Phase II Dose Selection for Alpha Synuclein –Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain
AbstractThis modeling and simulation analysis was aimed at selecting doses of cinpanemab (BIIB054), a monoclonal antibody targeting aggregated α‐synuclein, for a phase II study in Parkinson’s disease (PD). Doses and regimens were proposed based on anticipated target concentration in brain interstitial fluid (ISF);in vitro/in vivo data on the affinity of monoclonal antibodies to the target protein; and safety, tolerability, and pharmacokinetic data (1 –135 mg/kg intravenous administration) from a phase I single ascending dose (SAD) study. A population pharmacokinetic modeling approach was used to select ...
Source: CPT: Pharmacometrics and Systems Pharmacology - July 2, 2020 Category: Drugs & Pharmacology Authors: Mita Kuchimanchi, Michael Monine, Kumar Kandadi Muralidharan, Caroline Woodward, Natasha Penner Tags: ARTICLE Source Type: research

QSP ‐IO: A quantitative systems pharmacology toolbox for mechanistic multi‐scale modeling for immuno‐oncology applications
AbstractImmunotherapy has shown great potential in the treatment of cancer, however, only a fraction of patients respond to treatment and many experience autoimmune ‐related side effects. The pharmaceutical industry has relied on mathematical models to study the behavior of candidate drugs and more recently, complex, whole‐body, quantitative systems pharmacology (QSP) models have become increasingly popular for discovery and development. QSP modeling has th e potential to discover novel predictive biomarkers, as well as test the efficacy of treatment plans and combination therapies through virtual clinical trails. In t...
Source: CPT: Pharmacometrics and Systems Pharmacology - July 2, 2020 Category: Drugs & Pharmacology Authors: Richard J. Sov é, Mohammad Jafarnejad, Chen Zhao, Hanwen Wang, Huilin Ma, Aleksander S. Popel Tags: TUTORIAL Source Type: research

Phase II Dose Selection for Alpha Synuclein –Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain
AbstractThis modeling and simulation analysis was aimed at selecting doses of cinpanemab (BIIB054), a monoclonal antibody targeting aggregated α‐synuclein, for a phase II study in Parkinson’s disease (PD). Doses and regimens were proposed based on anticipated target concentration in brain interstitial fluid (ISF);in vitro/in vivo data on the affinity of monoclonal antibodies to the target protein; and safety, tolerability, and pharmacokinetic data (1 –135 mg/kg intravenous administration) from a phase I single ascending dose (SAD) study. A population pharmacokinetic modeling approach was used to select ...
Source: CPT: Pharmacometrics and Systems Pharmacology - July 2, 2020 Category: Drugs & Pharmacology Authors: Mita Kuchimanchi, Michael Monine, Kumar Kandadi Muralidharan, Caroline Woodward, Natasha Penner Tags: ARTICLE Source Type: research

Population Pharmacokinetics and Exposure –Response of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With Myelodysplastic Syndromes
This report describes the population pharmacokinetics and exposure–response relationship of luspatercept in 260 patients with anemia due to myelodysplastic syndromes. Luspatercept displayed linear and time‐invariant pharmacokinetics over a dose range of 0.125–1.7 5 mg/kg administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept exposure, supporting the weight‐based dosing. The probability of achieving transfusion independence ≥ 8 weeks increased with time‐averaged luspatercept serum expos ure, reaching the plateau at doses...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 30, 2020 Category: Drugs & Pharmacology Authors: Nianhang Chen, Nastya Kassir, Abderrahmane Laadem, Stephen E. Maxwell, Priya Sriraman, Ana Carolina Giuseppi, Steve Ritland, Peter G. Linde, Balasubrahmanyam Budda, Joseph G. Reynolds, Simon Zhou, Maria Palmisano Tags: Article Source Type: research

