gPKPDviz: A flexible R shiny tool for pharmacokinetic/pharmacodynamic simulations using mrgsolve
AbstractGPKPDviz is a Shiny application (app) dedicated to real-time simulation, visualization, and assessment of the pharmacokinetic/pharmacodynamic (PK/PD) models. Within the app, gPKPDviz is capable of generating virtual populations and complex dosing and sampling scenarios, which, together with the streamlined workflow, is designed to efficiently assess the impact of covariates and dosing regimens on PK/PD end points. The actual population data from clinical trials can be loaded into the app for simulation if desired. The app-generated dosing regimens include single or multiple dosing, and more complex regimens, such a...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 27, 2023 Category: Drugs & Pharmacology Authors: Tong Lu, Victor Poon, Logan Brooks, Erick Velasquez, Eric Anderson, Kyle Baron, Jin Y. Jin, Matts K ågedal Tags: TUTORIAL Source Type: research

Use of physiologically ‐based pharmacokinetic modeling to understand the effect of omeprazole administration on the pharmacokinetics of oral extended‐release nifedipine
This study used physiologically-based pharmacokinetic (PBPK ) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to charac terize the potential impact of pH. The PBPK models incorporated two-stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nife...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 22, 2023 Category: Drugs & Pharmacology Authors: Ming ‐Liang Tan, Zongming Gao, Andrew Babiskin, Myong‐Jin Kim, Lanyan Fang, Lei Zhang, Liang Zhao Tags: ARTICLE Source Type: research

Physiologically Based Pharmacokinetic Modelling of Prominent Oral Contraceptive Agents and Applications in Drug ‐Drug Interactions
AbstractConsiderable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin-only pill (PoP). Acceptance of COC drug-drug interaction (DDI) assessment using PBPK is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE) DDI potential with COCs. Guidance rec...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 22, 2023 Category: Drugs & Pharmacology Authors: Gareth J. Lewis, Deepak Ahire, Kunal S. Taskar Tags: ARTICLE Source Type: research

Tumor growth inhibition ‐overall survival modeling in non‐small cell lung cancer: A case study from GEMSTONE‐302
This study aimed to identify an appropriate TGI-OS model for patients with non-small cell lung cancer from the GEMSTONE-302 study of sugemalimab. We used three TGI models to delineate tumor trajectories and investigated three OS model for linking TGI metric to OS. All three TGI models accurately captured tumor profiles at the individual level. The published atezolizumab-based TGI-OS model predicted survival time satisfactorily through simulation-based evaluation, whereas the other published model built from multi-treatment underestimated OS. Our study-specific TGI-OS model identified time-to-growth as the most significant ...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 21, 2023 Category: Drugs & Pharmacology Authors: Yucheng Sheng, Shu ‐wen Teng, Jingru Wang, Hao Wang, Archie N. Tse Tags: ARTICLE Source Type: research

Nivolumab and ipilimumab population pharmacokinetics in support of pediatric dose recommendations —going beyond the body‐size effect
This study approach may be applicable to the optimization of pediatric dosing o f other mAbs and possibly other biologics. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - December 20, 2023 Category: Drugs & Pharmacology Authors: Zheyi Hu, Sihang Liu, Yue Zhao, Shengnan Du, Lora Hamuro, Jun Shen, Amit Roy, Li Zhu Tags: ARTICLE Source Type: research

Tumor Growth Inhibition ‐Overall Survival Modeling in Non‐Small Cell Lung Cancer: A Case Study from GEMSTONE‐302
This study aimed to identify an appropriate TGI-OS model for non-small cell lung cancer (NSCLC) patients from the GEMSTONE-302 study of sugemalimab. We employed three TGI models to delineate tumor trajectories and investigated three OS model for linking TGI metric to overall survival. All three TGI models accurately captured tumor profiles at individual level. The published atezolizumab-based TGI-OS model predicted survival time satisfactorily through simulation-based evaluation, whereas the other published model built from multi-treatment underestimated overall survival. Our study-specific TGI-OS model identified time-to-...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 19, 2023 Category: Drugs & Pharmacology Authors: Yucheng Sheng, Shu ‐wen Teng, Jingru Wang, Hao Wang, Archie N. Tse Tags: ARTICLE Source Type: research

Development and application of neonatal physiology ‐based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment
AbstractAntimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multi-centre neonatal sepsis trial. Although neonatal pharmacokinetics have been described for these drugs, the physiological variability within neonatal populations makes population pharmacokinetics in this group uncertain. Physiology-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, paediatric and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Si...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 18, 2023 Category: Drugs & Pharmacology Authors: Christopher A. Darlow, Neil Parrott, Richard W. Peck, William Hope Tags: ARTICLE Source Type: research

