placeholder
and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Document type
Language
Year
  • 1
    Language: English
    In: Journal of pharmaceutical sciences, 2002-01, Vol.91 (1), p.129-156
    Description: In drug discovery and nonclinical development the volume of distribution at steady state (Vss) of each novel drug candidate is commonly determined under in vivo conditions. Therefore, it is of interest to predict Vss without conducting in vivo studies. The traditional description of Vss corresponds to the sum of the products of each tissue:plasma partition coefficient (Pt:p) and the respective tissue volume in addition to the plasma volume. Because data on volumes of tissues and plasma are available in the literature for mammals, the other input parameters needed to estimate Vss are the Pt:p's, which can potentially be predicted with established tissue composition‐based equations. In vitro data on drug lipophilicity and plasma protein binding are the input parameters used in these equations. Such a mechanism‐based approach would be particularly useful to provide first‐cut estimates of Vss prior to any in vivo studies and to explore potential unexpected deviations between sets of predicted and in vivo Vss data, when the in vivo data become available during the drug development process. The objective of the present study was to use tissue composition‐based equations to predict rat and human Vss prior to in vivo studies for 123 structurally unrelated compounds (acids, bases, and neutrals). The predicted data were compared with in vivo data obtained from the literature or at Roche. Overall, the average ratio of predicted‐to‐experimental rat and human Vss values was 1.06 (SD = 0.817, r = 0.78, n = 147). In fact, 80% of all predicted values were within a factor of two of the corresponding experimental values. The drugs can therefore be separated into two groups. The first group contains 98 drugs for which the predicted Vss were within a factor of two of those experimentally determined (average ratio of 1.01, SD = 0.39, r = 0.93, n = 118), and the second group includes 25 other drugs for which the predicted and experimental Vss differ by a factor larger than two (average ratio of 1.32, SD = 1.74, r = 0.42, n = 29). Thus, additional relevant distribution processes were neglected in predicting Vss of drugs of the second group. This was true especially in the case of some cationic‐amphiphilic bases. The present study is the first attempt to develop and validate a mechanistic distribution model for predicting rat and human Vss of drugs prior to in vivo studies. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:129–156, 2002
    Subject(s): animal alternatives ; Animals ; Biological and medical sciences ; Chemical Phenomena ; Chemistry, Physical ; disposition ; drug discovery ; General pharmacology ; Humans ; Medical sciences ; Models, Biological ; Models, Chemical ; partition coefficients ; PBPK modeling ; Pharmaceutical Preparations - administration & dosage ; Pharmaceutical Preparations - metabolism ; Pharmacokinetics ; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions ; Pharmacology. Drug treatments ; physiologically-based pharmacokinetics ; QSAR ; Rats ; Tissue Distribution ; toxicokinetics
    ISSN: 0022-3549
    E-ISSN: 1520-6017
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: mAbs, 2011-01-01, Vol.3 (1), p.61-66
    Description: The pharmacokinetics (PK) of therapeutic antibodies is determined by target and non-target mediated mechanisms. These antibody-specific factors need to be considered during prediction of human PK based upon preclinical information. Principles of allometric scaling established for small molecules using data from multiple animal species cannot be directly applied to antibodies. Here, different methods for projecting human clearance (CL) from animal PK data for 13 therapeutic monoclonal antibodies (mAbs) exhibiting linear PK over the tested dose ranges were examined: simple allometric scaling (CL versus body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent and scaling from only cynomolgus monkey PK data. A better correlation was obtained between the observed human CL and the estimated human CL based on cynomolgus monkey PK data and an allometric scaling exponent of 0.85 for CL than other scaling approaches. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 0.85 for CL and 1.0 for volume of distribution. In conclusion, we expanded our previous work and others and further confirmed that PK from cynomolgus monkey alone can be successfully scaled to project human PK profiles within linear range using simplify allometry and Dedrick plots with fixed exponent.
