CPT: Pharmacometrics & Systems Pharmacology最新文献

Development of a physiologically-based pharmacokinetic model for Ritonavir characterizing exposure and drug interaction potential at both acute and steady-state conditions.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-23 DOI: 10.1002/psp4.13293

Lien Thi Ngo, Woojin Jung, Tham Thi Bui, Hwi-Yeol Yun, Jung-Woo Chae, Jeremiah D Momper

{"title":"Development of a physiologically-based pharmacokinetic model for Ritonavir characterizing exposure and drug interaction potential at both acute and steady-state conditions.","authors":"Lien Thi Ngo, Woojin Jung, Tham Thi Bui, Hwi-Yeol Yun, Jung-Woo Chae, Jeremiah D Momper","doi":"10.1002/psp4.13293","DOIUrl":"https://doi.org/10.1002/psp4.13293","url":null,"abstract":"Ritonavir (RTV) is a potent CYP3A inhibitor that is widely used as a pharmacokinetic (PK) enhancer to increase exposure to select protease inhibitors. However, as a strong and complex perpetrator of CYP3A interactions, RTV can also enhance the exposure of other co-administered CYP3A substrates, potentially causing toxicity. Therefore, the prediction of drug-drug interactions (DDIs) and estimation of dosing requirements for concomitantly administered drugs is imperative. In this study, we aimed to develop a physiologically-based PK (PBPK) model for RTV using the PK-sim® software platform. A total of 13 clinical PK studies of RTV covering a wide dose range (100 to 600 mg including both single and multiple dosing), and eight clinical DDI studies with RTV on CYP3A and P-gp substrates, including alprazolam, midazolam, rivaroxaban, clarithromycin, fluconazole, sildenafil, and digoxin were used for the model development and evaluation. Chronopharmacokinetic differences (between morning vs. evening doses) and limitations in parameter estimation for biochemical processes of RTV from in vitro studies were incorporated in the PBPK model. The final developed PBPK model predicted 100% of RTV AUClast and Cmax within a twofold dimension error. The geometric mean fold error (GMFE) from all PK datasets was 1.275 and 1.194, respectively. In addition, 97% of the DDI profiles were predicted with the DDI ratios within a twofold dimension error. The GMFE values from all DDI datasets were 1.297 and 1.212, respectively. Accordingly, this model could be applied to the prediction of DDI profiles of RTV and CYP3A substrates and used to estimate dosing requirements for concomitantly administered drugs.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876588","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

Mirikizumab pharmacokinetics and exposure-response in pediatric patients with moderate-to-severe ulcerative colitis.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-18 DOI: 10.1002/psp4.13286

Yuki Otani, Laiyi Chua, Wendy J Komocsar, Amy Larkin, Jordan Johns, Xin Zhang

{"title":"Mirikizumab pharmacokinetics and exposure-response in pediatric patients with moderate-to-severe ulcerative colitis.","authors":"Yuki Otani, Laiyi Chua, Wendy J Komocsar, Amy Larkin, Jordan Johns, Xin Zhang","doi":"10.1002/psp4.13286","DOIUrl":"https://doi.org/10.1002/psp4.13286","url":null,"abstract":"Mirikizumab is a p19-directed anti-interleukin-23 antibody approved for the treatment of adults with moderate-to-severe ulcerative colitis (UC). Here, we report the first data of mirikizumab pharmacokinetics (PK) and exposure-response (E/R) relationships in pediatric participants (aged 2 to <18 years weighing >10 kg) with moderate-to-severe UC from the phase II, open-label study SHINE-1 (NCT04004611). PK parameters were analyzed using a model developed previously in adults with fixed-exponent allometry for body weight. Serum samples collected from 26 participants during the 12-week induction and 40-week maintenance periods of SHINE-1 were analyzed. Estimated body weight-adjusted systemic clearance, volume of distribution, and subcutaneous bioavailability were 0.021 L/h, 0.069 L/kg, and 49.8%, respectively. Covariate analysis identified no clinically significant covariates other than body weight. In the exposure range studied, E/R analysis using post hoc grouping by average concentration quartile and comparison of observed change from baseline in modified Mayo Score (MMS) at Week 12 with the adult model prediction revealed no obvious E/R relationship in clinical response, clinical remission, or endoscopic response, consistent with observations in adults. The E/R relationship for observed change from baseline in MMS at Week 12 is also similar to the adult model prediction. The PK modeling and E/R analyses suggested optimal doses of intravenous mirikizumab 300 mg for weight >40 kg, 5 mg/kg for weight ≤40 kg every 4 weeks (Q4W) during induction, and subcutaneous mirikizumab 200 mg (>40 kg), 100 mg (>20 to ≤40 kg), or 50 mg (≤20 kg) Q4W during maintenance therapy for pediatric patients with moderate-to-severe UC.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853499","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

