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https://www.readbyqxmd.com/read/29725996/population-pharmacokinetic-analysis-of-alirocumab-in-healthy-volunteers-or-hypercholesterolemic-subjects-using-a-michaelis-menten-approximation-of-a-target-mediated-drug-disposition-model-support-for-a-biologics-license-application-submission-part-i
#1
Jean-Marie Martinez, Aurélie Brunet, Fabrice Hurbin, A Thomas DiCioccio, Clémence Rauch, David Fabre
BACKGROUND: Alirocumab, a human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to significantly reduce low-density lipoprotein cholesterol levels; pharmacokinetics (PK) are governed by non-linear, target-mediated drug disposition (TMDD). OBJECTIVES: We aimed to develop and qualify a population PK (PopPK) model to characterize the PK profile of alirocumab, evaluate the impact of covariates on alirocumab PK and on individual patient exposures, and estimate individual predicted concentrations for a subsequent PK/pharmacodynamic (PD) analysis...
May 3, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29675601/asymptotic-analysis-of-a-tmdd-model-when-a-reaction-contributes-to-the-destruction-of-its-product
#2
Lida I Michalaki, Dimitris A Goussis
The multi-scale dynamics of a two-compartment with first order absorption Target-Mediated Drug Disposition (TMDD) pharmacokinetics model is analysed, using the Computational Singular Perturbation (CSP) algorithm. It is shown that the process evolves along two Slow Invariant Manifolds (SIMs), on which the most intense components of the model are equilibrated, so that the less intensive are the driving ones. The CSP tools allow for the identification of the components of the TMDD model that (i) constrain the evolution of the process on the SIMs, (ii) drive the system along the SIMs and (iii) generate the fast time scales...
April 19, 2018: Journal of Mathematical Biology
https://www.readbyqxmd.com/read/29649283/design-and-preclinical-characterization-of-alxn1210-a-novel-anti-c5-antibody-with-extended-duration-of-action
#3
Douglas Sheridan, Zhao-Xue Yu, Yuchun Zhang, Rekha Patel, Fang Sun, Melissa A Lasaro, Keith Bouchard, Bruce Andrien, Andre Marozsan, Yi Wang, Paul Tamburini
Eculizumab, a monoclonal antibody (mAb) directed against complement protein C5, is considered to be the current standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. This study describes the generation and preclinical attributes of ALXN1210, a new long-acting anti-C5 mAb, obtained through select modifications to eculizumab to both largely abolish target-mediated drug disposition (TMDD) and increase recycling efficiency via the neonatal Fc receptor (FcRn)...
2018: PloS One
https://www.readbyqxmd.com/read/29571739/title-translational-pk-pd-characterization-and-tmdd-modeling-of-an-anti-tfpi-antibody-pf-06741086
#4
Chuenlei Parng, Pratap Singh, Debra D Pittman, Katherine Wright, Beth Leary, Sunita Patel-Hett, Swapnil Rakhe, James Stejskal, Marjorie Peraza, Dawn Dufield, John E Murphy, Robert Webster
Tissue factor pathway inhibitor (TFPI) exhibits multiple isoforms which are known to present in multiple locations such as plasma, endothelium and platelets. TFPI is an endogenous negative modulator of the coagulation pathway, and therefore neutralization of TFPI function can potentially increase coagulation activity. A human monoclonal antibody, PF-06741086, which interacts with all isoforms of TFPI is currently being tested in clinic for treating hemophilia patients with and without inhibitors. To support clinical development of PF-06741086, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06741086 were characterized in monkeys...
March 20, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29420255/development-and-translational-application-of-a-minimal-physiologically-based-pharmacokinetic-model-for-a-monoclonal-antibody-against-interleukin-23-il-23-in-il-23-induced-psoriasis-like-mice
#5
Xi Chen, Xiling Jiang, Rajitha Doddareddy, Brian Geist, Thomas McIntosh, William J Jusko, Honghui Zhou, Weirong Wang
The interleukin (IL)-23/Th 17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic pharmacokinetics (PK)/pharmacodynamics (PD) study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like mouse model...
April 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28946506/the-effect-of-ultrasonic-vibration-and-surfactant-additive-on-fabrication-of-53-5gr-mm-silicon-echelle-grating-with-low-surface-roughness-in-alkaline-koh-solution
#6
Qingbin Jiao, Chunlin Zhu, Xin Tan, Xiangdong Qi, Bayanheshig
In the silicon echelle grating fabrication process, the "pseudo-mask" formed by the hydrogen bubbles generated during the etching process is the reason causing high surface roughness and poor surface quality of blazed plane. Based upon the ultrasonic mechanical effect and contact angle reduced by surfactant additive, ultrasonic vibration, isopropyl alcohol (IPA) and 2,4,7,9-Tetramethyl-5-decyne-4,7-diol (TMDD) were used to improve surface quality of 53.5gr/mm echelle grating. The surface roughness Rq is smaller than 18nm, 7nm and 2nm when using ultrasonic vibration, IPA and TMDD respectively...
January 2018: Ultrasonics Sonochemistry
https://www.readbyqxmd.com/read/28918570/mathematical-description-of-drug-target-interactions-application-to-biologics-that-bind-to-targets-with-two-binding-sites
#7
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...
February 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28876162/capacity-limits-of-asialoglycoprotein-receptor-mediated-liver-targeting
#8
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...
November 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
#9
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
#10
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...
October 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
#11
RANDOMIZED CONTROLLED TRIAL
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
#12
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...
January 2018: 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
#13
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
#14
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...
December 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
#15
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...
October 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
#16
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...
May 2017: AAPS Journal
https://www.readbyqxmd.com/read/28074396/target-mediated-drug-disposition-with-drug-drug-interaction-part-ii-competitive-and-uncompetitive-cases
#17
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
#18
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
#19
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)...
October 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
#20
RANDOMIZED CONTROLLED TRIAL
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
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