Tumor Growth Dynamic Modeling in Oncology Drug Development and Regulatory Approval: Past, Present, and Future Opportunities
AbstractModel ‐informed drug development (MIDD) approaches have rapidly advanced in drug development in recent years. Additionally, the Prescription Drug User Fee Act (PDUFA) VI has specific commitments to further enhance MIDD. Tumor growth dynamic (TGD) modeling, as one of the commonly utilized MIDD approaches in oncology, fulfills the purposes to accelerate the drug development, to support new drug and biologics license applications, and to guide the market access. Increasing knowledge of TGD modeling methodologies, encouraging applications in clinical setting for patients’ survival, and complementing assessment ...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 26, 2020 Category: Drugs & Pharmacology Authors: Nidal Al ‐Huniti, Yan Feng, Jingyu Jerry Yu, Zheng Lu, Mario Nagase, Diansong Zhou, Jennifer Sheng Tags: REVIEW Source Type: research

Issue Information
CPT: Pharmacometrics& Systems Pharmacology, Volume 9, Issue 6, Page 303-306, June 2020. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - June 21, 2020 Category: Drugs & Pharmacology Tags: Issue Information Source Type: research

Data Digitizing: Accurate and Precise Data Extraction for Quantitative Systems Pharmacology and Physiologically ‐Based Pharmacokinetic Modeling
In quantitative systems pharmacology (QSP) and physiologically ‐based pharmacokinetic (PBPK) modeling, data digitizing is a valuable tool to extract numerical information from published data presented as graphs. To quantify their relevance, a literature search revealed a remarkable mean increase of 16% per year in publications citing digitizing software toget her with QSP or PBPK. Accuracy, precision, confounder influence, and variability were investigated using scaled median symmetric accuracy (ζ), thus finding excellent accuracy (mean ζ = 0.99%). Although significant, no relevant confounders were fo...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 21, 2020 Category: Drugs & Pharmacology Authors: Jan ‐Georg Wojtyniak, Hannah Britz, Dominik Selzer, Matthias Schwab, Thorsten Lehr Tags: Article Source Type: research

A Physiologically ‐Based Quantitative Systems Pharmacology Model of the Incretin Hormones GLP‐1 and GIP and the DPP4 Inhibitor Sitagliptin
Incretin hormones glucagon ‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) play a major role in regulation of postprandial glucose and the development of type 2 diabetes mellitus. The incretins are rapidly metabolized, primarily by the enzyme dipeptidyl‐peptidase 4 (DPP4), and the neut ral endopeptidase (NEP), although the exact metabolization pathways are unknown. We developed a physiologically‐based (PB) quantitative systems pharmacology model of GLP‐1 and GIP and their metabolites that describes the secretion of the incretins in response to intraduodenal glucose infusions a n...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 21, 2020 Category: Drugs & Pharmacology Authors: Pavel Balazki, Stephan Schaller, Thomas Eissing, Thorsten Lehr Tags: Article Source Type: research

Issue Information
CPT: Pharmacometrics& Systems Pharmacology, Volume 9, Issue 6, Page 303-306, June 2020. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - June 21, 2020 Category: Drugs & Pharmacology Tags: Issue Information Source Type: research

Mini ‐Review: Comprehensive drug disposition knowledge generated in the modern human radiolabelled adme study
AbstractThe human radiolabeled ADME study offers a quantitative and comprehensive overall picture of the disposition of a drug including excretion pattern and metabolite profiles in circulation and excreta. The data gathered from the ADME study are highly informative for developing a cohesive strategy for clinical pharmacology studies. Elements of standard ADME study design are described. An exciting new development in human ADME studies is the application of accelerator mass spectrometry (AMS) as the detection technique for carbon ‐14, in replacement of radioactivity measurements. This technology permits administration ...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 20, 2020 Category: Drugs & Pharmacology Authors: Douglas K. Spracklin, Danny Chen, Arthur J. Bergman, Ernesto Callegari, R. Scott Obach Tags: REVIEW ARTICLE Source Type: research

A Quantitative Systems Pharmacology Model of Gaucher Disease Type 1 Provides Mechanistic Insight Into the Response to Substrate Reduction Therapy With Eliglustat
In this study, we have developed a quantitative systems pharmacology (QSP) model, which recapitulates the effects of eliglustat, the only first‐line SRT approved for GD1, on treatment‐naïve or patients with ERT‐stabilized adult GD1. This multiscale model represents the mechanism of action of eliglustat that leads toward reduction of spleen volume. Model capabilities were illustrated through the application of the model to predict ERT and eliglustat responses in virtual populations of adult patients with GD1, representing patients across a spectrum of disease severity as defined by geno type‐phenotype relations...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 19, 2020 Category: Drugs & Pharmacology Authors: Ruth Abrams, Chanchala D. Kaddi, Mengdi Tao, Randolph J. Leiser, Giulia Simoni, Federico Reali, John Tolsma, Paul Jasper, Zachary Rijn, Jing Li, Bradley Niesner, Jeffrey S. Barrett, Luca Marchetti, M. Judith Peterschmitt, Karim Azer, Susana Tags: Article Source Type: research