Physiologically based pharmacokinetic modeling and simulation of topiramate in populations with renal and hepatic impairment and considerations for drug-drug interactions. 基于生理学的托吡酯在肝肾功能受损人群中的药代动力学建模和模拟，以及对药物间相互作用的考虑。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-15 DOI: 10.1002/psp4.13292

Shuqing Chen, Chaozhuang Shen, Yuchen Tian, Yuhe Peng, Jing Hu, Haitang Xie, Ping Yin

{"title":"Physiologically based pharmacokinetic modeling and simulation of topiramate in populations with renal and hepatic impairment and considerations for drug-drug interactions.","authors":"Shuqing Chen, Chaozhuang Shen, Yuchen Tian, Yuhe Peng, Jing Hu, Haitang Xie, Ping Yin","doi":"10.1002/psp4.13292","DOIUrl":"https://doi.org/10.1002/psp4.13292","url":null,"abstract":"Topiramate (TPM) is a broad-spectrum antiepileptic drug (AED) commonly prescribed for approved and off-label uses. Routine monitoring is suggested for clinical usage of TPM in special population due to its broad side effect profile. Therefore, it is crucial to further explore its pharmacokinetic characteristics. Physio-chemical properties of TPM were initially determined from online database and further optimized while establishing the PBPK model for healthy adults using the PK-Sim software. The model was then extrapolated to patients with renal impairment and patients who were hepatically impaired. A drug-drug interaction (DDI) model was also built to simulate plasma TPM concentrations while concomitantly used with carbamazepine (CBZ). The goodness-of-fit method and average fold error (AFE) method were used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. Almost all of the predicted concentration fell within twofold error range of corresponding observed concentrations. The AFE ratio of predicted to observed values of Cmax and AUC0-inf was all within 0.5 and 2. It is recommended that the doses be reduced to 70%, 50%, and 40% of the healthy adult dose for the chronic kidney disease (CKD) stage 3, stage 4, and stage 5 patients, respectively, and reduced to ~70%, and 35% for the Child-Pugh-B, and Child-Pugh C scored patient with hepatic impairment, respectively. If TPM is co-administered with CBZ, increasing TPM doses to 150%-175% of the monotherapy dose is recommended according to model simulation.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827651","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

Clinical modeling of motor function to predict treatment efficacy and enable in silico treatment comparisons in infantile-onset Pompe disease.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-13 DOI: 10.1002/psp4.13287

Fatiha Rachedi, Rana Jreich, Susan Sparks, Atef Zaher, Kristina An Haack, Alicia Granados, Zhaoling Meng

