based on this property. SULT subtype-specific binding interactions of 7-hydrocoumarins were assessed against the modelled optimal arrangement needed for sulfonation. 3-(4-Methoxyphenyl)-7-hydroxycoumarin (<strong>11</strong>) and 3-(4-hydroxyphenyl)-7-hydroxycoumarin (<strong>9</strong>) were selective substrates for SULT1E1, whereas 3-(1H-1,2,4-triazol-1-yl)-7-hydroxycoumarin (<strong>14</strong>) was a selective SULT1A1 substrate. Other tested 7-hydroxycoumarin were sulfonated by more than two SULTs. Sulfonation of most 7-hydroxycoumarins by SULT1A1 or SULT1C4 followed Michaelis-Menten kinetics, while substrate inhibition kinetics occurred in sulfonation of several derivatives by SULT1E1. Selective sulfonation of derivatives <strong>9</strong> and <strong>11</strong> by SULT1E1 was due to the enzyme’s long and cylindrical active site that assures optimal 7‑hydroxyl group placement in the precursory reaction state. SULT1A1 and SULT1C4 preferred smaller derivatives as substrates than the SULT1E. Estrogens potently inhibited the sulfonation of 3,4-dimethyl-7-hydroxycoumarin (<strong>4</strong>) by SULT1E1 (IC₅₀ below 1 µM). SULT1A1 and SULT1C4 were less potently inhibited by the estrogens. Several 7-hydroxycoumarin derivatives share common binding interaction patterns with the estrogens at SULT1E1 and SULT1A1 active sites. Fluorescent 7-hydroxycoumarins could serve as convenient probe substrates for SULTs to evaluate their inhibition by new chemical entities during drug development. 7-Hydroxycoumarins <strong>9</strong> or <strong>11</strong> could be used as selective probe substrates for SULT1E1 and <strong>14</strong> for SULT1A1.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107249"},"PeriodicalIF":4.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920028","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":"Cosolvent effects on the complexation of the antifungal propiconazole nitrate with β-cyclodextrin: A combined molecular dynamics and NMR study","authors":"Dragos L. Isac ,&nbsp;Petru Tîrnovan ,&nbsp;Alina Nicolescu ,&nbsp;Adrian Fifere ,&nbsp;Andrei Neamtu ,&nbsp;Mariana Pinteala","doi":"10.1016/j.ejps.2025.107248","DOIUrl":"10.1016/j.ejps.2025.107248","url":null,"abstract":"<div><div>Understanding the effects of cosolvents in cyclodextrin (CyD)-drug complexation is essential for optimizing drug formulations, as cosolvents influence solubility, stability, and binding affinity. In this study, the inclusion complexation of propiconazole nitrate (PCZH<img>NO₃) with β-cyclodextrin (β-CyD) in mixed dimethyl sulfoxide (DMSO)/water solvent systems was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy. MD simulations revealed that DMSO exhibits a strong affinity for the β-CyD cavity, effectively displacing water molecules even at low concentrations highlighting the competitive nature of DMSO and PCZH<img>NO₃ for inclusion within the β-CyD cavity. Enhanced sampling simulation techniques and potential of mean force (PMF) calculations demonstrated that complexation is most favorable at low DMSO concentrations (∼5 % v/v), with a gradual decrease in binding affinity as DMSO levels increase, ultimately leading to complex destabilization at high DMSO ratios. ¹H-NMR and ROESY spectra confirmed these findings, with chemical shift variations and ROESY cross-peaks indicating a weakening of host-guest interactions with increasing DMSO concentration. The results provide molecular-level insights into the role of cosolvents in modulating drug-CyD interactions, highlighting the need to tailor solvent environments to enhance the stability and efficacy of β-CyD inclusion complexes for pharmaceutical applications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107248"},"PeriodicalIF":4.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925239","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":"TLD: An optimized liposomal doxorubicin formulation with small vesicle size for improved anti-tumor efficacy","authors":"Sime Brkic ,&nbsp;Silvia Erni ,&nbsp;Younes Louaguenouni ,&nbsp;Marianna Carone ,&nbsp;E. Henrik Peters ,&nbsp;Andreas Schreiber ,&nbsp;Andreas Zumbuehl ,&nbsp;Alberto Gabizon ,&nbsp;Stéfan Halbherr ,&nbsp;Camille Peitsch","doi":"10.1016/j.ejps.2025.107246","DOIUrl":"10.1016/j.ejps.2025.107246","url":null,"abstract":"<div><div>Talidox (TLD) is an innovative liposomal doxorubicin formulation designed to enhance drug delivery efficiency and reduce systemic toxicity over existing liposomal doxorubicin formulations. This publication consolidates 10 years of preclinical research on TLD, integrating physicochemical characterization, and <em>in vitro</em> and in vivo efficacy. TLD has a reduced particle size and optimized drug-to-lipid ratio compared to Caelyx, aiming to improve tumor penetration and uptake and therefore therapeutic efficacy. The preclinical studies in breast cancer and soft tissue sarcoma models highlight the improved efficacy of TLD over free doxorubicin combined with a very good safety profile. This is complemented by the already published favorable risk-benefit ratio of TLD found in clinical trials.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107246"},"PeriodicalIF":4.