Timing of antiviral treatment initiation is critical to reduce SARS ‐CoV‐2 viral load
AbstractWe modeled the viral dynamics of 13 untreated patients infected with SARS ‐CoV‐2 to infer viral growth parameters and predict the effects of antiviral treatments. In order to reduce peak viral load by more than 2 logs, drug efficacy needs to be greater than 90% if treatment is administered after symptom onset; an efficacy of 60% could be sufficient if treatment is ini tiated before symptom onset. Given their pharmacokinetic/pharmacodynamic properties, current investigated drugs may be in a range of 6‐87% efficacy. They may help control virus if administered very early, but may not have a major effect in sever...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 18, 2020 Category: Drugs & Pharmacology Authors: Antonio Gon çalves, Julie Bertrand, Ruian Ke, Emmanuelle Comets, Xavier de Lamballerie, Denis Malvy, Andrés Pizzorno, Olivier Terrier, Manuel Rosa Calatrava, France Mentré, Patrick Smith, Alan S Perelson, Jérémie Guedj Tags: ARTICLE Source Type: research

Data Digitizing: Accurate and Precise Data Extraction for Quantitative Systems Pharmacology and Physiologically ‐Based Pharmacokinetic Modeling
In quantitative systems pharmacology (QSP) and physiologically ‐based pharmacokinetic (PBPK) modeling, data digitizing is a valuable tool to extract numerical information from published data presented as graphs. To quantify their relevance, a literature search revealed a remarkable mean increase of 16% per year in publications citing digitizing software toget her with QSP or PBPK. Accuracy, precision, confounder influence, and variability were investigated using scaled median symmetric accuracy (ζ), thus finding excellent accuracy (mean ζ = 0.99%). Although significant, no relevant confounders were fo...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 16, 2020 Category: Drugs & Pharmacology Authors: Jan ‐Georg Wojtyniak, Hannah Britz, Dominik Selzer, Matthias Schwab, Thorsten Lehr Tags: Article Source Type: research

A Physiologically ‐Based Quantitative Systems Pharmacology Model of the Incretin Hormones GLP‐1 and GIP and the DPP4 Inhibitor Sitagliptin
Incretin hormones glucagon ‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) play a major role in regulation of postprandial glucose and the development of type 2 diabetes mellitus. The incretins are rapidly metabolized, primarily by the enzyme dipeptidyl‐peptidase 4 (DPP4), and the neut ral endopeptidase (NEP), although the exact metabolization pathways are unknown. We developed a physiologically‐based (PB) quantitative systems pharmacology model of GLP‐1 and GIP and their metabolites that describes the secretion of the incretins in response to intraduodenal glucose infusions a n...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 16, 2020 Category: Drugs & Pharmacology Authors: Pavel Balazki, Stephan Schaller, Thomas Eissing, Thorsten Lehr Tags: Article Source Type: research

Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin with Different Dosing Regimens used in COVID ‐19 Clinical Trials
AbstractAzithromycin, a broad ‐spectrum macrolide antibiotic, is being investigated in patients with COVID‐19. A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (PBM/PML), and alveolar macrophage (AM) concentrations using published data and compared against preclinical EC 90 for SARS‐CoV‐2. The final model described the data reported in 8 publications adequately. Consistent with its known properties, concentrations were higher in AM and PBM/PML, followed by lung tissue, and lowest systemically. Simulated PBM/PML concentrations exceeded EC90 following the first d...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 8, 2020 Category: Drugs & Pharmacology Authors: Jim H. Hughes, Kevin Sweeney, Sima Ahadieh, Daniele Ouellet Tags: ARTICLE Source Type: research