{"title":"Clinical modeling of motor function to predict treatment efficacy and enable in silico treatment comparisons in infantile-onset Pompe disease.","authors":"Fatiha Rachedi, Rana Jreich, Susan Sparks, Atef Zaher, Kristina An Haack, Alicia Granados, Zhaoling Meng","doi":"10.1002/psp4.13287","DOIUrl":"https://doi.org/10.1002/psp4.13287","url":null,"abstract":"Infantile-onset Pompe disease (IOPD) is a rare, deadly, quickly-progressing degenerative disease. Even with life-sustaining treatment (e.g., alglucosidase alfa [ALGLU]), many patients experience continued motor impairment. The Mini-COMET trial evaluated avalglucosidase alfa (AVAL) versus ALGLU on motor and other outcomes in IOPD. However, treatment groups were imbalanced at baseline and the trial was not powered to directly compare treatments. To supplement this limited data, we developed a modeling and simulation approach to compare AVAL versus ALGLU head-to-head in in silico (i.e., computer-simulated) trials. We first developed a longitudinal clinical model to establish the relationship between changes in motor function and changes in urinary hexose tetrasaccharide (uHex4), an established biomarker in IOPD. This model was based on pooled data from Mini-COMET (n = 21) and COMET trials (n = 100 patients with late-onset Pompe disease, LOPD). We then conducted in silico trials mimicking Mini-COMET. Simulated trials were informed by motor data generated from the clinical model and uHex4 profiles simulated in a quantitative systems pharmacology model. The virtual IOPD population was based on observed Mini-COMET baseline characteristics but engineered to have well-balanced baseline characteristics across treatment cohorts. In silico trials showed that patients with IOPD would have the greatest improvements in motor function with AVAL 40 mg/kg every other week (Q2W), suboptimal improvement with ALGLU 40 mg/kg Q2W, and no improvement with ALGLU 20 mg/kg Q2W. This study provides information on the relative efficacy of IOPD treatments and mitigates the confounding effects of imbalanced treatment cohorts. Our approach could also be applied in other rare diseases.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817323","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 tutorial on pharmacometric Markov models.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-13 DOI: 10.1002/psp4.13278

Qing Xi Ooi, Elodie Plan, Martin Bergstrand

{"title":"A tutorial on pharmacometric Markov models.","authors":"Qing Xi Ooi, Elodie Plan, Martin Bergstrand","doi":"10.1002/psp4.13278","DOIUrl":"https://doi.org/10.1002/psp4.13278","url":null,"abstract":"The Markov chain is a stochastic process in which the future value of a variable is conditionally independent of the past, given its present value. Data with Markovian features are characterized by: frequent observations relative to the expected changes in values, many consecutive same-category or similar-value observations at the individual level, and a positive correlation observed between the current and previous values for that variable. In drug development and clinical settings, the data available commonly present Markovian features and are increasingly often modeled using Markov elements or dedicated Markov models. This tutorial presents the main characteristics, evaluations, and applications of various Markov modeling approaches including the discrete-time Markov models (DTMM), continuous-time Markov models (CTMM), hidden Markov models, and item-response theory model with Markov sub-models. The tutorial has a specific emphasis on the use of DTMM and CTMM for modeling ordered-categorical data with Markovian features. Although the main body of this tutorial is written in a software-neutral manner, annotated NONMEM code for all key Markov models is included in the Supplementary Information.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817390","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

Advancing pharmacometrics in Africa-Transition from capacity development toward job creation.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-09 DOI: 10.1002/psp4.13291

Goonaseelan Colin Pillai, Samer Mouksassi, Innocent G Asiimwe, Craig R Rayner, Steven Kern, Phumla Sinxadi, Paolo Denti, Eric Decloedt, Catriona Waitt, Bernhards R Ogutu, Rik de Greef

{"title":"Advancing pharmacometrics in Africa-Transition from capacity development toward job creation.","authors":"Goonaseelan Colin Pillai, Samer Mouksassi, Innocent G Asiimwe, Craig R Rayner, Steven Kern, Phumla Sinxadi, Paolo Denti, Eric Decloedt, Catriona Waitt, Bernhards R Ogutu, Rik de Greef","doi":"10.1002/psp4.13291","DOIUrl":"https://doi.org/10.1002/psp4.13291","url":null,"abstract":"Trained pharmacometricians remain scarce in Africa due to limited training opportunities, lack of a pharmaceutical product development ecosystem, and emigration to high-income countries. The Applied Pharmacometrics Training (APT) fellowship program was established to address these gaps and specifically foster job creation for talent retention. We review the APT program's progress over 3 years and encourage collaboration to enhance local clinical data analysis in Africa. Initiated in 2021 by Pharmacometrics Africa, a non-profit educational entity, with support from partners including the Bill & Melinda Gates Foundation and Certara, the APT program targets African doctoral-level scientists and clinicians. This 6-month program is jointly managed by partners, with Pharmacometrics Africa handling logistics and sponsor liaison. Job creation initiatives include inviting fellows to join consulting teams or local research centers. Over the 3 year reporting period, 177 applications were received, with 27 individuals (41% female, median age 35 years) from nine African countries selected into and completing the full program. The fellows worked on 13 data analysis projects, with six so far being presented at international conferences and/or submitted for publication in peer-reviewed journals. Nine fellows have joined consulting teams or research centers working from offices in Africa. Currently, in the 3rd year, the APT program has demonstrated success in skills development, job creation, and fostering a critical mass of African pharmacometricians. Collaboration is essential for the sustainable advancement of model-informed drug development in Africa.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794539","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

