CPT: Pharmacometrics & Systems Pharmacology最新文献_第3页

Population PK modeling of certolizumab pegol in pregnant women with chronic inflammatory diseases. 慢性炎症性疾病孕妇使用曲妥珠单抗 pegol 的人群 PK 模型。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-09-01 DOI: 10.1002/psp4.13220

Denis Menshykau, Jagdev Sidhu, Laura Shaughnessy, Rocio Lledo-Garcia, Pinky Dua, Marie Teil, Akash Khandelwal

{"title":"Population PK modeling of certolizumab pegol in pregnant women with chronic inflammatory diseases.","authors":"Denis Menshykau, Jagdev Sidhu, Laura Shaughnessy, Rocio Lledo-Garcia, Pinky Dua, Marie Teil, Akash Khandelwal","doi":"10.1002/psp4.13220","DOIUrl":"https://doi.org/10.1002/psp4.13220","url":null,"abstract":"Certolizumab pegol (CZP; CIMZIA™) is the only Fc-free tumor necrosis factor inhibitor with data from a clinical study demonstrating no to minimal placental transfer. The pharmacokinetics (PK) of certolizumab pegol during pregnancy and postpartum in women with chronic inflammatory diseases were assessed using a population PK model based on data from the CHERISH study (NCT04163016), a longitudinal, prospective, open-label PK phase IB study. Model development was performed in NONMEM using a frequentist prior approach, with prior information based on a population PK model for certolizumab pegol in non-pregnant adult patients (NCT04740814). A one-compartment model with first-order absorption (Ka = 0.236 1/day) and linear elimination (CL/F = 0.416 L/day) from the central compartment (V/F = 7.86 L) best described certolizumab pegol PK in the CHERISH study. The structural model parameters were estimated with good precision (RSE < 25%). Baseline BW was included as a covariate on CL/F and V/F. Pregnancy trimester and time-varying log-transformed anti-drug antibody (ADA) titer were identified as the only significant covariates for CL/F with a comparable influence on CL/F. Individuals with higher ADA titer (75th percentile) during pregnancy exhibited CL/F up to 1.43-fold higher relative to individuals postpartum that showed median levels of ADA titer. However, the confidence interval for the combined effect of pregnancy stage and ADA titer effects on CL/F overlapped with the CL/F range of the typical individual postpartum. In addition, simulations showed a large overlap in certolizumab pegol concentrations between pregnant and non-pregnant adults. The findings of this population PK analysis support the maintenance of established certolizumab pegol dosing regimens throughout pregnancy.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105167","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}

引用次数: 0

Population pharmacokinetics and exposure-response analyses of safety (ARIA-E and isolated ARIA-H) of lecanemab in subjects with early Alzheimer's disease. 对早期阿尔茨海默氏症患者进行的来卡尼单抗群体药代动力学和暴露-反应安全性分析（ARIA-E 和单独的 ARIA-H）。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-29 DOI: 10.1002/psp4.13224

Oneeb Majid, Youfang Cao, Brian A Willis, Seiichi Hayato, Osamu Takenaka, Bojan Lalovic, Sree Harsha Sreerama Reddy, Natasha Penner, Larisa Reyderman, Sanae Yasuda, Ziad Hussein

{"title":"Population pharmacokinetics and exposure-response analyses of safety (ARIA-E and isolated ARIA-H) of lecanemab in subjects with early Alzheimer's disease.","authors":"Oneeb Majid, Youfang Cao, Brian A Willis, Seiichi Hayato, Osamu Takenaka, Bojan Lalovic, Sree Harsha Sreerama Reddy, Natasha Penner, Larisa Reyderman, Sanae Yasuda, Ziad Hussein","doi":"10.1002/psp4.13224","DOIUrl":"https://doi.org/10.1002/psp4.13224","url":null,"abstract":"Lecanemab (Leqembi®) was recently approved by health authorities in the United States, Japan, and China to treat early Alzheimer's disease (AD), including patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease upon confirmation of amyloid beta pathology. Extensively and sparsely sampled PK profiles from 1619 AD subjects and 21,929 serum lecanemab observations from two phase I, one phase II, and one phase III studies were well characterized using a two-compartment model with first-order elimination. The final PK model quantified covariate effects of body weight and sex on clearance and central volume of distribution, ADA-positive status, and albumin on clearance, and of Japanese ethnicity on central and peripheral volumes of distribution. Exposure to lecanemab was comparable between two lecanemab-manufacturing processes. However, none of the identified covariates in the model had a clinically relevant impact on model-predicted lecanemab Cmax or AUC at steady state following 10 mg/kg bi-weekly. Importantly, age, a well-recognized risk factor for AD, was not found to significantly affect lecanemab PK. The incidence of ARIA-E as a function of lecanemab exposure was modeled using a logit function with data pooled from 2641 subjects from the phase II and phase III studies, in which a total of 177 incidences of ARIA-E were observed. The probability of ARIA-E was significantly correlated with model-predicted Cmax and predicted to be higher in subjects homozygous for APOE4. The incidence of isolated ARIA-H was not associated with lecanemab exposure and was similar between placebo and lecanemab-treated subjects.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105166","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}

