Journal of Pharmacokinetics and Pharmacodynamics最新文献

Population pharmacokinetic-pharmacodynamic modeling and dose selection of GS1-144 based on luteinizing hormone suppression in postmenopausal women. 基于促黄体生成素抑制的绝经后妇女GS1-144人群药代动力学建模和剂量选择。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-10-16 DOI: 10.1007/s10928-026-10071-6

Kun Wang, Zhongyi Sun, Fengyan Xu, Yuting Yang, Tangping Zhao, Guangli Ma, Chao Pan, Guangping Mao, Hongshuang Shen, Yongze Yu, Haijun Chen, Xiaoyan Zhu

{"title":"Population pharmacokinetic-pharmacodynamic modeling and dose selection of GS1-144 based on luteinizing hormone suppression in postmenopausal women.","authors":"Kun Wang, Zhongyi Sun, Fengyan Xu, Yuting Yang, Tangping Zhao, Guangli Ma, Chao Pan, Guangping Mao, Hongshuang Shen, Yongze Yu, Haijun Chen, Xiaoyan Zhu","doi":"10.1007/s10928-026-10071-6","DOIUrl":"https://doi.org/10.1007/s10928-026-10071-6","url":null,"abstract":"GS1-144 is a novel neurokinin-3 receptor (NK3R) antagonist under development for the treatment of vasomotor symptoms (VMS) associated with menopause. Suppression of luteinizing hormone (LH), a downstream marker of hypothalamic kisspeptin-neurokinin B-dynorphin (KNDy) neuronal activity, provides a measurable peripheral pharmacodynamic marker of central NK3R antagonism. The objective was to select a dose and dosing frequency for Phase II. A population pharmacokinetic-pharmacodynamic (PK-PD) model was developed using data from postmenopausal women. Individual pharmacokinetic parameter estimates were carried into a turnover model of serum LH. Model-based simulations using Bayesian estimates predicted GS1-144 and LH profiles for 7 days under once-daily doses of 30, 45, 60, and 90 mg and twice-daily doses of 15, 30, and 60 mg. Pharmacodynamic (PD) metrics included the minimum LH concentration, the maximum percentage reduction from baseline, and the LH area under the curve below baseline. GS1-144 produced dose-dependent LH suppression across once-daily and twice-daily regimens. Simulated LH profiles showed a rapid onset followed by recovery. 30 mg once daily, 60 mg once daily and 30 mg twice daily differed in depth and duration of suppression: 60 mg once daily gave the deepest suppression and 30 mg twice daily the largest integrated suppression at lower peak exposure. Integrated evaluation of absolute LH suppression, relative reduction from baseline, and sustained PD effects support GS1-144 doses of 30 mg once daily, 60 mg once daily, and 30 mg twice daily as providing pharmacologically meaningful NK3R target engagement. These regimens are recommended for Phase II evaluation in VMS associated with menopause.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207014","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

Modified frequency-based sensitivity analysis for oscillatory system models. 改进的基于频率的振荡系统模型灵敏度分析。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-10-15 DOI: 10.1007/s10928-026-10067-2

Xinyue Ma, Donald E Mager

{"title":"Modified frequency-based sensitivity analysis for oscillatory system models.","authors":"Xinyue Ma, Donald E Mager","doi":"10.1007/s10928-026-10067-2","DOIUrl":"https://doi.org/10.1007/s10928-026-10067-2","url":null,"abstract":"Global sensitivity analysis (GSA) is a critical and widely used method for evaluating model performance, as it quantifies input variability and uncertainty in both linear and nonlinear systems, with or without parameter interactions. However, for quantitative systems pharmacology or systems biology models with complex dynamics and time-dependent output exhibiting a single dominant oscillatory frequency, the classic GSA computed on fixed-time outputs may overlook parameters controlling oscillatory behaviors. To address this, a Fourier-based approach was refined to extract a single dominant oscillatory frequency across model simulated temporal profiles and define them as the quantity of interest (QoI) to compute the Sobol indices. Surrogate modeling was used to improve computational efficiency, which reduced computation time by at least 10-fold while recovering the ranking of influential parameters. This methodology was applied to several cases, including one involving dexamethasone treatment, to showcase how drug-induced perturbations can alter parameter sensitivity. In conclusion, these cases demonstrate the utility and efficiency of a Fourier-based GSA for identifying parameters controlling a dominant frequency in oscillatory system models.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194527","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

