scholarly journals Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies

2021 ◽  
Vol 23 (5) ◽  
Author(s):  
Roberto A. Abbiati ◽  
Michael Pourdehnad ◽  
Soraya Carrancio ◽  
Daniel W. Pierce ◽  
Shailaja Kasibhatla ◽  
...  
Keyword(s):  
B Cell Lymphoma ◽  
Patient Characteristics ◽  
Response To Treatment ◽  
Low Grade ◽  
Systems Pharmacology ◽  
Quantitative Systems Pharmacology ◽  
Clinical Dose ◽  
Optimal Dosing ◽  
Virtual Population ◽  
Dose Dependent

AbstractAvadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.

scholarly journals Quantitative systems pharmacology modeling of avadomide-induced neutropenia enables virtual clinical dose and schedule finding studies

2021 ◽  
Author(s):  
Roberto A. Abbiati ◽  
Michael Pourdehnad ◽  
Soraya Carrancio ◽  
Daniel W. Pierce ◽  
Shailaja Kasibhatla ◽  
...  
Keyword(s):  
B Cell Lymphoma ◽  
Patient Characteristics ◽  
Response To Treatment ◽  
Low Grade ◽  
Systems Pharmacology ◽  
Quantitative Systems Pharmacology ◽  
Clinical Dose ◽  
Optimal Dosing ◽  
Virtual Population ◽  
Dose Dependent

AbstractAvadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia, however the identification of optimal dosing schedules remains a clinical challenge.Quantitative Systems Pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development.We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage.The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort.Model utility was demonstrated by simulating avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low grade-neutropenia.

scholarly journals Efficient Generation and Selection of Virtual Populations in Quantitative Systems Pharmacology Models

2015 ◽  
Author(s):  
Richard Allen ◽  
Theodore R Rieger ◽  
Cynthia J Musante
Keyword(s):  
Clinical Population ◽  
Virtual Patients ◽  
Systems Pharmacology ◽  
System Behavior ◽  
Quantitative Systems Pharmacology ◽  
Novel Technique ◽  
Virtual Population ◽  
Model Predictions ◽  
Baseline Characteristics ◽  
Selection Of

Quantitative systems pharmacology models mechanistically describe a biological system and the effect of drug treatment on system behavior. Because these models rarely are identifiable from the available data, the uncertainty in physiological parameters may be sampled to create alternative parameterizations of the model, sometimes termed "Virtual Patients". In order to reproduce the statistics of a clinical population, Virtual Patients are often weighted to form a Virtual Population that reflects the baseline characteristics of the clinical cohort. Here we introduce a novel technique to efficiently generate Virtual Patients and, from this ensemble, demonstrate how to select a Virtual Population that matches the observed data without the need for weighting. This approach improves confidence in model predictions by mitigating the risk that spurious Virtual Patients become over-represented in Virtual Populations.

scholarly journals Should the CIWA-Ar be the standard monitoring strategy for alcohol withdrawal syndrome in the intensive care unit?

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tessa L. Steel ◽  
Shewit P. Giovanni ◽  
Sarah C. Katsandres ◽  
Shawn M. Cohen ◽  
Kevin B. Stephenson ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Alcohol Withdrawal ◽  
Withdrawal Syndrome ◽  
Alcohol Withdrawal Syndrome ◽  
Patient Characteristics ◽  
Response To Treatment ◽  
Alternative Measure ◽  
Icu Patients ◽  
Verbal Responses

Abstract Background The Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) is commonly used in hospitals to titrate medications for alcohol withdrawal syndrome (AWS), but may be difficult to apply to intensive care unit (ICU) patients who are too sick or otherwise unable to communicate. Objectives To evaluate the frequency of CIWA-Ar monitoring among ICU patients with AWS and variation in CIWA-Ar monitoring across patient demographic and clinical characteristics. Methods The study included all adults admitted to an ICU in 2017 after treatment for AWS in the Emergency Department of an academic hospital that standardly uses the CIWA-Ar to assess AWS severity and response to treatment. Demographic and clinical data, including Richmond Agitation-Sedation Scale (RASS) assessments (an alternative measure of agitation/sedation), were obtained via chart review. Associations between patient characteristics and CIWA-Ar monitoring were tested using logistic regression. Results After treatment for AWS, only 56% (n = 54/97) of ICU patients were evaluated using the CIWA-Ar; 94% of patients had a documented RASS assessment (n = 91/97). Patients were significantly less likely to receive CIWA-Ar monitoring if they were intubated or identified as Black. Conclusions CIWA-Ar monitoring was used inconsistently in ICU patients with AWS and completed less often in those who were intubated or identified as Black. These hypothesis-generating findings raise questions about the utility of the CIWA-Ar in ICU settings. Future studies should assess alternative measures for titrating AWS medications in the ICU that do not require verbal responses from patients and further explore the association of race with AWS monitoring.

scholarly journals Quantitative systems pharmacology in neuroscience: Novel methodologies and technologies

2021 ◽  
Author(s):  
Peter Bloomingdale ◽  
Tatiana Karelina ◽  
Murat Cirit ◽  
Sarah F. Muldoon ◽  
Justin Baker ◽  
...  
Keyword(s):  
Systems Pharmacology ◽  
Quantitative Systems Pharmacology

scholarly journals A 25-year retrospective, single center analysis of 343 WHO grade II/III glioma patients: implications for grading and temozolomide therapy

2021 ◽  
Author(s):  
Eike Steidl ◽  
Katharina Filipski ◽  
Pia S. Zeiner ◽  
Marlies Wagner ◽  
Emmanouil Fokas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Markers ◽  
Treatment Time ◽  
Real Life ◽  
Patient Characteristics ◽  
Low Grade ◽  
Who Grade ◽  
Idh1 R132h ◽  
Treatment Data ◽  
Grade Ii

Abstract Purpose Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p < 0.01) but not for oligodendroglioma (p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p < 0.001/ = 0.06; OS data immature) the effect, mainly in combination with temozolomide, was weaker in astrocytomas (median radiochemotherapy 6.7/chemotherapy 2.3/radiotherapy 2.0 years; p < 0.001/ = 0.11) and did not translate to improved OS (median 8.4 years). Conclusion This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.

Response to: “The Role of Quantitative Systems Pharmacology in the Design of First-in-Human Trials”

2018 ◽  
Vol 104 (5) ◽  
pp. 798-798
Author(s):  
Kevin Blake ◽  
Milton Bonelli ◽  
Stefano Ponzano ◽  
Harald Enzmann ◽  
Keyword(s):  
Systems Pharmacology ◽  
Quantitative Systems Pharmacology ◽  
Human Trials
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