    Subject(s): Algorithms ; allometric scaling ; Animals ; Antibodies, Monoclonal - blood ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Monoclonal - therapeutic use ; Antibodies, Monoclonal, Humanized ; Binding ; Biology ; Bioscience ; Calcium ; Cancer ; Cell ; clearance ; Cycle ; Drug Evaluation, Preclinical ; Humans ; Landes ; Macaca fascicularis ; Metabolic Clearance Rate ; Mice ; Models, Biological ; monoclonal antibody ; Organogenesis ; pharmacokinetics ; Proteins ; Rats ; Report ; Species Specificity ; species-invariant time method
    ISSN: 1942-0862
    E-ISSN: 1942-0870
    Source: Taylor & Francis Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: mAbs, 2012-11-01, Vol.4 (6), p.753-760
    Description: A majority of human therapeutic antibody candidates show pharmacokinetic properties suitable for clinical use, but an unexpectedly fast antibody clearance is sometimes observed that may limit the clinical utility. Pharmacokinetic data in cynomolgus monkeys collected for a panel of 52 antibodies showed broad distribution of target-independent clearance values (2.4-61.3 mL/day/kg), with 15 (29%) having clearance 〉 10 mL/day/kg. Alteration in the interaction with the recycling FcRn receptor did not account for the faster than expected clearance observed for the antibodies; off-target binding was presumed to account for the fast clearance. We developed an assay based on ELISA detection of non-specific binding to baculovirus particles that can identify antibodies having increased risk for fast clearance. This assay can be used during lead generation or optimization to identify antibodies with increased risk of having fast clearance in both humans and cynomolgus monkeys, and thus increase the likelihood of obtaining a suitable drug candidate.
    Subject(s): Animals ; Antibodies, Monoclonal - metabolism ; antibody ; Baculoviridae - immunology ; baculovirus ; Binding ; Biology ; Bioscience ; Calcium ; Cancer ; Cell ; Cycle ; Drug Discovery ; Enzyme-Linked Immunosorbent Assay ; FcRn ; Humans ; Landes ; Macaca fascicularis ; Metabolic Clearance Rate ; non-specific binding ; Organogenesis ; pharmacokinetics ; Protein Binding ; Proteins ; Report ; Risk Adjustment ; Virion - metabolism
    ISSN: 1942-0862
    E-ISSN: 1942-0870
    Source: Taylor & Francis Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    Language: English
    In: Journal of immunology research, 2016-08-08, Vol.2016, p.2342187-9
    Description: Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents.
    Subject(s): Animals ; Biological Products - adverse effects ; Biological Products - immunology ; Biological Products - pharmacokinetics ; Biological Products - pharmacology ; Computer Simulation ; Disease Management ; Humans ; Immunologic Factors - immunology ; Immunologic Factors - pharmacology ; Immunomodulation ; Models, Biological ; Models, Immunological ; Protein Engineering ; Proteins - adverse effects ; Proteins - immunology ; Proteins - pharmacokinetics ; Proteins - pharmacology ; Review ; Risk Factors ; Treatment Outcome
    ISSN: 2314-8861
    E-ISSN: 2314-7156
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Language: English
    In: Biopharmaceutics & drug disposition, 2016-03, Vol.37 (2), p.75-92
    Description: The mechanisms of absorption, distribution, metabolism and elimination of small and large molecule therapeutics differ significantly from one another and can be explored within the framework of a physiologically based pharmacokinetic (PBPK) model. This paper briefly reviews fundamental approaches to PBPK modeling, in which drug kinetics within tissues and organs are explicitly represented using physiologically meaningful parameters. The differences in PBPK models applied to small/large molecule drugs are highlighted, thus elucidating differences in absorption, distribution and elimination properties between these two classes of drugs in a systematic manner. The absorption of small and large molecules differs with respect to their common extravascular routes of delivery (oral versus subcutaneous). The role of the lymphatic system in drug distribution, and the involvement of tissues as sites of elimination (through catabolism and target mediated drug disposition) are unique features of antibody distribution and elimination that differ from small molecules, which are commonly distributed into the tissues but are eliminated primarily by liver metabolism. Fundamental differences exist in the ability to predict human pharmacokinetics based upon preclinical data due to differing mechanisms governing small and large molecule disposition. These differences have influence on the evolving utilization of PBPK modeling in the discovery and development of small and large molecule therapeutics. Copyright © 2015 John Wiley & Sons, Ltd.