引用次数: 0

Evaluation of model-integrated evidence approaches for pharmacokinetic bioequivalence studies using model averaging methods. 使用模型平均法评估药代动力学生物等效性研究的模型整合证据方法。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-28 DOI: 10.1002/psp4.13217

Henrik Bjugård Nyberg, Xiaomei Chen, Mark Donnelly, Lanyan Fang, Liang Zhao, Mats O Karlsson, Andrew C Hooker

{"title":"Evaluation of model-integrated evidence approaches for pharmacokinetic bioequivalence studies using model averaging methods.","authors":"Henrik Bjugård Nyberg, Xiaomei Chen, Mark Donnelly, Lanyan Fang, Liang Zhao, Mats O Karlsson, Andrew C Hooker","doi":"10.1002/psp4.13217","DOIUrl":"https://doi.org/10.1002/psp4.13217","url":null,"abstract":"Conventional approaches for establishing bioequivalence (BE) between test and reference formulations using non-compartmental analysis (NCA) may demonstrate low power in pharmacokinetic (PK) studies with sparse sampling. In this case, model-integrated evidence (MIE) approaches for BE assessment have been shown to increase power, but may suffer from selection bias problems if models are built on the same data used for BE assessment. This work presents model averaging methods for BE evaluation and compares the power and type I error of these methods to conventional BE approaches for simulated studies of oral and ophthalmic formulations. Two model averaging methods were examined: bootstrap model selection and weight-based model averaging with parameter uncertainty from three different sources, either from a sandwich covariance matrix, a bootstrap, or from sampling importance resampling (SIR). The proposed approaches increased power compared with conventional NCA-based BE approaches, especially for the ophthalmic formulation scenarios, and were simultaneously able to adequately control type I error. In the rich sampling scenario considered for oral formulation, the weight-based model averaging method with SIR uncertainty provided controlled type I error, that was closest to the target of 5%. In sparse-sampling designs, especially the single sample ophthalmic scenarios, the type I error was best controlled by the bootstrap model selection method.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105165","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}

引用次数: 0

A fully automatic tool for development of population pharmacokinetic models. 开发群体药代动力学模型的全自动工具。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-27 DOI: 10.1002/psp4.13222

Xiaomei Chen, Rikard Nordgren, Stella Belin, Alzahra Hamdan, Shijun Wang, Tianwu Yang, Zhe Huang, Simon J Carter, Simon Buatois, João A Abrantes, Andrew C Hooker, Mats O Karlsson

{"title":"A fully automatic tool for development of population pharmacokinetic models.","authors":"Xiaomei Chen, Rikard Nordgren, Stella Belin, Alzahra Hamdan, Shijun Wang, Tianwu Yang, Zhe Huang, Simon J Carter, Simon Buatois, João A Abrantes, Andrew C Hooker, Mats O Karlsson","doi":"10.1002/psp4.13222","DOIUrl":"https://doi.org/10.1002/psp4.13222","url":null,"abstract":"Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi-step, challenging, and time-consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open-source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter-individual variability (IIV) model, the inter-occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072240","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}

引用次数: 0

A stacking ensemble machine learning model for evaluating cardiac toxicity of drugs based on in silico biomarkers. 基于硅学生物标志物评估药物心脏毒性的堆叠集合机器学习模型。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-26 DOI: 10.1002/psp4.13229

Yunendah Nur Fuadah, Ali Ikhsanul Qauli, Muhammad Adnan Pramudito, Aroli Marcellinus, Ulfa Latifa Hanum, Ki Moo Lim

