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Book ; Online: The Emerging Discipline of Quantitative Systems Pharmacology

Ermakov, Sergey / Leil, Tarek A.

2015

Abstract: In 2011, the National Institutes of Health (NIH), in collaboration with leaders from the pharmaceutical industry and the academic community, published a white paper describing the emerging discipline of Quantitative Systems Pharmacology (QSP), and ... ...

Abstract	In 2011, the National Institutes of Health (NIH), in collaboration with leaders from the pharmaceutical industry and the academic community, published a white paper describing the emerging discipline of Quantitative Systems Pharmacology (QSP), and recommended the establishment of NIH-supported interdisciplinary research and training programs for QSP. QSP is still in its infancy, but has tremendous potential to change the way we approach biomedical research. QSP is really the integration of two disciplines that have been increasingly useful in biomedical research; "Systems Biology" and "Quantitative Pharmacology".- Systems Biology is the field of biomedical research that seeks to understand the relationships between genes and biologically active molecules to develop qualitative models of these systems; and Quantitative Pharmacology is the field of biomedical research that seeks to use computer aided modeling and simulation to increase our understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, and to aid in the design of pre-clinical and clinical experiments. The purpose of QSP modeling is to develop quantitative computer models of biological systems and disease processes, and the effects of drug PK and PD on those systems. QSP models allow testing of numerous potential experiments "in-silico" to eliminate those associated with a low probability of success, avoiding the potential costs of evaluating all of those failed experiments in the real world.- At the same time, QSP models allow us to develop our understanding of the interaction between drugs and biological systems in a more systematic and rigorous manner. As the need to be more cost-efficient in the use of research funding increases, biomedical researchers will be required to gain the maximum insight from each experiment that is conducted. This need is even more acute in the pharmaceutical industry, where there is tremendous competition to develop innovative therapies in a highly regulated environment, combined with very high research and development (R&D) costs for bringing new drugs to market (~$1.3 billion/drug). Analogous modeling & simulation approaches have been successfully integrated into other disciplines to improve the fundamental understanding of the science and to improve the efficiency of R&D (e.g., physics, engineering, economics, etc.).-
Keywords	Science (General) ; Therapeutics. Pharmacology
Size	1 electronic resource (97 p.)
Publisher	Frontiers Media SA
Document type	Book ; Online
Note	English ; Open Access
HBZ-ID	HT020091832
ISBN	9782889196425 ; 2889196429
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Pharmacokinetics, Pharmacodynamics, and Safety of Edoxaban in Pediatric Subjects: A Phase I Single-Dose Study.

Zou, Peng / Zahir, Hamim / Duggal, Anil / Pandya, Grishma / Jin, James / Leil, Tarek A

Clinical pharmacology and therapeutics

2024

Abstract: This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring ... ...

Abstract	This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13), and 12 to < 18 years (N = 15)) receiving tablet or oral suspension of edoxaban at doses expected to be equivalent to 30 or 60 mg once daily (q.d.) in adult subjects with VTE. Sixty-six pediatric subjects were enrolled and completed the study. Edoxaban plasma concentration peaked between 1 and 3 hours and declined rapidly until 4-8 hours. The range of mean total apparent clearance across 5 age cohorts at low and high doses was 0.47 to 1.11 L/h/kg. The ranges of mean volume of central compartment and apparent peripheral volume were 2.31 to 3.59 L/kg and 1.92 to 4.14 L/kg, respectively. Across all age groups, the estimated median exposures were within the 0.5- to 1.5-fold of the median area under the plasma drug concentration-time curve (AUC) in adult subjects receiving corresponding doses (30 mg q.d. for low dose and 60 mg q.d. for high dose). In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time, and anti-Factor Xa activity) showed a linear PK-PD relationship and were in line with previous adult data. The results support further evaluation of the pediatric doses in larger pivotal trials.
Language	English
Publishing date	2024-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.3196
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Article ; Online: Virtual Populations for Quantitative Systems Pharmacology Models.