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931603","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":"Fluoroquinolones as versatile scaffolds: Potential for targeting classical and novel mechanisms to combat antibacterial resistance","authors":"Ahmed M. Kamal El-sagheir ,&nbsp;Michaela Wenzel ,&nbsp;Jari Yli-Kauhaluoma","doi":"10.1016/j.ejps.2025.107247","DOIUrl":"10.1016/j.ejps.2025.107247","url":null,"abstract":"<div><div>Antibiotics play an essential role in combating infectious diseases. Due to the emergence of multidrug-resistant bacteria, the efficacy of antibiotic therapy is continually decreasing. Consequently, there is an urgent need for the development of novel antibiotics, preferably with novel targets that have not yet been clinically exploited and/or multiple mechanisms of action, reducing the probability of fast resistance development. Recently, several new promising antibacterial targets have been identified, including <em>N</em>-acetylglucosamine-6-phosphate deacetylase, glucosamine-6-phosphate synthase, metal-dependent deacetylase, and carbonic anhydrase. Additionally, inhibition of biofilm formation enhances bacterial susceptibility to antibiotics and potentially minimizes the risk of resistance development. This review discusses fluoroquinolones as versatile scaffolds, covering their structure-activity relationships, recent modifications and their role in inhibiting multiple bacterial targets. Multi-target fluoroquinolone derivatives exhibit enhanced activity against multidrug-resistant bacteria, including Gram-positive, Gram-negative, and mycobacterial species. Therefore, the continued optimization of fluoroquinolone structures represents an attractive approach to combat antibacterial resistance and achieve better therapeutic outcomes.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107247"},"PeriodicalIF":4.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947829","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":"Modeling and ex vivo evaluation of electrostatic precipitation-enhanced intraperitoneal aerosol drug delivery","authors":"Mohammad Rahimi-Gorji ,&nbsp;Yiwen Long ,&nbsp;Amrit Sareen ,&nbsp;Charlotte Debbaut ,&nbsp;Ghader Ghorbaniasl ,&nbsp;Wouter Willaert ,&nbsp;Wim Ceelen","doi":"10.1016/j.ejps.2025.107244","DOIUrl":"10.1016/j.ejps.2025.107244","url":null,"abstract":"<div><div>Peritoneal metastases (PM) remain a significant clinical challenge due to their resistance to systemic chemotherapy. Intraperitoneal aerosolized drug delivery (IPADD) has shown promise as a localized treatment option; however, its efficacy is often limited by inadequate aerosol droplet distribution and poor tissue penetration. In this study, we enhance IPADD using electrostatic precipitation (eIPADD) and evaluate its performance through computational simulations and <em>in vitro</em>/<em>ex vivo</em> experiments. A realistic 3D reconstruction of the human peritoneal cavity was used to simulate the effects of electrostatic fields on droplet distribution and deposition. The results demonstrated that multiple electrodes improved aerosol homogeneity and tissue penetration depth. These findings were validated in vitro, where eIPADD significantly increased droplet coverage and tissue penetration, particularly in anatomically challenging regions. Importantly, increasing the number of electrodes from one to three further enhanced droplet distribution uniformity and tissue penetration depth. While raising the electrical potential improved deposition in key areas, benefits plateaued beyond 10 kV, suggesting a threshold in efficacy. Nevertheless, optimizing voltage within this range, in conjunction with the increased electrode count, remains critical for achieving consistent drug delivery across the peritoneal surfaces and maximizing therapeutic outcomes. Our findings suggest that eIPADD has the potential to address the limitations of conventional IPADD, providing a more effective and uniform drug delivery method for treating PM.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107244"},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902264","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":"Controlled release and extended pulmonary retention of inhaled therapeutics: A review","authors":"Sorawee Yanwinitchai,&nbsp;Robert O. Williams III","doi":"10.1016/j.ejps.2025.107242","DOIUrl":"10.1016/j.ejps.2025.107242","url":null,"abstract":"<div><div>The advancement of controlled release systems for pulmonary therapeutic products has become a significant focus in pharmaceutical research. Various strategies have been employed to regulate the release rate of therapeutic agents, targeting both the release enhancement of poorly water-soluble drugs and prolonging the release of highly water-soluble compounds. These efforts primarily focus on chemical modifications of the active pharmaceutical ingredients (APIs) and the creation of innovative formulations that incorporate biodegradable natural or synthetic excipients. This review offers a comprehensive overview of advancements in controlled release inhalable drugs, beginning with the overview of pulmonary drug delivery. It addresses the classification of current inhalable products, the advantages of pulmonary administration, and the mechanisms involved in the particle deposition within the lungs. This review explores controlled release techniques, which are primarily divided into two main approaches: (i) chemical modification of active pharmaceutical ingredients (APIs) and (ii) specialized formulations.