    Subject(s): Animals ; Antibodies ; Antibodies, Monoclonal - pharmacokinetics ; Biopharmaceutics ; Health aspects ; Humans ; Models ; Models, Biological ; PBPK ; small molecules ; Viral antibodies
    ISSN: 0142-2782
    E-ISSN: 1099-081X
    Source: Hellenic Academic Libraries Link
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: British journal of pharmacology, 2012-05, Vol.166 (1), p.368-377
    Description: BACKGROUND AND PURPOSE Neuropilin‐1 (NRP1) is a VEGF receptor that is widely expressed in normal tissues and is involved in tumour angiogenesis. MNRP1685A is a rodent and primate cross‐binding human monoclonal antibody against NRP1 that exhibits inhibition of tumour growth in NPR1‐expressing preclinical models. However, widespread NRP1 expression in normal tissues may affect MNRP1685A tumour uptake. The objective of this study was to assess MNRP1685A biodistribution in tumour‐bearing mice to understand the relationships between dose, non‐tumour tissue uptake and tumour uptake. EXPERIMENTAL APPROACH Non‐tumour‐bearing mice were given unlabelled MNRP1685A at 10 mg·kg−1. Tumour‐bearing mice were given 111In‐labelled MNRP1685A along with increasing amounts of unlabelled antibody. Blood and tissues were collected from all animals to determine drug concentration (unlabelled) or radioactivity level (radiolabelled). Some animals were imaged using single photon emission computed tomography – X‐ray computed tomography. KEY RESULTS MNRP1685A displayed faster serum clearance than pertuzumab, indicating that target binding affected MNRP1685A clearance. I.v. administration of 111In‐labelled MNRP1685A to tumour‐bearing mice yielded minimal radioactivity in the plasma and tumour, but high levels in the lungs and liver. Co‐administration of unlabelled MNRP1685A with the radiolabelled antibody was able to competitively block lungs and liver radioactivity uptake in a dose‐dependent manner while augmenting plasma and tumour radioactivity levels. CONCLUSIONS AND IMPLICATIONS These results indicate that saturation of non‐tumour tissue uptake is required in order to achieve tumour uptake and acceptable exposure to antibody. Utilization of a rodent and primate cross‐binding antibody allows for translation of these results to clinical settings.
    Subject(s): Animals ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Monoclonal, Humanized - pharmacokinetics ; antibody ; biodistribution ; Biological and medical sciences ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - pathology ; dose escalation ; Dose-Response Relationship, Drug ; Female ; Humans ; Indium Radioisotopes - chemistry ; Iodine Radioisotopes - chemistry ; Medical sciences ; Mice ; Mice, Nude ; Multimodal Imaging - methods ; Neoplasms, Experimental ; neuropilin-1 ; Neuropilin-1 - immunology ; Pharmacology. Drug treatments ; Positron-Emission Tomography ; Research Papers ; Tissue Distribution ; Tomography, X-Ray Computed
    ISSN: 0007-1188
    E-ISSN: 1476-5381
    Source: Academic Search Ultimate
    Source: Wiley Online Library All Journals
    Source: PubMed Central
    Source: Get It Now
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: Journal of immunology research, 2016-08-23, Vol.2016, p.8141269-2
    Subject(s): Animals ; Antibodies, Monoclonal - adverse effects ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - therapeutic use ; Biological Products - adverse effects ; Biological Products - immunology ; Biological Products - therapeutic use ; Biological Therapy - adverse effects ; Biological Therapy - methods ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Isoantibodies - blood ; Isoantibodies - immunology ; Proteins - adverse effects ; Proteins - immunology ; Proteins - therapeutic use ; Treatment Outcome
    ISSN: 2314-8861
    E-ISSN: 2314-7156
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    Language: English
    In: mAbs, 2012-03-01, Vol.4 (2), p.243-255
    Description: Subcutaneous (SC) delivery is a common route of administration for therapeutic monoclonal antibodies (mAbs) with pharmacokinetic (PK)/pharmacodynamic (PD) properties requiring long-term or frequent drug administration. An ideal in vivo preclinical model for predicting human PK following SC administration may be one in which the skin and overall physiological characteristics are similar to that of humans. In this study, the PK properties of a series of therapeutic mAbs following intravenous (IV) and SC administration in Göttingen minipigs were compared with data obtained previously from humans. The present studies demonstrated: (1) minipig is predictive of human linear clearance; (2) the SC bioavailabilities in minipigs are weakly correlated with those in human; (3) minipig mAb SC absorption rates are generally higher than those in human and (4) the SC bioavailability appears to correlate with systemic clearance in minipigs. Given the important role of the neonatal Fc-receptor (FcRn) in the PK of mAbs, the in vitro binding affinities of these IgGs against porcine, human and cynomolgus monkey FcRn were tested. The result showed comparable FcRn binding affinities across species. Further, mAbs with higher isoelectric point tended to have faster systemic clearance and lower SC bioavailability in both minipig and human. Taken together, these data lend increased support for the use of the minipig as an alternative predictive model for human IV and SC PK of mAbs.
