Quantitative Systems Pharmacology Model-Based Predictions of Clinical Endpoints to Optimize Warfarin and Rivaroxaban Anti-Thrombosis Therapy.

Background: Tight monitoring of efficacy and safety of anticoagulants such as warfarin is imperative to optimize the benefit-risk ratio of anticoagulants in patients. The standard tests used are measurements of prothrombin time (PT), usually expressed as international normalized ratio (INR), and activated partial thromboplastin time (aPTT).

Objective: To leverage a previously developed quantitative systems pharmacology (QSP) model of the human coagulation network to predict INR and aPTT for warfarin and rivaroxaban, respectively.

A clinical population pharmacokinetic/pharmacodynamic model for BIIB059, a monoclonal antibody for the treatment of systemic and cutaneous lupus erythematosus.

A population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model.

A pre-clinical quantitative model predicts the pharmacokinetics/pharmacodynamics of an anti-BDCA2 monoclonal antibody in humans.

BIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we utilized pre-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to develop a non-human primate (NHP) model and to address whether the NHP model can be successfully scaled to predict the human PK/PD.

A Semi-Mechanistic Population Pharmacokinetic Model of Nusinersen: An Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy.

A pharmacokinetic (PK) model was developed for nusinersen, an antisense oligonucleotide (ASO) that is the first approved treatment for spinal muscular atrophy (SMA). The model was built with data from 92 nonhuman primates (NHPs) following intrathecal doses (0.3-7 mg) and characterized the PK in cerebrospinal fluid (CSF), plasma, total spinal cord, brain, and pons.

Perspective on the State of Pharmacometrics and Systems Pharmacology Integration.

Reliance on modeling and simulation in drug discovery and development has dramatically increased over the past decade. Two disciplines at the forefront of this activity, pharmacometrics and systems pharmacology (SP), emerged independently from different fields; consequently, a perception exists that only few examples integrate these approaches. Herein, we review the state of pharmacometrics and SP integration and describe benefits of combining these approaches in a model-informed drug discovery and development framework.

Systems pharmacology to predict drug safety in drug development.

Ensuring that drugs are safe and effective is a very high priority for drug development and the US Food and Drug Administration review process. This is especially true today because of faster approval times and smaller clinical trials, especially in oncology and rare diseases. In light of these trends, systems pharmacology is seen as an essential strategy to understand and predict adverse drug events during drug development by analyzing interactions between drugs and multiple targets rather than the traditional "one-drug-one-target" approach.

Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8.

Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GCs). Here we identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulated the initial developmental bifurcation of activated B cells as well as the GC response. IRF8 dampened signaling via the B cell antigen receptor (BCR), facilitated antigen-specific interaction with helper T cells, and promoted antibody affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts.

Bacterial sugar utilization gives rise to distinct single-cell behaviours.

Inducible utilization pathways reflect widespread microbial strategies to uptake and consume sugars from the environment. Despite their broad importance and extensive characterization, little is known how these pathways naturally respond to their inducing sugar in individual cells. Here, we performed single-cell analyses to probe the behaviour of representative pathways in the model bacterium Escherichia coli.

Trade-offs in engineering sugar utilization pathways for titratable control.

Titratable systems are common tools in metabolic engineering to tune the levels of enzymes and cellular components as part of pathway optimization. For nonmodel microorganisms with limited genetic tools, inducible sugar utilization pathways offer built-in titratable systems. However, these pathways can exhibit undesirable single-cell behaviors that hamper the uniform and tunable control of gene expression.

Stochastic simulations of a synthetic bacteria-yeast ecosystem.

Background: The field of synthetic biology has greatly evolved and numerous functions can now be implemented by artificially engineered cells carrying the appropriate genetic information. However, in order for the cells to robustly perform complex or multiple tasks, co-operation between them may be necessary. Therefore, various synthetic biological systems whose functionality requires cell-cell communication are being designed.

proTeOn and proTeOff, new protein devices that inducibly activate bacterial gene expression.

Using an original workflow, we have modeled, constructed, and characterized two new molecular devices that inducibly activate gene expression in Escherichia coli. The devices, prokaryotic-TetOn and prokaryotic-TetOff, were built by fusing an inducible DNA-binding protein domain to a transcription activation domain and constructing a complementary synthetic promoter sequence through which they could control downstream gene expression. In particular, the transactivators were built using variants of the tetracycline repressor, TetR, and the transactivating domain of the LuxR activator.

Stochastic simulations of the tetracycline operon.

Background: The tetracycline operon is a self-regulated system. It is found naturally in bacteria where it confers resistance to antibiotic tetracycline. Because of the performance of the molecular elements of the tetracycline operon, these elements are widely used as parts of synthetic gene networks where the protein production can be efficiently turned on and off in response to the presence or the absence of tetracycline.