Response Letter to the Editor: “Assumption Checking Before Application of the Prespecified QT Linear Mixed Effect Model is Essential”
CPT: Pharmacometrics& Systems Pharmacology, EarlyView. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - June 8, 2020 Category: Drugs & Pharmacology Authors: Yeamin Huh, Steve Riley, Timothy Nicholas Tags: Response Letter to the Editor Source Type: research

Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin with Different Dosing Regimens used in COVID ‐19 Clinical Trials
AbstractAzithromycin, a broad ‐spectrum macrolide antibiotic, is being investigated in patients with COVID‐19. A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (PBM/PML), and alveolar macrophage (AM) concentrations using published data and compared against preclinical EC 90 for SARS‐CoV‐2. The final model described the data reported in 8 publications adequately. Consistent with its known properties, concentrations were higher in AM and PBM/PML, followed by lung tissue, and lowest systemically. Simulated PBM/PML concentrations exceeded EC90 following the first d...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 8, 2020 Category: Drugs & Pharmacology Authors: Jim H. Hughes, Kevin Sweeney, Sima Ahadieh, Daniele Ouellet Tags: ARTICLE Source Type: research

Response Letter to the Editor: “Assumption Checking Before Application of the Prespecified QT Linear Mixed Effect Model is Essential”
CPT: Pharmacometrics& Systems Pharmacology, EarlyView. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - June 8, 2020 Category: Drugs & Pharmacology Authors: Yeamin Huh, Steve Riley, Timothy Nicholas Tags: Response Letter to the Editor Source Type: research

Estimation of equipotent doses for anti ‐inflammatory effects of prednisolone and AZD9567, an oral selective non‐steroidal glucocorticoid receptor modulator
AbstractAZD9567 is a potent and selective non ‐steroidal oral glucocorticoid receptor modulator. It is developed as an anti‐inflammatory drug with improved safety profile compared to steroids like prednisolone. Throughout the clinical development of AZD9567, dose selection and data interpretation require a method for determining doses with the same anti‐inflammatory effect as prednisolone. Equipotent doses of AZD9567 and prednisolone were defined by the same average inhibition of TNFα release, a biomarker of anti‐inflammatory effect, measured in a lipopolysaccharide‐stimulated whole blood ex vivo assay. Bas...
Source: CPT: Pharmacometrics and Systems Pharmacology - June 5, 2020 Category: Drugs & Pharmacology Authors: Joachim Almquist, Muhammad Waqas Sadiq, Ulf G Eriksson, Tove Hegelund Myrb äck, Susanne Prothon, Jacob Leander Tags: ARTICLE Source Type: research

Physiologically ‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions
Fenebrutinib is a CYP3A substrate and time ‐dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitorin vitro. Physiologically ‐based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug‐drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measur ement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B. A mechanistic‐absorption model accounting...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 29, 2020 Category: Drugs & Pharmacology Authors: Yuan Chen, Fang Ma, Nicholas S. Jones, Kenta Yoshida, Po ‐Chang Chiang, Matthew R. Durk, Matthew R. Wright, Jin Yan Jin, Leslie W. Chinn Tags: Article Source Type: research

Salvaging CNS Clinical Trials halted due to COVID ‐19
ABSTRACTThe COVID ‐19 pandemic has halted many ongoing CNS clinical trials, especially in Alzheimer’s disease. These long‐duration trials involve many stakeholders, especially the patients and their family members, who have demonstrated their commitment to developing new therapeutic interventions for this devas tating disease. We certainly do not want to lose all the knowledge we have gained from these ongoing trials because of the pandemic.While some of these trials will need to restart, others can re ‐start at different points along the trial protocol with substantial protocol amendments. However, there is an...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 28, 2020 Category: Drugs & Pharmacology Authors: Hugo Geerts, Piet H. van der Graaf Tags: PERSPECTIVE Source Type: research

Importance of stability analysis when using non ‐linear semi‐mechanistic models to describe drug‐induced haematotoxicity
ABSTRACTStability analysis, often overlooked in pharmacometrics, is essential to explore dynamical systems. The model developed by Friberg1 to describe drug ‐induced haematotoxicity is widely used to support decisions across drug development, and parameter values are often identified from observed blood counts. We use stability analysis to study the parametric dependence of stable and unstable solutions of several Friberg‐type models, and highlight the risks associated with system instability in the context of non‐linear mixed effects modelling. We emphasize the consequences of unstable solutions on prediction perfor...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 26, 2020 Category: Drugs & Pharmacology Authors: Chiara Fornari, Carmen Pin, James W.T. Yates, Jerome T. Mettetal, Teresa A. Collins Tags: ARTICLE Source Type: research