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107242"},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931601","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 and pharmacodynamics studies of Relugolix long-acting microcrystalline formulation in male Beagle dogs","authors":"Chunxian Li ,&nbsp;Jingxian Wang ,&nbsp;Jianxin Wang ,&nbsp;Miao Yu ,&nbsp;Pei Zhao ,&nbsp;Jing Yu ,&nbsp;Xiaohong Guo ,&nbsp;Zhanling Luo ,&nbsp;Xiaolai Yang","doi":"10.1016/j.ejps.2025.107245","DOIUrl":"10.1016/j.ejps.2025.107245","url":null,"abstract":"<div><div>Relugolix is the first oral GnRH receptor antagonist. However, its oral formulation requires daily administration, leading to poor patient adherence and suboptimal treatment outcomes for long-term users. To address these issues, we developed a long-acting microcrystalline formulation of relugolix administered once every 28 days.This study systematically evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety profile of the drug following intramuscular administration in male Beagle dogs. In this study, we established a HPLC-MS/MS method for blood concentration detection, used a highly specific and stable ELISA method to measure serum testosterone levels, and assessed the safety of the drug in male Beagle dogs. The HPLC-MS/MS method showed good linearity (R²=0.9991). The intra-day precision varied between 2.8 % and 10.9 %, while the inter-day precision ranged from 1.6 % to 5.4 %. In terms of accuracy, the intra-day values ranged from -7.3 % to -3.2 %, and the inter-day accuracy ranged from -10.2 % to 0.8 %. Furthermore, key parameters such as stability, extraction recovery, and matrix effects met the FDA bioanalytical method validation guidelines. PK studies showed that the AUC and Tmax exhibited significant sustained-release characteristics, and the half-life was notably extended compared to Orgovyx. PD analysis showed a significant negative correlation between blood drug concentration and testosterone suppression (testosterone levels began to decline after administration, and castration levels were maintained between 504–1008 h). Safety assessments revealed that although no treatment-related deaths or significant weight changes were observed, some hematological parameters (RBC, HGB increases), liver function indicators (ALT, AST increases), and triglyceride (TG) levels showed statistically significant changes (<em>p</em> &lt; 0.05). This suggests potential concerns regarding hemodynamic effects, hepatotoxicity, and lipid metabolism abnormalities. This study is the first to systematically evaluate the PK/PD characteristics of the long-acting micronized formulation of relugolix, providing key data for its clinical translation, but further validation through large sample and cross-species studies is needed.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107245"},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902265","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":"Towards model-informed precision dosing of cyclosporine in adult renal transplantation: Assessing population pharmacokinetic models and multi-model strategies","authors":"Feiyan Liu ,&nbsp;Junjun Mao ,&nbsp;Zeneng Cheng ,&nbsp;Luyang Xu ,&nbsp;Shan Huang","doi":"10.1016/j.ejps.2025.107241","DOIUrl":"10.1016/j.ejps.2025.107241","url":null,"abstract":"<div><h3>Background</h3><div>Cyclosporine’s narrow therapeutic index and pharmacokinetic variability challenge its optimal dosing in renal transplantation. Model-informed precision dosing (MIPD), utilizing population pharmacokinetic (popPK) models and Bayesian forecasting, can enhance dosing optimization and improve clinical outcomes. This study evaluated the predictive performance of published popPK models and multi-model strategies for cyclosporine, using therapeutic drug monitoring (TDM) data and full pharmacokinetic (PK) profiles.</div></div><div><h3>Methods</h3><div>We evaluated 15 published popPK models and 2 multi-model strategies (averaging/selection) using TDM data (1,856 concentrations from 114 patients) and full-PK profiles (259 concentrations from 24 patients). Bayesian forecasting with objective function value (OFV)- and Akaike information criterion (AIC)-based weighting was applied to predict cyclosporine peak concentration (C₂) and area under the curve (AUC). Predictive accuracy and precision were assessed using relative bias (rBias) and relative root mean square error (rRMSE).</div></div><div><h3>Results</h3><div>The two-compartment model with first-order absorption and transit compartments (Press et al., 2010) provided the best prediction for C₂ (rBias = -1.40%, rRMSE = 5.38%), while the model with lag time and covariates postoperative days, age, and weight (Baek et al., 2014) excelled in AUC prediction (rBias = 4.82%, rRMSE = 1.92%). Multi-model averaging/selection performed comparably to top-performing single popPK models for C₂ (rBias &lt;10% with OFV-based weighting) but underperformed for AUC prediction (rBias &gt;20%).</div></div><div><h3>Conclusion</h3><div>While single popPK models provide reliable predictions for specific PK endpoints, multi-model strategies do not consistently outperform individual models. The optimal model selection for MIPD should be fit-for-purpose to ensure optimal cyclosporine dosing and improved clinical outcomes in renal transplantation.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107241"},"PeriodicalIF":4.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947880","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}