{"title":"A stacking ensemble machine learning model for evaluating cardiac toxicity of drugs based on in silico biomarkers.","authors":"Yunendah Nur Fuadah, Ali Ikhsanul Qauli, Muhammad Adnan Pramudito, Aroli Marcellinus, Ulfa Latifa Hanum, Ki Moo Lim","doi":"10.1002/psp4.13229","DOIUrl":"https://doi.org/10.1002/psp4.13229","url":null,"abstract":"This study addresses the critical issue of drug-induced torsades de pointes (TdP) risk assessment, a vital aspect of new drug development due to its association with arrhythmia and sudden cardiac death. Existing methodologies, particularly those reliant on a single biomarker derived from CiPA O'Hara-Rudy (CiPAORdv1.0) ventricular cell model without the hERG dynamic as input to the individual machine learning model, have limitations in capturing the complexity inherent in the comprehensive range of factors influencing drug-induced TdP risk. This study aims to overcome these limitations by proposing a stacking ensemble machine learning approach by integrating multiple in silico biomarkers derived from the CiPAORdv1.0 with hERG dynamic characteristics. The ensemble machine learning model consisted of three artificial neural network (ANN) models as baseline model and support vector machine (SVM), logistic regression (LR), random forest (RF), and extreme gradient boosting (XGBoost) models as meta-classifier. The highest AUC score of 1.00 (0.90-1.00) for high risk, 0.97 (0.84-1.00) for intermediate risk, and 1.00 (0.87-1.00) for low risk were obtained using seven biomarkers derived from the CiPAORdv1.0 with hERG dynamic characteristics. Furthering our investigation, we explored the model's robustness by incorporating interindividual variability into the generation of in silico biomarkers from a population of human ventricular cell models. This study also enabled an analysis of TdP risk classification under high clinical exposure and therapeutic scenarios for several drugs. Additionally, from a sensitivity analysis, we revealed four important ion channels, namely, CaL, NaL, Na, and Kr channels that affect significantly the important biomarkers for TdP risk prediction.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055164","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}

引用次数: 0

Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic end points. 开发和比较用于药代动力学终点生物等效性研究的模型整合证据方法。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-23 DOI: 10.1002/psp4.13216

Xiaomei Chen, Henrik B Nyberg, Mark Donnelly, Liang Zhao, Lanyan Fang, Mats O Karlsson, Andrew C Hooker

{"title":"Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic end points.","authors":"Xiaomei Chen, Henrik B Nyberg, Mark Donnelly, Liang Zhao, Lanyan Fang, Mats O Karlsson, Andrew C Hooker","doi":"10.1002/psp4.13216","DOIUrl":"https://doi.org/10.1002/psp4.13216","url":null,"abstract":"By applying nonlinear mixed-effect (NLME) models, model-integrated evidence (MIE) approaches are able to analyze bioequivalence (BE) data with pharmacokinetic end points that have sparse sampling, which is problematic for non-compartmental analysis (NCA). However, MIE approaches may suffer from inflation of type I error due to underestimation of parameter uncertainty and to the assumption of asymptotic normality. In this study, we developed a MIE BE analysis method that is based on a pre-defined model and consists of several steps including model fitting, uncertainty assessment, simulation, and BE determination. The presented MIE approach has several improvements compared with the previously reported model-integrated methods: (1) treatment, sequence, and period effects are only added to absorption parameters (such as relative bioavailability and rate of absorption) instead of all PK parameters; (2) a simulation step is performed to generate confidence intervals of the pharmacokinetic metrics for BE assessment; and (3) in an effort to maintain type I error, two more advanced parameter uncertainty evaluation approaches are explored, a nonparametric (case resampling) bootstrap, and sampling importance resampling (SIR). To evaluate the developed method and compare the uncertainty assessment methods, simulation experiments were performed for BE studies using a two-way crossover design with different amounts of information (sparse to rich designs) and levels of variability. Based on the simulation results, the method using SIR for parameter uncertainty quantification controls type I error at the nominal level of 0.05 (i.e., the significance level set for BE evaluation) even for studies with small sample size and/or sparse sampling. As expected, our MIE approach for BE assessment exhibited higher power than the NCA-based method, especially as the data becomes sparser and/or more variable.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035388","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}

引用次数: 0

Quantitative systems pharmacology model of α-synuclein pathology in Parkinson's disease-like mouse for investigation of passive immunotherapy mechanisms. 帕金森病样小鼠α-突触核蛋白病理学定量系统药理学模型，用于研究被动免疫疗法机制。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-23 DOI: 10.1002/psp4.13223

Olga Ivanova, Tatiana Karelina

{"title":"Quantitative systems pharmacology model of α-synuclein pathology in Parkinson's disease-like mouse for investigation of passive immunotherapy mechanisms.","authors":"Olga Ivanova, Tatiana Karelina","doi":"10.1002/psp4.13223","DOIUrl":"https://doi.org/10.1002/psp4.13223","url":null,"abstract":"The main pathophysiological hallmark of Parkinson's disease (PD) is the accumulation of aggregated alpha-synuclein (αSyn). Microglial activation is an early event in PD and may play a key role in pathological αSyn aggregation and transmission, as well as in clearance of αSyn and immunotherapy efficacy. Our aim was to investigate how different proposed mechanisms of anti-αSyn immunotherapy may contribute to pathology reduction in various PD-like mouse models. Our mechanistic model of PD pathology in mouse includes αSyn production, aggregation, degradation and distribution in neurons, secretion into interstitial fluid, internalization, and subsequent clearance by neurons and microglia. It describes the influence of neuroinflammation on PD pathogenesis and dopaminergic neurodegeneration. Multiple data from mouse PD models were used for calibration and validation. Simulations of anti-αSyn passive immunotherapy adequately reproduce preclinical data and suggest that (1) immunotherapy is efficient in the reduction of aggregated αSyn in various models of PD-like pathology; (2) prevention of aSyn spread only does not reduce the pathology; (3) a decrease in microglial inflammatory activation and aSyn aggregation may be alternative therapy approaches in PD-like pathology.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035389","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}