Population Pharmacodynamic Model of Neutrophil Margination and Tolerance to Describe Effect of Sarilumab on Absolute Neutrophil Count in Patients with Rheumatoid Arthritis
AbstractEvidence suggests that effects of interleukin ‐6 pathway inhibitors sarilumab, tocilizumab, and sirukumab on absolute neutrophil count (ANC) are due to margination of circulating neutrophils into rapidly mobilizable non‐circulating pools. We developed a population pharmacodynamic model using compartments for neutrophil margination and ANC‐ specific tolerance to describe rapid, transient ANC changes in blood following administration of subcutaneous sarilumab and intravenous/subcutaneous tocilizumab based on data from 322 patients with rheumatoid arthritis in two single‐dose (NCT02097524, NCT02404558) and one...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 26, 2020 Category: Drugs & Pharmacology Authors: Pavel Kovalenko, Anne Paccaly, Anita Boyapati, Christine Xu, Gregory St John, Michael C. Nivens, John D. Davis, Ronda Rippley, A. Thomas DiCioccio Tags: ARTICLE Source Type: research

Importance of stability analysis when using non ‐linear semi‐mechanistic models to describe drug‐induced haematotoxicity
ABSTRACTStability analysis, often overlooked in pharmacometrics, is essential to explore dynamical systems. The model developed by Friberg1 to describe drug ‐induced haematotoxicity is widely used to support decisions across drug development, and parameter values are often identified from observed blood counts. We use stability analysis to study the parametric dependence of stable and unstable solutions of several Friberg‐type models, and highlight the risks associated with system instability in the context of non‐linear mixed effects modelling. We emphasize the consequences of unstable solutions on prediction perfor...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 26, 2020 Category: Drugs & Pharmacology Authors: Chiara Fornari, Carmen Pin, James W.T. Yates, Jerome T. Mettetal, Teresa A. Collins Tags: ARTICLE Source Type: research

Population Pharmacodynamic Model of Neutrophil Margination and Tolerance to Describe Effect of Sarilumab on Absolute Neutrophil Count in Patients with Rheumatoid Arthritis
AbstractEvidence suggests that effects of interleukin ‐6 pathway inhibitors sarilumab, tocilizumab, and sirukumab on absolute neutrophil count (ANC) are due to margination of circulating neutrophils into rapidly mobilizable non‐circulating pools. We developed a population pharmacodynamic model using compartments for neutrophil margination and ANC‐ specific tolerance to describe rapid, transient ANC changes in blood following administration of subcutaneous sarilumab and intravenous/subcutaneous tocilizumab based on data from 322 patients with rheumatoid arthritis in two single‐dose (NCT02097524, NCT02404558) and one...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 26, 2020 Category: Drugs & Pharmacology Authors: Pavel Kovalenko, Anne Paccaly, Anita Boyapati, Christine Xu, Gregory St John, Michael C. Nivens, John D. Davis, Ronda Rippley, A. Thomas DiCioccio Tags: ARTICLE Source Type: research

A Novel Physiologically  Based Model of Creatinine Renal Disposition to Integrate Current Knowledge of Systems Parameters and Clinical Observations
Creatinine is the most common clinical biomarker of renal function. As a substrate for renal transporters, its secretion is susceptible to inhibition by drugs, resulting in transient increase in serum creatinine and false impression of damage to kidney. Novel physiologically  based models for creatinine were developed here and (dis)qualified in a stepwise manner until consistency with clinical data. Data from a matrix of studies were integrated, including systems data (common to all models), proteomics‐informedin vitro–in vivo extrapolation of all relevant transporter clearances, exogenous administration of cr...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 22, 2020 Category: Drugs & Pharmacology Authors: Daniel Scotcher, Vikram Arya, Xinning Yang, Ping Zhao, Lei Zhang, Shiew ‐Mei Huang, Amin Rostami‐Hodjegan, Aleksandra Galetin Tags: Article Source Type: research

