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https://www.readbyqxmd.com/read/28144911/pharmacokinetic-steady-states-highlight-interesting-target-mediated-disposition-properties
#1
Johan Gabrielsson, Lambertus A Peletier
In this paper, we derive explicit expressions for the concentrations of ligand L, target R and ligand-target complex RL at steady state for the classical model describing target-mediated drug disposition, in the presence of a constant-rate infusion of ligand. We demonstrate that graphing the steady-state values of ligand, target and ligand-target complex, we obtain striking and often singular patterns, which yield a great deal of insight and understanding about the underlying processes. Deriving explicit expressions for the dependence of L, R and RL on the infusion rate, and displaying graphs of the relations between L, R and RL, we give qualitative and quantitive information for the experimentalist about the processes involved...
January 31, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28074396/target-mediated-drug-disposition-with-drug-drug-interaction-part-ii-competitive-and-uncompetitive-cases
#2
Gilbert Koch, William J Jusko, Johannes Schropp
We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions...
January 10, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28074395/target-mediated-drug-disposition-with-drug-drug-interaction-part-i-single-drug-case-in-alternative-formulations
#3
Gilbert Koch, William J Jusko, Johannes Schropp
Target-mediated drug disposition (TMDD) describes drug binding with high affinity to a target such as a receptor. In application TMDD models are often over-parameterized and quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are essential to reduce the number of parameters. However, implementation of such approximations becomes difficult for TMDD models with drug-drug interaction (DDI) mechanisms. Hence, alternative but equivalent formulations are necessary for QE or QSS approximations. To introduce and develop such formulations, the single drug case is reanalyzed...
January 10, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28063030/target-mediated-drug-disposition-population-pharmacokinetics-model-of-alirocumab-in-healthy-volunteers-and-patients-pooled-analysis-of-randomized-phase-i-ii-iii-studies
#4
Nassim Djebli, Jean-Marie Martinez, Laura Lohan, Sonia Khier, Aurélie Brunet, Fabrice Hurbin, David Fabre
BACKGROUND AND OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 inhibition with monoclonal antibodies such as alirocumab significantly reduces low-density lipoprotein-cholesterol levels ± other lipid-lowering therapies. We aimed to develop and qualify a population pharmacokinetics (PopPK) model for alirocumab in healthy subjects and patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. METHODS: This TMDD model was developed using a subset of the alirocumab clinical trial database, including nine phase I/II/III studies (n = 527); the model was subsequently expanded to a larger data set of 13 studies (n = 2870)...
January 6, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27861991/impact-of-target-mediated-elimination-on-the-dose-and-regimen-of-evolocumab-a-human-monoclonal-antibody-against-proprotein-convertase-subtilisin-kexin-type-9-pcsk9
#5
John P Gibbs, Sameer Doshi, Mita Kuchimanchi, Anita Grover, Maurice G Emery, Michael G Dodds, Megan A Gibbs, Ransi Somaratne, Scott M Wasserman, Dirk Blom
Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target-mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low-density lipoprotein cholesterol (LDL-C). Data were pooled from 2 clinical studies: a single-dose escalation study in healthy subjects (7-420 mg SC; n = 44) and a multiple-dose escalation study in statin-treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57)...
November 15, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27637171/use-of-a-target-mediated-drug-disposition-model-to-predict-the-human-pharmacokinetics-and-target-occupancy-of-gc1118-an-anti-epidermal-growth-factor-receptor-antibody
#6
Wan-Su Park, Seunghoon Han, Jongtae Lee, Taegon Hong, Jonghwa Won, Yangmi Lim, Kyuhyun Lee, Han Yeul Byun, Dong-Seok Yim
GC1118 is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that is currently under clinical development. In this study, the pharmacokinetics (PK) of GC1118 were modelled in monkeys to predict human PK and receptor occupancy (RO) profiles. The serum concentrations of GC1118 and its comparator (cetuximab) were assessed in monkeys with a non-compartmental analysis and a target-mediated drug disposition (TMDD) model after intravenous infusion (3-25 mg/kg) of these drugs. The scaling exponent of the EGFR synthesis rate was determined using a sensitivity analysis...
March 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/27612462/a-cell-level-model-of-pharmacodynamics-mediated-drug-disposition
#7
Wojciech Krzyzanski, John M Harrold, Liviawati S Wu, Juan Jose Perez-Ruixo
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...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27489162/small-molecule-compounds-exhibiting-target-mediated-drug-disposition-tmdd-a-minireview
#8
REVIEW
Guohua An
Nonlinearities are commonplace in pharmacokinetics, and 1 special source is the saturable binding of the drug to a high-affinity, low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Compared with large-molecule compounds undergoing TMDD, which has been well recognized due to its high prevalence, TMDD in small-molecule compounds is more counterintuitive and has not been well appreciated. With more and more potent small-molecule drugs acting on highly specific targets being developed as well as increasingly sensitive analytical techniques becoming available, many small-molecule compounds have recently been reported to have nonlinear pharmacokinetics imparted by TMDD...