Cheng, Yougan / Straube, Ronny / Alnaif, Abed E / Huang, Lu / Leil, Tarek A / Schmidt, Brian J

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2486, Page(s) 129–179

Abstract: Quantitative systems pharmacology (QSP) places an emphasis on dynamic systems modeling, incorporating considerations from systems biology modeling and pharmacodynamics. The goal of QSP is often to quantitatively predict the effects of clinical ... ...

Abstract	Quantitative systems pharmacology (QSP) places an emphasis on dynamic systems modeling, incorporating considerations from systems biology modeling and pharmacodynamics. The goal of QSP is often to quantitatively predict the effects of clinical therapeutics, their combinations, and their doses on clinical biomarkers and endpoints. In order to achieve this goal, strategies for incorporating clinical data into model calibration are critical. Virtual population (VPop) approaches facilitate model calibration while faced with challenges encountered in QSP model application, including modeling a breadth of clinical therapies, biomarkers, endpoints, utilizing data of varying structure and source, capturing observed clinical variability, and simulating with models that may require more substantial computational time and resources than often found in pharmacometrics applications. VPops are frequently developed in a process that may involve parameterization of isolated pathway models, integration into a larger QSP model, incorporation of clinical data, calibration, and quantitative validation that the model with the accompanying, calibrated VPop is suitable to address the intended question or help with the intended decision. Here, we introduce previous strategies for developing VPops in the context of a variety of therapeutic and safety areas: metabolic disorders, drug-induced liver injury, autoimmune diseases, and cancer. We introduce methodological considerations, prior work for sensitivity analysis and VPop algorithm design, and potential areas for future advancement. Finally, we give a more detailed application example of a VPop calibration algorithm that illustrates recent progress and many of the methodological considerations. In conclusion, although methodologies have varied, VPop strategies have been successfully applied to give valid clinical insights and predictions with the assistance of carefully defined and designed calibration and validation strategies. While a uniform VPop approach for all potential QSP applications may be challenging given the heterogeneity in use considerations, we anticipate continued innovation will help to drive VPop application for more challenging cases of greater scale while developing new rigorous methodologies and metrics.
MeSH term(s)	Algorithms ; Calibration ; Models, Biological ; Network Pharmacology ; Pharmacology ; Systems Biology/methods
Language	English
Publishing date	2022-04-18
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2265-0_8
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Article: Editorial: The emerging discipline of quantitative systems pharmacology.

Leil, Tarek A / Ermakov, Sergey

Frontiers in pharmacology

2015 Volume 6, Page(s) 129

Language	English
Publishing date	2015-06-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2015.00129
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Article: Quantitative Systems Pharmacology can reduce attrition and improve productivity in pharmaceutical research and development.

Leil, Tarek A / Bertz, Richard

Frontiers in pharmacology

2014 Volume 5, Page(s) 247

Abstract: The empirical hypothesis generation and testing approach to pharmaceutical research and development (R&D), and biomedical research has proven very effective over the last half-century; resulting in tremendous increases productivity and the rates of ... ...

Abstract	The empirical hypothesis generation and testing approach to pharmaceutical research and development (R&D), and biomedical research has proven very effective over the last half-century; resulting in tremendous increases productivity and the rates of approval for new drug applications at the Food and Drug Administration (FDA). However, as discovery of new therapeutic approaches for diseases with unmet medical need becomes more challenging, the productivity and efficiency of the traditional approach to drug discovery and development is diminishing. Innovative approaches are needed, such as those offered by Quantitative Systems Pharmacology (QSP) modeling and simulation. This "systems" approach to modeling and simulation can be used to guide the hypothesis generation and testing process in pharmaceutical R&D, in a manner similar to its adoption in other industries in the past. Embedding QSP into the existing processes within pharmaceutical discovery and development will be required in order to realize the full beneficial impact of this innovative approach.
Language	English
Publishing date	2014-11-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2014.00247
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Article ; Online: Model-Based Meta-Analysis Compares DAS28 Rheumatoid Arthritis Treatment Effects and Suggests an Expedited Trial Design for Early Clinical Development.

Leil, Tarek A / Lu, Yasong / Bouillon-Pichault, Marion / Wong, Robert / Nowak, Miroslawa

Clinical pharmacology and therapeutics

2020 Volume 109, Issue 2, Page(s) 517–527

Abstract: A nonlinear mixed effects modeling approach was used to conduct a model-based meta-analysis (MBMA) of longitudinal, summary-level, baseline-corrected 28-joint Disease Activity Score (ΔDAS28) clinical trial data from seven approved rheumatoid arthritis ( ... ...