Prior-informed population pharmacokinetic-pharmacodynamic modeling of dexamethasone in horses. 事先告知人群地塞米松在马体内的药动学-药效学模型。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-26 DOI: 10.1007/s10928-026-10062-7

Ruihong Yu, Pierre-Louis Toutain, Carl Ekstrand, William J Jusko

{"title":"Prior-informed population pharmacokinetic-pharmacodynamic modeling of dexamethasone in horses.","authors":"Ruihong Yu, Pierre-Louis Toutain, Carl Ekstrand, William J Jusko","doi":"10.1007/s10928-026-10062-7","DOIUrl":"10.1007/s10928-026-10062-7","url":null,"abstract":"Dexamethasone (DEX) is widely used in equine practice with diverse studies having characterized its pharmacokinetics (PK) and pharmacodynamics (PD) including our published comprehensive meta-analysis. Individual DEX concentrations in plasma and urine and serum cortisol from five studies (n = 32 horses) were analyzed using a minimal physiologically-based PK (mPBPK) model and a circadian baseline-indirect response PD model. The previous meta-analysis provided complex structural models to assess sources of variability across an array of studies involving intravenous (IV), intramuscular (IM) and intra-articular (IA) dosing of various formulations. Here we compare three population estimation approaches: first-order conditional estimation with interaction (FOCEI), FOCEI with informative priors (FOCEI-Priors), and full Bayesian estimation. The primary covariate found was hepatic clearance of DEX being 17% higher in adult female horses (0.59 L/h/kg) than in geldings (0.49 L/h/kg). Between-subject variability was identified for some parameters. Standard FOCEI required extensive fixing of parameters to achieve convergence. FOCEI-Priors exhibited robust estimation performance, resulting in well-captured DEX PK and cortisol profiles, precise parameter estimates, and satisfactory model diagnostics. Bayesian estimation failed in the posterior exploration for cortisol PD, likely due to its greater sensitivity to prior specification and data variability. This work demonstrated effective population extensions of complex, prior-informed, mechanistic mPBPK/PD models to confirm determinants and assess variability of DEX disposition and adrenal effects in horses.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149061999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of two model-based Bayesian approaches for vancomycin dosing in general hospitalized patients. 两种基于模型的贝叶斯方法对普通住院患者万古霉素剂量的评价。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-26 DOI: 10.1007/s10928-026-10066-3

Athar Salah Al-Khirbash, Mohammed Al Za'abi, Juhaina Salim Al-Maqbali, Sabariah Noor Harun, Siti Maisharah Sheikh Ghadzi

{"title":"Evaluation of two model-based Bayesian approaches for vancomycin dosing in general hospitalized patients.","authors":"Athar Salah Al-Khirbash, Mohammed Al Za'abi, Juhaina Salim Al-Maqbali, Sabariah Noor Harun, Siti Maisharah Sheikh Ghadzi","doi":"10.1007/s10928-026-10066-3","DOIUrl":"10.1007/s10928-026-10066-3","url":null,"abstract":"Recent guidelines recommend Bayesian forecasting for vancomycin dosing. However, the agreement and predictive performance of different pharmacokinetic models remain unclear in hospitalized patients in general. This study evaluated two model-based Bayesian approaches implemented in platforms: the Goti et al. model in DoseMeRx and the Rodvold et al. model in PrecisePK. This single-centre prospective cohort study was conducted at Sultan Qaboos University Hospital, Oman, between April and October 2025. Adult inpatients aged ≥ 18 years with normal renal function were included; patients who were critically ill, pregnant, transplant recipients or receiving renal replacement therapy, or had malignancy were excluded. Agreement between the Goti et al. and Rodvold et al. models was assessed using the concordance correlation coefficient (ρc) and weighted Cohen's kappa (κw). Predictive performance was evaluated using relative bias (rBias) and relative root mean squared error (rRMSE). Models were considered clinically acceptable if rBias was within ± 20%. 90 patients were included. The models showed poor concordance (ρc = 0.59; 95% CI 0.44-0.71) and fair agreement (κw = 0.36; 95% CI 0.23-0.50). The Goti et al. model displayed poor predictive performance in prior predictions (rBias 33.92%; rRMSE 72.86%) and posterior predictions (rBias 20.17%; rRMSE 50.49%). The Rodvold et al. prior model also exhibited bias (rBias - 19.17%; rRMSE 51.52%). In contrast, the Rodvold et al. posterior model achieved clinically acceptable performance (rBias 0.47%; rRMSE 13.18%). The disagreement between the models suggests they may lead to different dosing decisions. The Rodvold et al. posterior model demonstrated acceptable accuracy and precision, making it more suitable for model-informed precision dosing. Further studies in larger and more diverse populations are needed.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062017","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