引用次数: 0

Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subcutaneous implant. 对伊斯拉曲韦预防 HIV-1 的疗效和毒性进行建模后发现，口服药物的疗效并不理想，但皮下植入药物的疗效却很好。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-20 DOI: 10.1002/psp4.13212

Hee-Yeong Kim, Lanxin Zhang, Craig W Hendrix, Jessica E Haberer, Max von Kleist

{"title":"Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subcutaneous implant.","authors":"Hee-Yeong Kim, Lanxin Zhang, Craig W Hendrix, Jessica E Haberer, Max von Kleist","doi":"10.1002/psp4.13212","DOIUrl":"https://doi.org/10.1002/psp4.13212","url":null,"abstract":"HIV prevention with pre-exposure prophylaxis (PrEP) constitutes a major pillar in fighting the ongoing epidemic. While daily oral PrEP adherence may be challenging, long-acting (LA-)PrEP in oral or implant formulations could overcome frequent dosing with convenient administration. The novel drug islatravir (ISL) may be suitable for LA-PrEP, but dose-dependent reductions in <math> <semantics><mrow><mi>CD</mi> <msup><mn>4</mn> <mo>+</mo></msup> </mrow> <annotation>$$ mathrm{CD}{4}^{+} $$</annotation></semantics> </math> T cell and lymphocyte counts were observed at high doses. We developed a mathematical model to predict ISL pro-drug levels in plasma and active intracellular ISL-triphosphate concentrations after oral vs. subcutaneous implant dosing. Using phase II trial data, we simulated antiviral effects and estimated HIV risk reduction for multiple dosages and dosing frequencies. We then established exposure thresholds where no adverse effects on immune cells were observed. Our findings suggest that implants with 56-62 mg ISL offer effective HIV risk reduction without reducing lymphocyte counts. Oral 0.1 mg daily, 3-5 mg weekly, and 10 mg biweekly ISL provide comparable efficacy, but weekly and biweekly doses may affect lymphocyte counts, while daily dosing regimen offered no advantage over existing oral PrEP. Oral 0.5-1 mg on demand provided <math> <semantics><mrow><mo>></mo> <mn>90</mn> <mo>%</mo></mrow> <annotation>$$ >90% $$</annotation></semantics> </math> protection, while not being suitable for post-exposure prophylaxis. These findings suggest ISL could be considered for further development as a promising and safe agent for implantable PrEP.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008458","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}

引用次数: 0

Bayesian sparse regression for exposure-response analyses of efficacy and safety endpoints to justify the clinical dose of valemetostat for adult T-cell leukemia/lymphoma. 贝叶斯稀疏回归用于疗效和安全性终点的暴露-反应分析，以证明伐麦司他治疗成人T细胞白血病/淋巴瘤的临床剂量是合理的。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-18 DOI: 10.1002/psp4.13203

Masato Fukae, James Rogers, Ramon Garcia, Masaya Tachibana, Takako Shimizu

{"title":"Bayesian sparse regression for exposure-response analyses of efficacy and safety endpoints to justify the clinical dose of valemetostat for adult T-cell leukemia/lymphoma.","authors":"Masato Fukae, James Rogers, Ramon Garcia, Masaya Tachibana, Takako Shimizu","doi":"10.1002/psp4.13203","DOIUrl":"https://doi.org/10.1002/psp4.13203","url":null,"abstract":"Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T-cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure-response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150-200 mg), and six safety endpoints in patients with non-Hodgkin lymphoma (n = 102, 150-300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment-emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184-887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter-individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999563","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}

引用次数: 0

Enhancing inclusivity in clinical trials: Model-informed drug development for pregnant individuals in the era of personalized medicine. 增强临床试验的包容性：在个性化医疗时代，针对孕妇的模型化药物开发。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-08-18 DOI: 10.1002/psp4.13218

André Dallmann, Peter L Bonate, Janelle Burnham, Blessy George, Lynne Yao, Jane Knöchel

引用次数: 0