Abstract	A nonlinear mixed effects modeling approach was used to conduct a model-based meta-analysis (MBMA) of longitudinal, summary-level, baseline-corrected 28-joint Disease Activity Score (ΔDAS28) clinical trial data from seven approved rheumatoid arthritis (RA) drugs (abatacept, adalimumab, certolizumab, etanercept, rituximab, tocilizumab, and tofacitinib), representing 130 randomized clinical trials in 27,355 patients. All of the drugs except tocilizumab were found to have relatively similar ΔDAS28 time courses and efficacy (baseline-corrected and placebo-corrected) at 24 weeks and beyond of approximately 0.87-1.3 units in the typical RA patient population. Tocilizumab was estimated to have a differentially greater response of 1.99 at 24 weeks, likely due to its disproportionate effect on the acute-phase cytokine interleukin-6. Baseline DAS28, disease duration, percentage of male participants, and the year of conduct of the trial were found to have statistically significant effects on the timing and/or magnitude of ΔDAS28 in the control arms. Clinical trial simulations using the present MBMA indicated that abatacept, certolizumab, etanercept, tocilizumab, and tofacitinib would be expected to have a greater than 70% probability of showing a statistically significant difference vs. control at Week 6 with a sample size of ~ 30 patients per arm. In future RA clinical trials, an interim analysis conducted as early as 6 weeks after treatment initiation, with relatively small sample sizes, should be sufficient to detect the ΔDAS28 treatment effect vs. placebo.
MeSH term(s)	Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/drug therapy ; Clinical Trials as Topic ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Treatment Outcome
Chemical Substances	Antirheumatic Agents
Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.2023
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Article ; Online: Antibodies to Modulate Surface Receptor Systems Are Often Bivalent and Must Compete in a Two-Dimensional Cell Contact Region.

Schmidt, Brian J / Bee, Christine / Han, Minhua / Jing, Yawu / Cheng, Yougan / Tenney, Daniel J / Leil, Tarek A

CPT: pharmacometrics & systems pharmacology

2019 Volume 8, Issue 12, Page(s) 873–877

MeSH term(s)	Antibodies/chemistry ; Antibodies/pharmacology ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Models, Theoretical
Chemical Substances	Antibodies ; Membrane Proteins
Language	English
Publishing date	2019-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12468
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Article ; Online: Evaluating a Multiscale Mechanistic Model of the Immune System to Predict Human Immunogenicity for a Biotherapeutic in Phase 1.

Hamuro, Lora / Tirucherai, Giridhar S / Crawford, Sean M / Nayeem, Akbar / Pillutla, Renuka C / DeSilva, Binodh S / Leil, Tarek A / Thalhauser, Craig J

The AAPS journal

2019 Volume 21, Issue 5, Page(s) 94

Abstract: A mechanistic model of the immune response was evaluated for its ability to predict anti-drug antibody (ADA) and their impact on pharmacokinetics (PK) and pharmacodynamics (PD) for a biotherapeutic in a phase 1 clinical trial. Observed ADA incidence ... ...

Abstract	A mechanistic model of the immune response was evaluated for its ability to predict anti-drug antibody (ADA) and their impact on pharmacokinetics (PK) and pharmacodynamics (PD) for a biotherapeutic in a phase 1 clinical trial. Observed ADA incidence ranged from 33 to 67% after single doses and 27-50% after multiple doses. The model captured the single dose incidence well; however, there was overprediction after multiple dosing. The model was updated to include a T-regulatory (Treg) cell mediated tolerance, which reduced the overprediction (relative decrease in predicted incidence rate of 21.5-59.3% across multidose panels) without compromising the single dose predictions (relative decrease in predicted incidence rate of 0.6-13%). The Treg-adjusted model predicted no ADA impact on PK or PD, consistent with the observed data. A prospective phase 2 trial was simulated, including co-medication effects in the form of corticosteroid-induced immunosuppression. Predicted ADA incidences were 0-10%, depending on co-medication dosage. This work demonstrates the utility in applying an integrated, iterative modeling approach to predict ADA during different stages of clinical development.
MeSH term(s)	Adrenal Cortex Hormones/administration & dosage ; Antibodies/immunology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Humans ; Immune System/immunology ; Models, Biological ; Prospective Studies ; Proteins/administration & dosage ; Proteins/pharmacokinetics ; Proteins/pharmacology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Adrenal Cortex Hormones ; Antibodies ; Proteins
Language	English
Publishing date	2019-07-24
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-019-0361-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans.