Formalizing method choice: a data-driven selection of mechanistic models for predicting human heart drug partitioning. 形式化方法选择：预测人类心脏药物分配的机制模型的数据驱动选择。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-25 DOI: 10.1007/s10928-026-10057-4

Seweryn Ulaszek, Bartek Lisowski, Monika Jesionek, Barbara Wiśniowska, Sebastian Polak

{"title":"Formalizing method choice: a data-driven selection of mechanistic models for predicting human heart drug partitioning.","authors":"Seweryn Ulaszek, Bartek Lisowski, Monika Jesionek, Barbara Wiśniowska, Sebastian Polak","doi":"10.1007/s10928-026-10057-4","DOIUrl":"10.1007/s10928-026-10057-4","url":null,"abstract":"We developed a workflow based on a human-derived dataset, aiming to predict the human heart-to-plasma partition coefficient, [Formula: see text]. The workflow combines established mechanistic tissue-composition models with an AI/ML-based selector that supports compound-specific selection among mechanistic heart [Formula: see text] prediction methods. Three published mechanistic approaches were implemented and parameterized in a harmonized manner consistent with the described methodologies to generate baseline [Formula: see text] predictions. The ML-based selector was trained using physicochemical, ADME, and pharmacokinetic descriptors to recognize compound-specific differences in model performance. This hybrid strategy preserves mechanistic interpretability while using empirical pattern recognition to formalize a priori model choice across compounds. In internal cross-validation, the selector reduced extreme outliers and provided a reproducible, data-driven rule for compound-specific method selection, although it did not materially outperform the strongest standalone mechanistic baseline in numerical error. Although no individual mechanistic method performed consistently across the full chemical space, the Poulin-Theil approach showed the best overall performance on human whole-heart data. The workflow was also applied prospectively to transthyretin stabilizers, for which reliable heart [Formula: see text] estimates may support further mechanistic modelling of cardiac drug exposure and downstream pharmacological effects. Together, these findings suggest that combining mechanistic calculators with an AI/ML-based selector may provide a practical basis for a priori, compound-specific method selection, reducing reliance on subjective choice of a single mechanistic approach.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modelling the tail-phase pharmacokinetics of long-acting cabotegravir and rilpivirine from early pregnancy to postpartum at steady state. 建立长效卡波特韦和利匹韦林从妊娠早期到产后稳定状态的尾期药代动力学模型。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-23 DOI: 10.1007/s10928-026-10065-4

Shakir Atoyebi, Catriona Waitt, Adeniyi Olagunju

{"title":"Modelling the tail-phase pharmacokinetics of long-acting cabotegravir and rilpivirine from early pregnancy to postpartum at steady state.","authors":"Shakir Atoyebi, Catriona Waitt, Adeniyi Olagunju","doi":"10.1007/s10928-026-10065-4","DOIUrl":"10.1007/s10928-026-10065-4","url":null,"abstract":"Long-acting cabotegravir and rilpivirine combination (LA-CAB/RPV) is approved for HIV treatment whilst LA-CAB alone is approved for HIV prevention, both in adults. However, individuals who become pregnant might prefer to discontinue it due to lack of definitive data on safety. The aim of this study was to characterise the tail-phase maternal and fetal pharmacokinetics of LA-CAB/RPV following discontinuation at steady-state early in pregnancy using physiologically-based pharmacokinetic modelling. A virtual population of non-pregnant women (n = 100 per scenario) initiated intramuscular injections of LA-CAB/RPV at the approved dosage and continued maintenance dose (400/600 mg once monthly or 600/900 mg once every two months) until steady state. We simulated discontinuation at steady state after only one injection during pregnancy. Tail-phase pharmacokinetics of CAB and RPV from LA injections were characterised during gestation and until 64 weeks postmenstrual age. Pharmacokinetic tails of LA-CAB/RPV were driven by the residual drug in the muscle depot which stabilised at steady state and reduced steadily upon dosing discontinuation. Upon discontinuation of the monthly dosing, predicted median (IQR) maternal plasma concentrations for LA-CAB were 415 (386-448) ng/mL at delivery and 125 (115-139) ng/mL at 64 weeks postmenstrual age. For LA-RPV, these were 11.6 (11.0-12.6) ng/mL and 7.84 (7.30-8.49) ng/mL at delivery and at 64 weeks postmenstrual age, respectively. Pharmacokinetic tails of LA-CAB/RPV extend to several months postpartum, with levels falling below established minimum effective concentration in most women after gestation week 33. Potential strategies to minimise potential risks associated with LA-CAB/RPV discontinuation in this population are needed.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of a model averaging algorithm for model-informed precision dosing in the context of parameter misspecifications. 在参数不规范的情况下，模型通知精确给药的模型平均算法的评价。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-22 DOI: 10.1007/s10928-026-10064-5