Implementing a Bayesian approach using Stan with Torsten: Population pharmacokinetics analysis of somatrogon. 与 Torsten 一起使用 Stan 实现贝叶斯方法：索马曲贡的群体药代动力学分析。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-09 DOI: 10.1002/psp4.13279

Yuchen Wang, Xinyi Pei, Tao Niu, Joan Korth-Bradley, Luke Fostvedt

{"title":"Implementing a Bayesian approach using Stan with Torsten: Population pharmacokinetics analysis of somatrogon.","authors":"Yuchen Wang, Xinyi Pei, Tao Niu, Joan Korth-Bradley, Luke Fostvedt","doi":"10.1002/psp4.13279","DOIUrl":"https://doi.org/10.1002/psp4.13279","url":null,"abstract":"Fully Bayesian approaches are not commonly implemented for population pharmacokinetic (PK) modeling. In this paper, we evaluate the use of Stan with R and Torsten for population PK modeling of somatrogon, a recombinant long-acting growth hormone approved for the treatment of growth hormone deficiency. As a software for Bayesian inference, Stan provides an easy way to conduct MCMC sampling for a wide range of models with efficient sampling algorithms, and there are several diagnostic tools to evaluate the MCMC convergence and other potential issues. Three different sets of priors were evaluated for estimation and prediction: a weakly informative uniform set, a moderately informative set, and a very informative set of priors. All three prior sets showed good performance and all chains mixed well. There were some minor differences in the final parameter posterior distributions while implementing different prior sets, but the posterior predictions covered the observations nicely, not only for the individuals included in posterior sampling but also for new individuals. The impact of a centered versus non-centered parameterization were evaluated, with the non-centered approach improving the estimation time, but it was still computationally intensive. Computational resources had the biggest impact on sampling time. Stan took approximately 2.5 h total for the MCMC sampling on a high-performance computing platform (6 cores) and may be reduced further with additional computational resources. The model and comparisons presented show that with adequate computational resources, the Bayesian approaches using Stan and Torsten are useful for population PK analysis, especially for the analysis of special populations, small sample datasets, and when complex model structures are needed.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799693","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 minimal physiologically-based pharmacokinetic modeling platform to predict intratumor exposure and receptor occupancy of an anti-LAG-3 monoclonal antibody.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-09 DOI: 10.1002/psp4.13285

Robin Michelet, Klas Petersson, Marc C Huisman, C Willemien Menke-van der Houven van Oordt, Iris H C Miedema, Andrea Thiele, Ghazal Montaseri, Alejandro Pérez-Pitarch, David Busse

{"title":"A minimal physiologically-based pharmacokinetic modeling platform to predict intratumor exposure and receptor occupancy of an anti-LAG-3 monoclonal antibody.","authors":"Robin Michelet, Klas Petersson, Marc C Huisman, C Willemien Menke-van der Houven van Oordt, Iris H C Miedema, Andrea Thiele, Ghazal Montaseri, Alejandro Pérez-Pitarch, David Busse","doi":"10.1002/psp4.13285","DOIUrl":"https://doi.org/10.1002/psp4.13285","url":null,"abstract":"In oncology drug development, measuring drug concentrations at the tumor site and at the targeted receptor remains an ongoing challenge. Positron emission tomography (PET)-imaging is a promising noninvasive method to quantify intratumor exposure of a radiolabeled drug (biodistribution data) and target saturation by treatment doses in vivo. Here, we present the development and application of a minimal physiologically-based pharmacokinetic (mPBPK) modeling approach to integrate biodistribution data in a quantitative platform to characterize and predict intratumor exposure and receptor occupancy (RO) of BI 754111, an IgG-based anti-lymphocyte-activation gene 3 (LAG-3) monoclonal antibody (mAb). Specifically, calibration and qualification of the predictions were performed using 89Zr-labeled BI 754111 biodistribution data, that is, PET-derived intratumor drug concentration data, tumor-to-plasma ratios, and data from Patlak analyses. The model predictions were refined iteratively by the inclusion of additional biological processes into the model structure and the use of sensitivity analyses to assess the impact of model assumptions and parameter uncertainty on the predictions and model robustness. The developed mPBPK model allowed an adequate description of observed tumor radioactivity concentrations and tumor-to-plasma ratios leading to subsequent adequate prediction of LAG-3 RO at different dose levels. In the future, the developed model could be used as a platform for the prediction and analysis of biodistribution data for other mAbs and may ultimately support dose optimization by identifying dosages resulting in saturated RO.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799691","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

