Translational two-pore PBPK model to characterize whole-body disposition of different-size endogenous and exogenous proteins.

Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans.

Navigating Between Right, Wrong, and Relevant: The Use of Mathematical Modeling in Preclinical Decision Making.

The goal of this mini-review is to summarize the collective experience of the authors for how modeling and simulation approaches have been used to inform various decision points from discovery to First-In-Human clinical trials. The article is divided into a high-level overview of the types of problems that are being aided by modeling and simulation approaches, followed by detailed case studies around drug design (Nektar Therapeutics, Genentech), feasibility analysis (Novartis Pharmaceuticals), improvement of preclinical drug design (Pfizer), and preclinical to clinical extrapolation (Merck, Takeda, and Amgen).

Computational Analysis of Cytokine Release Following Bispecific T-Cell Engager Therapy: Applications of a Logic-Based Model.

Bispecific T-cell engaging therapies harness the immune system to elicit an effective anticancer response. Modulating the immune activation avoiding potential adverse effects such as cytokine release syndrome (CRS) is a critical aspect to realizing the full potential of this therapy. The use of suitable exogenous intervention strategies to mitigate the CRS risk without compromising the antitumoral capability of bispecific antibody treatment is crucial.

Preclinical Assessment of a MUC12-Targeted BiTE (Bispecific T-cell Engager) Molecule.

MUC12 is a transmembrane mucin that is highly expressed in >50% of primary and metastatic colorectal tumors. MUC12 is also expressed by normal epithelial cells of the colon and small intestine. Although MUC12 localization in normal epithelial cells is restricted to the apical membrane, expression in tumors is depolarized and shows broad membrane localization.

GIPR antagonist antibodies conjugated to GLP-1 peptide are bispecific molecules that decrease weight in obese mice and monkeys.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters.

Spatial defects nanoengineering for bipolar conductivity in MoS.

Understanding the atomistic origin of defects in two-dimensional transition metal dichalcogenides, their impact on the electronic properties, and how to control them is critical for future electronics and optoelectronics. Here, we demonstrate the integration of thermochemical scanning probe lithography (tc-SPL) with a flow-through reactive gas cell to achieve nanoscale control of defects in monolayer MoS. The tc-SPL produced defects can present either p- or n-type doping on demand, depending on the used gasses, allowing the realization of field effect transistors, and p-n junctions with precise sub-μm spatial control, and a rectification ratio of over 10.

Quantification of Radiation Injury on Neutropenia and the Link between Absolute Neutrophil Count Time Course and Overall Survival in Nonhuman Primates Treated with G-CSF.

Purpose: To model absolute neutrophil count (ANC) suppression in response to acute radiation (AR) exposure and evaluate ANC time course as a predictor of overall survival (OS) in response to AR exposure with or without treatment with granulocyte colony-stimulating factor in nonhuman primates.

Methods: Source data were obtained from two pivotal studies conducted in rhesus macaques exposed to 750 cGy of whole body irradiation on day 0 that received either placebo, daily filgrastim, or pegfilgrastim (days 1 and 8 after irradiation). Animals were observed for 60 days with ANC measured every 1 to 2 days.

Prediction of Survival Benefit of Filgrastim in Adult and Pediatric Patients With Acute Radiation Syndrome.

Acute exposure to high doses of radiation leads to severe myelosuppression, but few treatments are currently available to treat hematopoietic syndrome of acute radiation syndrome. Granulocyte colony stimulating factors (e.g.

Pharmacokinetic-pharmacodynamic modelling of neutrophil response to G-CSF in healthy subjects and patients with chemotherapy-induced neutropenia.

Aim: The objective of the present study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia treated with filgrastim and pegfilgrastim.

Methods: Data were extracted from 10 phase I-III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids.

Optimal Affinity of a Monoclonal Antibody: Guiding Principles Using Mechanistic Modeling.

Affinity optimization of monoclonal antibodies (mAbs) is essential for developing drug candidates with the highest likelihood of clinical success; however, a quantitative approach for setting affinity requirements is often lacking. In this study, we computationally analyzed the in vivo mAb-target binding kinetics to delineate general principles for defining optimal equilibrium dissociation constant ([Formula: see text]) of mAbs against soluble and membrane-bound targets. Our analysis shows that in general [Formula: see text] to achieve 90% coverage for a soluble target is one tenth of its baseline concentration ([Formula: see text]), and is independent of the dosing interval, target turnover rate or the presence of competing ligands.

A cell-level model of pharmacodynamics-mediated drug disposition.

We aimed to develop a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model to analyze in vivo systems where the PD response to a drug has an appreciable effect on the pharmacokinetics (PK). An existing cellular level model of PD stimulation was combined with the standard target-mediated drug disposition (TMDD) model and the resulting model structure was parametrically identifiable from typical in vivo PK and PD data. The PD model of the cell population was controlled by the production rate k in and elimination rate k out which could be stimulated or inhibited by the number of bound receptors on a single cell.

Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice.

A mechanistic model describing the effects of chemotherapy and radiation on platelet counts and endogenous thrombopoietin (eTPO) in mice was developed. Thrombocytopenia was induced in mice by injection of carboplatin followed by the whole body irradiation on days 0, 28, and 56, with platelet and eTPO samples collected over 84 days. The pharmacodynamic model consisted of a series of aging compartments representing proliferating megakaryocyte precursors, megakaryocytes, and platelets with possible eTPO clearance through internalization.

Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies.

Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development.

Ubiquity: a framework for physiological/mechanism-based pharmacokinetic/pharmacodynamic model development and deployment.

Practitioners of pharmacokinetic/pharmacodynamic modeling routinely employ various software packages that enable them to fit differential equation based mechanistic or empirical models to biological/pharmacological data. The availability and choice of different analytical tools, while enabling, can also pose a significant challenge in terms of both, implementation and transferability. A package has been developed that addresses these issues by creating a simple text-based format, which provides methods to reduce coding complexity and enables the modeler to describe the components of the model based on the underlying physiochemical processes.

Functional interfacing of Rhodospirillum rubrum chromatophores to a conducting support for capture and conversion of solar energy.

Owing to the considerable current interest in replacing fossil fuels with solar radiation as a clean, renewable, and secure energy source, light-driven electron transport in natural photosynthetic systems offers a valuable blueprint for conversion of sunlight to useful energy forms. In particular, intracytoplasmic membrane vesicles (chromatophores) from the purple bacterium Rhodospirillum rubrum provide a fully functional and robust photosynthetic apparatus, ideal for biophysical investigations of energy transduction and incorporation into biohybrid photoelectrochemical devices. These vesicular organelles, which arise by invagination of the cytoplasmic membrane, are the sites of the photochemical reaction centers and the light harvesting 1 (LH1) complex.

Structural and functional proteomics of intracytoplasmic membrane assembly in Rhodobacter sphaeroides.

The results of a detailed structural and functional proteomic analysis of intracytoplasmic membrane (ICM) assembly in the model purple phototrophic bacterium Rhodobacter sphaeroides are reviewed in this report. Proteomics approaches have focused upon identification of membrane proteins temporally expressed during ICM development and spatially localized within the internal cell membranes, together with their structural and functional correlates. For the examination of temporal protein expression, procedures were established for the induction of ICM formation at low oxygen tension and for ICM remodeling in cells adapting to low intensity illumination, which permitted isolation by rate-zone sedimentation of ICM growth initiation sites (CM invaginations) in an upper-pigmented band (UPB), together with more mature ICM vesicles (chromatophores) as the main band.

Absorption, distribution, metabolism, and excretion (ADME) studies of biotherapeutics for autoimmune and inflammatory conditions.

Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of biotherapeutics is crucial for clinical, as well as commercial, success of these drugs. This review focuses on the common questions and challenges in ADME optimization of biotherapeutics for inflammatory conditions.

Combinatorial chemotherapeutic efficacy in non-Hodgkin lymphoma can be predicted by a signaling model of CD20 pharmacodynamics.

Combination chemotherapy represents the standard-of-care for non-Hodgkin lymphoma. However, the development of new therapeutic regimens is empirical and this approach cannot be used prospectively to identify novel or optimal drug combinations. Quantitative system pharmacodynamic models could promote the discovery and development of combination regimens based upon first principles.

Disposition of human recombinant lubricin in naive rats and in a rat model of post-traumatic arthritis after intra-articular or intravenous administration.

We have recently demonstrated that intra-articular (IA) administration of human recombinant lubricin, LUB:1, significantly inhibited cartilage degeneration and pain in the rat meniscal tear model of post-traumatic arthritis. In this report, we show that after a single IA injection to naïve rats and rats that underwent unilateral meniscal tear, [(125)I]LUB:1 had a tri-phasic disposition profile, with the alpha, beta, and gamma half-life estimates of 4.5 h, 1.

Interspecies scaling of receptor-mediated pharmacokinetics and pharmacodynamics of type I interferons.

Purpose: To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD).

Methods: PK and PD profiles of human IFN-beta1a, IFN-beta1b, and IFN-alpha2a in humans, monkeys, rats, and mice from nine studies were extracted from the literature by digitization. Concentration-time profiles from different species were fitted simultaneously using various allometric relationships to scale model-specific parameters.

Differential pharmacodynamic effects of paclitaxel formulations in an intracranial rat brain tumor model.

Nano- and microparticulate carriers can exert a beneficial impact on the pharmacodynamics of anticancer agents. To investigate the relationships between carrier and antitumor pharmacodynamics, paclitaxel incorporated in liposomes (L-pac) was compared with the clinical standard formulated in Cremophor-EL/ethanol (Cre-pac) in a rat model of advanced primary brain cancer. Three maximum-tolerated-dose regimens given by intravenous administration were investigated: 50 mg/kg on day 8 (d8) after implantation of 9L gliosarcoma tumors; 40 mg/kg on d8 and d15; 20 mg/kg on d8, d11, and d15.

Control-relevant modeling of the antitumor effects of 9-nitrocamptothecin in SCID mice bearing HT29 human colon xenografts.

The mathematical model structure selected to describe system behavior is at least partially dependent on the proposed use of the model. In this paper, a pharmacokinetic(PK)/pharmacodynamic (PD) model for use in drug delivery algorithm synthesis is developed. The antitumor agent 9-nitrocamptothecin (9NC) was administered orally to severe combined immunodeficient (SCID) mice bearing subcutaneously implanted HT29 human colon xenografts, and the effect of 9NC on those xenografts was characterized.