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https://www.readbyqxmd.com/read/28918570/mathematical-description-of-drug-target-interactions-application-to-biologics-that-bind-to-targets-with-two-binding-sites
#1
Leonid Gibiansky, Ekaterina Gibiansky
The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28876162/capacity-limits-of-asialoglycoprotein-receptor-mediated-liver-targeting
#2
Charlotte Bon, Thomas Hofer, Alain Bousquet-Mélou, Mark R Davies, Ben-Fillippo Krippendorff
The abundant cell surface asialoglycoprotein receptor (ASGPR) is a highly selective receptor found on hepatocytes that potentially can be exploited as a selective shuttle for delivery. Various nucleic acid therapeutics that bind ASGPR are already in clinical development, but this receptor-mediated delivery mechanism can be saturated, which will likely result in reduced selectivity for the liver and therefore increase the likelihood for systemic adverse effects. Therefore, when aiming to utilize this mechanism, it is important to optimize both the administration protocol and the molecular properties...
September 6, 2017: MAbs
https://www.readbyqxmd.com/read/28837693/alternative-vaccine-administration-by-powder-injection-needle-free-dermal-delivery-of-the-glycoconjugate-meningococcal-group-y-vaccine
#3
Nikolas T Weissmueller, Leanne Marsay, Heiko A Schiffter, Robert C Carlisle, Christine S Rollier, Robert K Prud'homme, Andrew J Pollard
Powder-injectors use gas propulsion to deposit lyophilised drug or vaccine particles in the epidermal and sub epidermal layers of the skin. We prepared dry-powder (Tg = 45.2 ± 0.5°C) microparticles (58.1 μm) of a MenY-CRM197 glyconjugate vaccine (0.5% wt.) for intradermal needle-free powder injection (NFPI). SFD used ultrasound atomisation of the liquid vaccine-containing excipient feed, followed by lyophilisation above the glass transition temperature (Tg' = - 29.9 ± 0.3°C). This resulted in robust particles (density~ 0...
2017: PloS One
https://www.readbyqxmd.com/read/28725976/target-mediated-drug-disposition-model-for-drugs-with-two-binding-sites-that-bind-to-a-target-with-one-binding-site
#4
Leonid Gibiansky, Ekaterina Gibiansky
The paper extended the TMDD model to drugs with two identical binding sites (2-1 TMDD). The quasi-steady-state (2-1 QSS), quasi-equilibrium (2-1 QE), irreversible binding (2-1 IB), and Michaelis-Menten (2-1 MM) approximations of the model were derived. Using simulations, the 2-1 QSS approximation was compared with the full 2-1 TMDD model. As expected and similarly to the standard TMDD for monoclonal antibodies (mAb), 2-1 QSS predictions were nearly identical to 2-1 TMDD predictions, except for times of fast changes following initiation of dosing, when equilibrium has not yet been reached...
July 19, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28593473/pharmacokinetic-pharmacodynamic-relationship-of-erenumab-amg-334-and-capsaicin-induced-dermal-blood-flow-in-healthy-and-migraine-subjects
#5
Thuy Vu, Peiming Ma, Jiyun Sunny Chen, Jan de Hoon, Anne Van Hecken, Lucy Yan, Liviawati Sutjandra Wu, Lisa Hamilton, Gabriel Vargas
PURPOSE: Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. METHODS: Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined...
September 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28421387/pharmacokinetics-of-monoclonal-antibodies-and-fc-fusion-proteins
#6
REVIEW
Liming Liu
There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1-2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life...
April 19, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28411280/interrelationships-between-infliximab-and-recombinant-tumor-necrosis-factor-%C3%AE-in-plasma-using-minimal-physiologically-based-pharmacokinetic-models
#7
Xi Chen, Debra C DuBois, Richard R Almon, William J Jusko
The soluble cytokine tumor necrosis factor-α (TNF-α) is an important target for many therapeutic proteins used in the treatment of rheumatoid arthritis. Biologics targeting TNF-α exert their pharmacologic effects through binding and neutralizing this cytokine and preventing it from binding to its cell surface receptors. The magnitude of their pharmacologic effects directly corresponds to the extent and duration of free TNF-α suppression. However, endogenous TNF-α is of low abundance, so it is quite challenging to assess the free TNF-α suppression experimentally...
July 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28401480/target-mediated-drug-disposition-pharmacokinetic-pharmacodynamic-model-of-bosentan-and-endothelin-1
#8
Anke-Katrin Volz, Andreas Krause, Walter Emil Haefeli, Jasper Dingemanse, Thorsten Lehr
BACKGROUND AND OBJECTIVES: Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model...
April 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28332443/migration-assessment-and-the-threshold-of-toxicological-concern-applied-to-the-safe-design-of-an-acrylic-adhesive-for-food-contact-laminates
#9
Elena Canellas, Paula Vera, Cristina Nerín
The suitability of an acrylic adhesive used on food packaging was studied. Six potential migrants were identified using GC-MS and UPLC-QTOF. Five compounds were intentionally added (2-butoxyethanol and 2,4,7,9-tetramethyl-5-decyne-4,7-diol 10 (TMDD) and TMDD ethoxylates). One of the compounds identified as 2-(12-(methacryloyloxy) dodecyl)malonic acid was a non -intentionally added substance (NIAS), which could be a methyl metacrylate derivative. A migration study from multilayers containing paper-adhesive-film was carried out...
April 7, 2017: Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment
https://www.readbyqxmd.com/read/28144911/pharmacokinetic-steady-states-highlight-interesting-target-mediated-disposition-properties
#10
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
#11
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...
February 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
#12
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...
February 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
#13
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
#14
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)...
May 2017: 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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