Sandra Witta, Sebastian G Wicha

{"title":"Evaluation of a model averaging algorithm for model-informed precision dosing in the context of parameter misspecifications.","authors":"Sandra Witta, Sebastian G Wicha","doi":"10.1007/s10928-026-10064-5","DOIUrl":"10.1007/s10928-026-10064-5","url":null,"abstract":"A primary challenge for integrating model-informed precision dosing (MIPD) in clinical settings is selecting the best-fit model for newly presented patients. A model averaging algorithm (MAA) proposed by Uster et al., addresses this by leveraging multiple models simultaneously. As the 'library' of population pharmacokinetic models for a given therapeutic expands, an understanding of how model misspecifications influence MAA can provide insight to guide the optimal selection of model combinations. The present simulation study evaluated the impact of parameter model misspecifications on MAA performance across three scenarios: (1) misspecified structural parameter (θCL), (2) misspecified residual error (σ²), and (3) misspecified interindividual variability on clearance (ω2CL). Predictive performance for Bayesian forecasting was assessed within each misspecification scenario for single candidate models, a re-estimated model and various combinations of models in MAA. Performance was evaluated for precision and accuracy. The results showed greatest MAA benefit under structural model misspecification, where combining models with opposing bias showed improved predictive performance. In the case of misspecified residual error and interindividual variability (IIV), MAA tended to down-weight models with high residual error or favor those with higher IIV, respectively. Overall, these findings can be used to inform the selection of model combinations to improve MAA performance, supporting more robust MIPD implementation.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In silico modeling of methadone-related ion current effects to predict QT interval prolongation. 美沙酮相关离子电流效应预测QT间期延长的计算机模拟。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-22 DOI: 10.1007/s10928-026-10059-2

Jacob A Lindsey, Omar A Aboshady, Min Yue, Sara K Quinney, James E Tisdale, Brian R Overholser

{"title":"In silico modeling of methadone-related ion current effects to predict QT interval prolongation.","authors":"Jacob A Lindsey, Omar A Aboshady, Min Yue, Sara K Quinney, James E Tisdale, Brian R Overholser","doi":"10.1007/s10928-026-10059-2","DOIUrl":"10.1007/s10928-026-10059-2","url":null,"abstract":"Methadone is commonly associated with QT interval prolongation, which can lead to torsades de pointes. This effect has primarily been attributed to blockade of the delayed rectifier potassium current, IKr. However, methadone inhibits other ion currents to varying degrees. A deeper understanding of how ion currents interact to produce drug-induced QT interval prolongation may support development of strategies to mitigate risk of potentially fatal arrhythmias. Given the difficulty of isolating the contributions of specific ion currents in drugs with multiple effects, this study used cardiac electrophysiology simulations to predict current-specific effects of methadone-induced QT interval prolongation. Action potential (AP) and electrocardiogram (ECG) models based on the Tusscher-Noble-Noble-Panfilov (2004) model were built using the Cardiac Safety Simulator version 2.2. Single-cell APs were simulated using published in vitro data of methadone's effects (half-maximal inhibitory concentration and Hill coefficient) on multiple ion currents. The model was extrapolated to simulate ECGs using population parameters from a clinical study, and outputs from both models were compared to published data. A stepwise modeling approach isolated individual ion current contribution toward proarrhythmia. The final ECG model predicted heart rate-corrected QT intervals (QTc) within 1.5% of the observed data at four concentration ranges. Evaluation of individual ion currents toward QTc interval modulation suggested that IKr and IK1 have a similar impact on methadone-related QTc interval prolongation. This study highlights the potential contribution of multiple ion currents to methadone's proarrhythmic effects and advances the understanding of ion current interplay underlying methadone-induced arrhythmia.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of an isavuconazole physiologically-based pharmacokinetic model for adult and pediatric populations. 成人和儿童依唑康唑生理药代动力学模型的建立。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-22 DOI: 10.1007/s10928-026-10061-8