Lu, Yasong / Griffen, Steven C / Boulton, David W / Leil, Tarek A

Frontiers in pharmacology

2014 Volume 5, Page(s) 274

Abstract: In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption ... ...

Abstract	In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of the majority of filtered glucose in the early part of proximal tubules, and SGLT1 reabsorbs the residual glucose in the distal part. Inhibition of SGLT2 is a viable mechanism for removing glucose from the body and improving glycemic control in patients with diabetes. Despite demonstrating high levels (in excess of 80%) of inhibition of glucose transport by SGLT2 in vitro, potent SGLT2 inhibitors, e.g., dapagliflozin and canagliflozin, inhibit renal glucose reabsorption by only 30-50% in clinical studies. Hypotheses for this apparent paradox are mostly focused on the compensatory effect of SGLT1. The paradox has been explained and the role of SGLT1 demonstrated in the mouse, but direct data in humans are lacking. To further explore the roles of SGLT1/2 in renal glucose reabsorption in humans, we developed a systems pharmacology model with emphasis on SGLT1/2 mediated glucose reabsorption and the effects of SGLT2 inhibition. The model was calibrated using robust clinical data in the absence or presence of dapagliflozin (DeFronzo et al., 2013), and evaluated against clinical data from the literature (Mogensen, 1971; Wolf et al., 2009; Polidori et al., 2013). The model adequately described all four data sets. Simulations using the model clarified the operating characteristics of SGLT1/2 in humans in the healthy and diabetic state with or without SGLT2 inhibition. The modeling and simulations support our proposition that the apparent moderate, 30-50% inhibition of renal glucose reabsorption observed with potent SGLT2 inhibitors is a combined result of two physiological determinants: SGLT1 compensation and residual SGLT2 activity. This model will enable in silico inferences and predictions related to SGLT1/2 modulation.
Language	English
Publishing date	2014-12-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2014.00274
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Article ; Online: Quantitative Extrapolation: An Approach to Validation of Adult Drug Efficacy in Pediatric Subjects.

Leil, Tarek A / Zee, Pamela / Suryawanshi, Satyendra / Male, Christoph / Portman, Ronald

Therapeutic innovation & regulatory science

2016 Volume 47, Issue 5, Page(s) 557–565

Abstract: Confirmation of efficacy in pediatric drug development has traditionally required large, fully powered efficacy studies that have proven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food ... ...

Abstract	Confirmation of efficacy in pediatric drug development has traditionally required large, fully powered efficacy studies that have proven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food and Drug Administration and European Medicines Agency is an appropriate solution when there is similarity of disease. When there is uncertainty regarding the degree of disease similarity, partial extrapolation may be utilized. The authors propose a more quantitative approach to partial extrapolation (ie, quantitative extrapolation), involving (1) integration of adult pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcome data using pharmacometric models, (2) extrapolation using the adult pharmacometric model to predict PD and efficacy outcomes in pediatric subjects, and (3) validation of pediatric predictions with a streamlined plan of pediatric trials (ie, a quantitative extrapolation plan). A case study is presented for quantitative extrapolation using dipeptidyl peptidase 4 (DPP-4) inhibitors. In this example, the authors demonstrate how adult PK, PD, and HbA1c data can be integrated using a pharmacometric model for DPP-4 inhibitors with pediatric dose selection and efficacy validated with relatively few pediatric subjects.
Language	English
Publishing date	2016-07-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2708397-4
ISSN	2168-4804 ; 2168-4790
ISSN (online)	2168-4804
ISSN	2168-4790
DOI	10.1177/2168479013500286
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