Individualized Absorption Models in Population Pharmacokinetic Analyses
CPT: Pharmacometrics& Systems Pharmacology, EarlyView. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - May 21, 2020 Category: Drugs & Pharmacology Authors: Mutaz M. Jaber, Mahmoud Al ‐Kofahi, Kyriakie Sarafoglou, Richard C. Brundage Tags: Perspective Source Type: research

Model ‐based analysis reveals a sustained and dose‐dependent acceleration of wound healing by VEGF‐A mRNA (AZD8601)
AbstractIntradermal delivery of AZD8601, an mRNA designed to produce vascular endothelial growth factor A (VEGF ‐A), has previously been shown to accelerate cutaneous wound healing in a murine diabetic model. Here, we develop population pharmacokinetic and pharmacodynamic models aiming to quantify the effect of AZD8601 injections on the dynamics of wound healing. A dataset of 584 open wound area measurement s from 131 mice was integrated from three independent studies encompassing different doses, dosing timepoints, and number of doses. Evaluation of several candidate models showed that wound healing acceleration is not ...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 21, 2020 Category: Drugs & Pharmacology Authors: Joachim Almquist, Michaela Rikard, Maria W ågberg, Anthony C. Bruce, Peter Gennemark, Regina Fritsche‐Danielson, Kenneth R. Chien, Shayn M. Peirce, Kenny Hansson, Anna Lundahl Tags: ARTICLE Source Type: research

Individualized Absorption Models in Population Pharmacokinetic Analyses
CPT: Pharmacometrics& Systems Pharmacology, EarlyView. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - May 21, 2020 Category: Drugs & Pharmacology Authors: Mutaz M. Jaber, Mahmoud Al ‐Kofahi, Kyriakie Sarafoglou, Richard C. Brundage Tags: Perspective Source Type: research

Model ‐based analysis reveals a sustained and dose‐dependent acceleration of wound healing by VEGF‐A mRNA (AZD8601)
AbstractIntradermal delivery of AZD8601, an mRNA designed to produce vascular endothelial growth factor A (VEGF ‐A), has previously been shown to accelerate cutaneous wound healing in a murine diabetic model. Here, we develop population pharmacokinetic and pharmacodynamic models aiming to quantify the effect of AZD8601 injections on the dynamics of wound healing. A dataset of 584 open wound area measurement s from 131 mice was integrated from three independent studies encompassing different doses, dosing timepoints, and number of doses. Evaluation of several candidate models showed that wound healing acceleration is not ...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 21, 2020 Category: Drugs & Pharmacology Authors: Joachim Almquist, Michaela Rikard, Maria W ågberg, Anthony C. Bruce, Peter Gennemark, Regina Fritsche‐Danielson, Kenneth R. Chien, Shayn M. Peirce, Kenny Hansson, Anna Lundahl Tags: ARTICLE Source Type: research

Issue Information
CPT: Pharmacometrics& Systems Pharmacology, Volume 9, Issue 5, Page 241-244, May 2020. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - May 20, 2020 Category: Drugs & Pharmacology Tags: Issue Information Source Type: research

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine ‐Drug Interactions
Creatinine is widely used as a biomarker of glomerular filtration, and, hence, renal function. However, transporter ‐mediated secretion also contributes to its renal clearance, albeit to a lesser degree. Inhibition of these transporters causes transient serum creatinine elevation, which can be mistaken as impaired renal function. The current study developed mechanistic models of creatinine kinetics within physi ologically based framework accounting for multiple transporters involved in creatinine renal elimination, assuming either unidirectional or bidirectional‐OCT2 transport (driven by electrochemical gradient). Robu...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 20, 2020 Category: Drugs & Pharmacology Authors: Daniel Scotcher, Vikram Arya, Xinning Yang, Ping Zhao, Lei Zhang, Shiew ‐Mei Huang, Amin Rostami‐Hodjegan, Aleksandra Galetin Tags: Article Source Type: research