Mary P Choules, Amit Desai, Laura Lynn Kovanda, Yukio Otsuka, Roger J Brüggemann, Peter L Bonate

{"title":"Development of an isavuconazole physiologically-based pharmacokinetic model for adult and pediatric populations.","authors":"Mary P Choules, Amit Desai, Laura Lynn Kovanda, Yukio Otsuka, Roger J Brüggemann, Peter L Bonate","doi":"10.1007/s10928-026-10061-8","DOIUrl":"10.1007/s10928-026-10061-8","url":null,"abstract":"Isavuconazonium sulfate is the water-soluble prodrug of the active triazole antifungal agent isavuconazole. Isavuconazonium sulfate is approved for the treatment of invasive aspergillosis and invasive mucormycosis in pediatric and adult populations. In the present analysis, an isavuconazole physiologically-based pharmacokinetic (PBPK) model was built and verified in adult and pediatric populations using the Simcyp® simulator. The verified pediatric model was then used to predict the magnitude of DDI risk in pediatric populations vs. adult populations. The simulations conducted were designed to match the observed clinical trials conducted in adults but with pediatric equivalent doses based on clinical guidelines. Based on the results of the analysis, isavuconazole DDI risk was similar between pediatric and adult populations. When the isavuconazole perpetrator DDI simulations were compared to adults, there was a trend of larger geometric mean (GM) AUCinf and Cmax ratios in patients 1 to < 3 years old receiving the 15 mg/kg dose. The GM AUCinf ratio in this study population ranged from 7 to 36% larger than predicted in the adult population. Based on the results of this analysis and literature reports, it is advisable to show greater caution when considering potential DDI in patients < 3-year-old, especially when receiving larger isavuconazonium sulfate doses. In addition, caution should be used in patients < 3 years-old when considering coadministration of isavuconazole with narrow therapeutic index medications such as digoxin and warfarin or medications with large variability in oral bioavailability such as midazolam.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A systems pharmacology model for paracetamol overdose and treatment. 扑热息痛过量及治疗的系统药理学模型。

IF 3.3 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2026-09-22 DOI: 10.1007/s10928-026-10060-9

Jingyun Li, Angela L Chiew, Geoffrey K Isbister, Stephen B Duffull

{"title":"A systems pharmacology model for paracetamol overdose and treatment.","authors":"Jingyun Li, Angela L Chiew, Geoffrey K Isbister, Stephen B Duffull","doi":"10.1007/s10928-026-10060-9","DOIUrl":"10.1007/s10928-026-10060-9","url":null,"abstract":"Paracetamol overdose is the leading cause of acute liver failure in many countries, including North America and the United Kingdom. While timely administration with the standard treatment is generally effective, the optimal treatment for scenarios such as \"massive\" overdose or modified release paracetamol overdose remains unknown. In this work we aim to develop and calibrate a systems pharmacology model for paracetamol-induced hepatotoxicity with the influence of administration of the antidote N-acetylcysteine (NAC). The system model integrates five components, including (1) input of paracetamol, (2) paracetamol metabolism of parent drug and metabolites, (3) physiological turnover of endogenous sulfur-containing substrates, including the metabolism of cysteine to produce glutathione and inorganic sulfate, etc., (4) a general model for the release of biomarkers from injured hepatocytes to blood, and (5) a PK model for NAC and three proposed mechanisms of NAC effect. The final systems model demonstrated a good description of the concentration-time courses of paracetamol, its metabolites and biomarkers after administration of a normal dose to a large overdose of paracetamol. The final model provides a quantitative and comprehensive understanding of the causal pathway of paracetamol-induced liver toxicity and its treatment, which allows the investigation of the 'what if' scenarios in the rescue of paracetamol poisoning.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"53 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025230","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