Issue Information
(Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - December 16, 2023 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

Power to identify exposure ‐response relationships in phase IIa pulmonary tuberculosis trials with multi‐dimensional bacterial load modeling
In conclusion, the power to identify an exposure-response relationship is low for TB drugs with moderate bactericidal activity or with a slow onset of activity. TTP provides the PK-PD model with more power to identify exposure-response relationships compared to CFU, and combined analysis or an unbalanced dosing group study design offers modest further improvement. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - December 16, 2023 Category: Drugs & Pharmacology Authors: Simon E. Koele, Thomas P. C. Dorlo, Caryn M. Upton, Rob E. Aarnoutse, Elin M. Svensson Tags: ARTICLE Source Type: research

Tumor growth inhibition modeling in patients with second line biliary tract cancer and first line non ‐small cell lung cancer based on bintrafusp alfa trials
AbstractThis analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability in tumor dynamics by pharmacometric and machine-learning (ML) approaches. Data originated from two clinical trials in patients with biliary tract cancer (BTC; NCT03833661) receiving BA and non-small cell lung cancer (NSCLC; NCT03631706) receiving BA or pembrolizumab. Individual drug exposure was estimated from previously developed population PK models. Population tum...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 13, 2023 Category: Drugs & Pharmacology Authors: Ana ‐Marija Milenković‐Grišić, Nadia Terranova, Diane R. Mould, Yulia Vugmeyster, Thomas Mrowiec, Andreas Machl, Pascal Girard, Karthik Venkatakrishnan, Akash Khandelwal Tags: ARTICLE Source Type: research

Supplementing clinical lactation studies with PBPK modeling to inform drug therapy in lactating mothers: Prediction of primaquine exposure as a case example
AbstractEvaluating the safety of primaquine (PQ) during breastfeeding requires an understanding of its pharmacokinetics (PKs) in breast milk and its exposure in the breastfed infant. Physiologically-based PK (PBPK) modeling is primed to assess the complex interplay of factors affecting the exposure of PQ in both the mother and the nursing infant. A published PBPK model for PQ describing the metabolism by monoamine oxidase A (MAO-A; 90% contribution) and cytochrome P450 2D6 (CYP2D6; 10%) in adults was applied to predict the exposure of PQ in mothers and their breastfeeding infants. Plasma exposures following oral daily dosi...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 12, 2023 Category: Drugs & Pharmacology Authors: Xian Pan, Khaled Abduljalil, Lisa M. Almond, Amita Pansari, Karen Rowland Yeo Tags: ARTICLE Source Type: research

gPKPDviz: A flexible R Shiny tool for pharmacokinetic/pharmacodynamic simulations using mrgsolve
AbstractgPKPDviz is a Shiny application (app) dedicated to real-time simulation, visualization, and assessment of the pharmacokinetic/pharmacodynamic (PK/PD) models. Within the app, gPKPDviz is capable of generating virtual populations and complex dosing and sampling scenarios, which, together with the streamlined workflow, is designed to efficiently assess the impact of covariates and dosing regimens on PK/PD endpoints. The actual population data from clinical trials can be loaded into the app for simulation if desired. The app-generated dosing regimens include single or multiple dosing, and more complex regimens such as ...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 12, 2023 Category: Drugs & Pharmacology Authors: Tong Lu, Victor Poon, Logan Brooks, Erick Velasquez, Eric Anderson, Kyle Baron, Jin Y. Jin, Matts Kagedal Tags: TUTORIAL Source Type: research

Microglial Roles in Alzheimer's Disease: An Agent ‐Based Model to Elucidate Microglial Spatiotemporal Response to Beta‐Amyloid
AbstractAlzheimer's Disease (AD) is characterized by beta-amyloid (A β) plaques in the brain and widespread neuronal damage. Due to high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia are innate phagocytotic immune cells which transition into a neuroprotective sta te and form barriers around plaques. We seek to understand the role of microglia in modifying Aβ dynamics and barrier formation. To quantify the influence of individual microglia behaviors (activation, chemotaxis, phagocytosis, and proliferation) on plaque si...
Source: CPT: Pharmacometrics and Systems Pharmacology - December 11, 2023 Category: Drugs & Pharmacology Authors: Catherine Weathered, Sophia Bardehle, Choya Yoon, Niyanta Kumar, Cheryl E. G. Leyns, Matthew E. Kennedy, Peter Bloomingdale, Elsje Pienaar Tags: ARTICLE Source Type: research