Variability in the Log Domain and Limitations to Its Approximation by the Normal Distribution
Pharmacometric models using lognormal distributions have become commonplace in pharmacokinetic –pharmacodynamic investigations. The extent to which it can be interpreted by traditional description of variability through the normal distribution remains elusive. In this tutorial, the comparison is made using formal approximation methods. The quality of the resulting approximation was assessed by the similarity of prediction intervals (PIs) to true values, illustrated using 80% PIs. Approximated PIs were close to true values when lognormal standard deviation (omega) was smaller than about 0.25, depending mostly on the d...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 20, 2020 Category: Drugs & Pharmacology Authors: Jeroen Elassaiss ‐Schaap, Kevin Duisters Tags: Tutorial Source Type: research

Genetic Algorithms as a Tool for Dosing Guideline Optimization: Application to Intermittent Infusion Dosing for Vancomycin in Adults
This paper demonstrates the use of a genetic algorithm (GA) for the optimization of a dosing guideline. GAs are well ‐suited to derive combinations of doses and dosing intervals that go into a dosing guideline when the number of possible combinations rule out the calculation of all possible outcomes. GAs also allow for different constraints to be imposed on the optimization process to safeguard the clinical feas ibility of the dosing guideline. In this work, we demonstrate the use of a GA for the optimization of intermittent vancomycin administration in adult patients. Constraints were placed on the dose strengths, the l...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 20, 2020 Category: Drugs & Pharmacology Authors: Pieter J. Colin, Douglas J. Eleveld, Alison H. Thomson Tags: Article Source Type: research

Issue Information
CPT: Pharmacometrics& Systems Pharmacology, Volume 9, Issue 5, Page 241-244, May 2020. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - May 20, 2020 Category: Drugs & Pharmacology Tags: Issue Information Source Type: research

Genetic Algorithms as a Tool for Dosing Guideline Optimization: Application to Intermittent Infusion Dosing for Vancomycin in Adults
This paper demonstrates the use of a genetic algorithm (GA) for the optimization of a dosing guideline. GAs are well ‐suited to derive combinations of doses and dosing intervals that go into a dosing guideline when the number of possible combinations rule out the calculation of all possible outcomes. GAs also allow for different constraints to be imposed on the optimization process to safeguard the clinical feas ibility of the dosing guideline. In this work, we demonstrate the use of a GA for the optimization of intermittent vancomycin administration in adult patients. Constraints were placed on the dose strengths, the l...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 19, 2020 Category: Drugs & Pharmacology Authors: Pieter J. Colin, Douglas J. Eleveld, Alison H. Thomson Tags: Article Source Type: research

Assumption Checking Before Application of the Prespecified QT Linear Mixed Effect Model is Essential
AbstractIn the paper, titled Evaluation of QT Liability for PF ‐05251749 in the Presence of Potential Circadian Rhythm Modification1, the authors presented results from assessment of QT ‐liability based on (i) clinical data and (ii) simulations using models for a drug that affects QT circadian rhythm. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Dinko Reki ć, Joanna Parkinson, Holly Kimko Tags: LETTER TO THE EDITOR Source Type: research

Leveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy
In conclusion, the study demonstrated an application of mechanism driven approach at early stage of a rare disease drug development to support lead compound optimization, e nable human dose, pharmacokinetics, and efficacy predictions. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - May 17, 2020 Category: Drugs & Pharmacology Authors: Hoa Q. Nguyen, Andrea Iskenderian, David Ehmann, Paul Jasper, Zhiwei Zhang, Haojing Rong, Devin Welty, Rangaraj Narayanan Tags: ARTICLE Source Type: research

Variability in the Log Domain and Limitations to Its Approximation by the Normal Distribution
Pharmacometric models using lognormal distributions have become commonplace in pharmacokinetic –pharmacodynamic investigations. The extent to which it can be interpreted by traditional description of variability through the normal distribution remains elusive. In this tutorial, the comparison is made using formal approximation methods. The quality of the resulting approximation was assessed by the similarity of prediction intervals (PIs) to true values, illustrated using 80% PIs. Approximated PIs were close to true values when lognormal standard deviation (omega) was smaller than about 0.25, depending mostly on the d...
Source: CPT: Pharmacometrics and Systems Pharmacology - May 15, 2020 Category: Drugs & Pharmacology Authors: Jeroen Elassaiss ‐Schaap, Kevin Duisters Tags: Tutorial Source Type: research