February 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27377311/physiologically-based-pharmacokinetic-modeling-to-predict-the-clinical-pharmacokinetics-of-monoclonal-antibodies
#9
Patrick M Glassman, Joseph P Balthasar
Accurate prediction of the clinical pharmacokinetics of new therapeutic entities facilitates decision making during drug discovery, and increases the probability of success for early clinical trials. Standard strategies employed for predicting the pharmacokinetics of small-molecule drugs (e.g., allometric scaling) are often not useful for predicting the disposition monoclonal antibodies (mAbs), as mAbs frequently demonstrate species-specific non-linear pharmacokinetics that is related to mAb-target binding (i...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27119518/minimal-physiologically-based-pharmacokinetic-mpbpk-model-for-a-monoclonal-antibody-against-interleukin-6-in-mice-with-collagen-induced-arthritis
#10
Xi Chen, Xiling Jiang, William J Jusko, Honghui Zhou, Weirong Wang
Therapeutic monoclonal antibodies (mAb) targeting soluble inflammatory cytokines exert their pharmacological effects in rheumatoid arthritis through binding and neutralizing free cytokines in target tissue sites. Therefore suppression of free cytokines in such sites directly relates to the magnitude of therapeutic response. Although the interrelationships between mAb and cytokines have been examined in the systemic circulation, less is known about the interaction of mAb and cytokines in inflamed joints. In the present study, the interplay between the mAb, CNTO 345, and its target IL-6 in serum as well as ankle joint synovial fluid were characterized in collagen-induced arthritic mice...
June 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27081038/phase-i-clinical-study-of-rg7356-an-anti-cd44-humanized-antibody-in-patients-with-acute-myeloid-leukemia
#11
Norbert Vey, Jacques Delaunay, Giovanni Martinelli, Walter Fiedler, Emmanuel Raffoux, Thomas Prebet, Carlos Gomez-Roca, Cristina Papayannidis, Maxim Kebenko, Peter Paschka, Randolph Christen, Ernesto Guarin, Ann-Marie Bröske, Monika Baehner, Michael Brewster, Antje-Christine Walz, Francesca Michielin, Valeria Runza, Valerie Meresse, Christian Recher
RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, inhibits cell adhesion and has been associated with macrophage activation in preclinical models. We report results of a phase I dose-escalation study of RG7356 in relapsed/refractory acute myeloid leukemia (AML).Eligible patients with refractory AML, relapsed AML after induction chemotherapy, or previously untreated AML not eligible for intensive chemotherapy were enrolled and received intravenous RG7356 at dosages ≤ 2400 mg every other week or ≤ 1200 mg weekly or twice weekly; dose escalation started at 300 mg...
May 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/26341624/temporal-pharmacokinetic-pharmacodynamic-interaction-between-human-cd3%C3%AE%C2%B5-antigen-targeted-monoclonal-antibody-otelixizumab-and-cd3%C3%AE%C2%B5-binding-and-expression-in-human-peripheral-blood-mononuclear-cell-static-culture
#12
Kevin R Page, Enrica Mezzalana, Alexander J MacDonald, Stefano Zamuner, Giuseppe De Nicolao, Andre van Maurik
Otelixizumab is a monoclonal antibody (mAb) directed to human CD3ε, a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes. This study investigated the temporal interaction between varying concentrations of otelixizumab, binding to human CD3 antigen, and expression of CD3/TCR complexes on lymphocytes in vitro, free from the confounding influence of changing lymphocyte frequencies observed in vivo. A static in vitro culture system was established in which primary human peripheral blood mononuclear cells (PBMCs) were incubated over an extended time course with titrated concentrations of otelixizumab...
November 2015: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/26225261/a-tutorial-on-target-mediated-drug-disposition-tmdd-models
#13
P Dua, E Hawkins, P H van der Graaf
Target-mediated drug disposition (TMDD) is the phenomenon in which a drug binds with high affinity to its pharmacological target site (such as a receptor) to such an extent that this affects its pharmacokinetic characteristics.1 The aim of this Tutorial is to provide an introductory guide to the mathematical aspects of TMDD models for pharmaceutical researchers. Examples of Berkeley Madonna2 code for some models discussed in this Tutorial are provided in the Supplementary Materials.
June 2015: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/26180901/preclinical-development-of-an-anti-5t4-antibody-drug-conjugate-pharmacokinetics-in-mice-rats-and-nhp-and-tumor-tissue-distribution-in-mice
#14
Mauricio Leal, JoAnn Wentland, Xiaogang Han, Yanhua Zhang, Brian Rago, Nicole Duriga, Franklin Spriggs, Eugene Kadar, Wei Song, James McNally, Quazi Shakey, Leslie Lorello, Judy Lucas, Puja Sapra
The pharmacokinetics of an antibody (huA1)-drug (auristatin microtubule disrupting MMAF) conjugate, targeting 5T4-expressing cells, were characterized during the discovery and development phases in female nu/nu mice and cynomolgus monkeys after a single dose and in S-D rats and cynomolgus monkeys from multidose toxicity studies. Plasma/serum samples were analyzed using an ELISA-based method for antibody and conjugate (ADC) as well as for the released payload using an LC-MS/MS method. In addition, the distribution of the Ab, ADC, and released payload (cys-mcMMAF) was determined in a number of tissues (tumor, lung, liver, kidney, and heart) in two tumor mouse models (H1975 and MDA-MB-361-DYT2 models) using similar LBA and LC-MS/MS methods...