Semi-mechanistic population PK/PD model to aid clinical understanding of myelodysplastic syndromes following treatment with Venetoclax and Azacitidine.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-09 DOI: 10.1002/psp4.13284

Neha Thakre, Corinna Maier, Jiuhong Zha, Benjamin Engelhardt, Johannes E Wolff, Sven Mensing

{"title":"Semi-mechanistic population PK/PD model to aid clinical understanding of myelodysplastic syndromes following treatment with Venetoclax and Azacitidine.","authors":"Neha Thakre, Corinna Maier, Jiuhong Zha, Benjamin Engelhardt, Johannes E Wolff, Sven Mensing","doi":"10.1002/psp4.13284","DOIUrl":"https://doi.org/10.1002/psp4.13284","url":null,"abstract":"Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenias, hypercellular bone marrow, and dysplastic hematopoietic progenitors. MDS remains a challenge to treat due to the complex interplay between disease-induced and treatment-related cytopenias. Venetoclax, a selective BCL-2 inhibitor, in combination with azacitidine, a hypomethylating agent, is currently being investigated in patients with previously untreated higher-risk MDS. We present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed using preliminary clinical data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naïve patients with higher-risk MDS. Longitudinal data from 57 patients were used to develop the model, which accounted for venetoclax PK and azacitidine treatment to describe time dynamics of bone marrow blasts, neutrophils, red blood cells, and platelets. The proliferation and maturation of progenitor cells in the bone marrow to peripheral cells is described via three parallel connected transit models including feedback terms. The model also accounted for bone marrow crowding and its impact on hematopoiesis. Model validation demonstrated adequate goodness-of-fit, visual and numerical predictive checks. Model predicted complete remission (CR) rates and marrow complete remission (mCR) rates closely matched observed rates in the clinical study, and simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints aligned with expected outcomes from various dosing regimens. Importantly, the semi-mechanistic model may aid understanding and discriminating between disease-driven and drug-induced cytopenias.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799671","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

Accelerating virtual patient generation with a Bayesian optimization and machine learning surrogate model.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-04 DOI: 10.1002/psp4.13288

Hiroaki Iwata, Ryuta Saito

{"title":"Accelerating virtual patient generation with a Bayesian optimization and machine learning surrogate model.","authors":"Hiroaki Iwata, Ryuta Saito","doi":"10.1002/psp4.13288","DOIUrl":"https://doi.org/10.1002/psp4.13288","url":null,"abstract":"The pharmaceutical industry has increasingly adopted model-informed drug discovery and development (MID3) to enhance productivity in drug discovery and development. Quantitative systems pharmacology (QSP), which integrates drug action mechanisms and disease complexities to predict clinical endpoints and biomarkers is central to MID3. QSP modeling has proven successful in metabolic and cardiovascular diseases and has expanded into oncology, immunotherapy, and infectious diseases. Despite its benefits, QSP model validation through clinical trial simulations using virtual patients (VPs) is challenging because of parameter variability and high computational costs. To address these challenges, this study proposes a hybrid method that combines Bayesian optimization with machine learning for efficient parameter screening. Our approach achieved an acceptance rate of 27.5% in QSP simulations, which is in sharp contrast with the 2.5% rate of conventional random search methods, indicating more than 10-fold improvement in efficiency. By facilitating faster and more diverse VPs generation, this method promises to advance clinical trial simulations and accelerate drug development in pharmaceutical research.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779569","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