    Subject(s): Administration, Intravenous ; animal model ; Animals ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Monoclonal - pharmacology ; Binding ; Biology ; Bioscience ; Calcium ; Cancer ; Cell ; Cycle ; Female ; Humans ; Injections, Subcutaneous ; Landes ; mAb IgG ; Male ; minipig ; Models, Immunological ; neonatal Fc receptor (FcRn) ; Organogenesis ; pharmacokinetics ; Proteins ; Report ; subcutaneous bioavailability ; Swine ; Swine, Miniature
    ISSN: 1942-0862
    E-ISSN: 1942-0870
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    In: mAbs, 2012-01-01, Vol.4 (1), p.101-109
    Description: The neonatal Fc receptor (FcRn) plays an important and well-known role in immunoglobulin G (IgG) catabolism; however, its role in the disposition of IgG after subcutaneous (SC) administration, including bioavailability, is relatively unknown. To examine the potential effect of FcRn on IgG SC bioavailability, we engineered three anti-amyloid β monoclonal antibody (mAb) reverse chimeric mouse IgG2a (mIgG2a) Fc variants (I253A.H435A, N434H and N434Y) with different binding affinities to mouse FcRn (mFcRn) and compared their SC bioavailability to that of the wild-type (WT) mAb in mice. Our results indicated that the SC bioavailability of mIgG2a was affected by mFcRn-binding affinity. Variant I253A.H435A, which did not bind to mFcRn at either pH 6.0 or pH 7.4, had the lowest bioavailability (41.8%). Variant N434Y, which had the greatest increase in binding affinity at both pH 6.0 and pH 7.4, had comparable bioavailability to the WT antibody (86.1% vs. 76.3%), whereas Variant N434H, which had modestly increased binding affinity at pH 6.0 to mFcRn and affinity comparable to the WT antibody at pH 7.4, had the highest bioavailability (94.7%). A semi-mechanism-based pharmacokinetic model, which described well the observed data with the WT antibody and variant I253A.H435A, is consistent with the hypothesis that the decreased bioavailability of variant I253A.H435A was due to loss of the FcRn-mediated protection from catabolism at the absorption site. Together, these data demonstrate that FcRn plays an important role in SC bioavailability of therapeutic IgG antibodies.
    Subject(s): Animals ; Antibodies, Monoclonal - genetics ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - metabolism ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Monoclonal - therapeutic use ; Antibody Affinity - immunology ; Binding ; binding affinity ; Biological Availability ; Biology ; Bioscience ; Calcium ; Cancer ; Cell ; Cycle ; FcRn ; Histocompatibility Antigens Class I - metabolism ; Humans ; Immunoglobulin G - genetics ; Immunoglobulin G - immunology ; Immunoglobulin G - metabolism ; Injections, Subcutaneous ; Landes ; Mice ; Mice, SCID ; monoclonal antibody ; Organogenesis ; Protein Binding ; Proteins ; Receptors, Fc - metabolism ; Report ; semi-mechanism-based pharmacokinetic model ; subcutaneous bioavailability
    ISSN: 1942-0862
    E-ISSN: 1942-0870
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: PloS one, 2011-03-15, Vol.6 (3), p.e17874
    Description: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p〉0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p〉0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (〉25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice. These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.
    Subject(s): Angiogenesis ; Animal models ; Animal tissues ; Animals ; Antibodies ; Antibodies - administration & dosage ; Antibodies - pharmacology ; Antigens ; Area Under Curve ; Biology ; Blood ; Blood flow ; Blood Vessels - drug effects ; Cancer ; Cell Fractionation ; Chemistry ; Computed tomography ; Computer Simulation ; Drug delivery systems ; Drug development ; Drugs ; Emission analysis ; Erythrocytes - diagnostic imaging ; Erythrocytes - drug effects ; Flow rates ; Flow velocity ; Glycoproteins ; Hemorheology - drug effects ; Homeopathy ; Immunoglobulins ; Immunology ; Indium ; Intravenous administration ; Kinetics ; Materia medica and therapeutics ; Mathematical models ; Medicine ; Melanoma ; Mice ; Models ; Organ Size - drug effects ; Permeability ; Pharmaceuticals ; Pharmacology ; Photon emission ; Physiological aspects ; Physiology ; Plasma ; Prediction models ; Quantitative analysis ; Radiochemistry ; Radioisotopes ; Regional Blood Flow - drug effects ; Rubidium ; Studies ; Technetium ; Therapeutics ; Tissue Distribution - drug effects ; Tomography ; Tomography, Emission-Computed, Single-Photon ; Tomography, X-Ray Computed ; Tumors ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factors - antagonists & inhibitors ; Viral antibodies
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...