November 18, 2015: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/26077506/a-priori-identifiability-of-target-mediated-drug-disposition-models-and-approximations
#15
Rena J Eudy, Matthew M Riggs, Marc R Gastonguay
A priori identifiability of mathematical models assures that for a given input/output experiment, the parameter set has one unique solution within a defined space, independent of the experimental design. Many biologic therapeutics exhibit target-mediated drug disposition (TMDD), and use of the full compartmental model describing this system is well documented. In practice, estimation of the full parameter set for TMDD models, given real-world clinical data, is characterized by convergence difficulties and unstable solutions...
September 2015: AAPS Journal
https://www.readbyqxmd.com/read/25931139/small-molecule-compounds-exhibiting-target-mediated-drug-disposition-a-case-example-of-abt-384
#16
REVIEW
Guohua An, Wei Liu, Sandeep Dutta
Nonlinearities are frequently encountered in pharmacokinetics, and they can occur when 1 or more processes of absorption, distribution, metabolism, and excretion are saturable. One special source of nonlinearity that has been noticed recently is the saturable binding of the drug to a high-affinity-low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Although TMDD can occur in both small-molecule compounds and large-molecule compounds, the latter has received much more attention because of its high prevalence...
October 2015: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/25869767/projecting-human-pharmacokinetics-of-monoclonal-antibodies-from-nonclinical-data-comparative-evaluation-of-prediction-approaches-in-early-drug-development
#17
REVIEW
Jing Wang, Suhasini Iyer, Paul J Fielder, John D Davis, Rong Deng
Currently, more than 350 monoclonal antibodies (mAbs) and mAb derivatives are under development as therapeutics. The prediction of mAb pharmacokinetics (PK)/pharmacodynamics (PD) plays a key role in starting dose selection for first-in-human (FIH) studies. This article presents a brief overview of the biology and mechanisms of absorption, distribution, metabolism and excretion (ADME) for mAbs. In addition, a detailed review of mAb human PK/PD prediction from nonclinical data is provided, including allometry for mAbs with linear or nonlinear PK, species-invariant time method, physiologically based PK (PBPK) modeling and target-mediated drug disposition (TMDD) model, bioavailability projection and immunogenicity impact on PK prediction...
March 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/25851130/farmed-and-wild-sea-bass-dicentrarchus-labrax-volatile-metabolites-a-comparative-study-by-spme-gc-ms
#18
COMPARATIVE STUDY
Natalia P Vidal, María J Manzanos, Encarnación Goicoechea, María D Guillén
BACKGROUND: Farmed and wild European sea bass (Dicentrarchus labrax) could be distinguished by its volatile metabolites, an issue not addressed until now. The aim of this work was to study these metabolites by solid-phase microextraction followed by gas chromatography/mass spectrometry (SPME-GC/MS). RESULTS: Both farmed and wild sea bass have a great number of volatile metabolites, most of them being in low concentrations. These include alcohols, aldehydes, ketones, alkylfurans, acids, aliphatic and aromatic hydrocarbons, terpenes, sulfur and nitrogen derivatives, 2,6-di-tert-butyl-4-methylphenol and one derived compound, as well as 2,4,7,9-tetramethyl-5-decyne-4,7-diol, this latter compound presumably resulting from environmental contamination...
March 15, 2016: Journal of the Science of Food and Agriculture
https://www.readbyqxmd.com/read/25727954/target-mediated-pharmacokinetic-pharmacodynamic-model-based-meta-analysis-and-dosing-regimen-optimization-of-a-long-acting-release-formulation-of-exenatide-in-patients-with-type-2-diabetes-mellitus
#19
Hanqing Li, Jiayin Xu, Xiaohong Fan
A hybrid pharmacokinetic/pharmacodynamic (PK/PD) model with extended-release (ER) process and target mediated drug disposition (TMDD) was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R)-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol...
February 2015: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/25577944/confirmation-of-the-molecular-structure-of-tetramethylene-diperoxide-dicarbamide-tmdd-and-its-sensitiveness-properties
#20
Mark Fitzgerald, Michael G Gardiner, David Armitt, Gregory W Dicinoski, Craig Wall
Conjecture existed as to the molecular structure of the crystalline organic peroxide reaction product derived from the acidified aqueous mixture of urea, formaldehyde, and hydrogen peroxide. This study used X-ray crystal structure determination to unequivocally define the reaction product as the 14-membered ring structure tetramethylene diperoxide dicarbamide (TMDD). Crystals of TMDD belong to the monoclinic space group Pc, a = 4.587(4), b = 16.080(2), c = 6.690(5) Å, β = 107.44(5)°. The crystal contains one crystallographically independent molecule with approximate Cs symmetry...
February 5, 2015: Journal of Physical Chemistry. A
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