Kraynov E.,Pfizer |
Kamath A.V.,Genentech |
Walles M.,Novartis |
Tarcsa E.,Drug Metabolism |
And 13 more authors.
Drug Metabolism and Disposition | Year: 2016
An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs. ©2016 by The American Society for Pharmacology and Experimental Therapeutics.
Zheng J.,Drug Metabolism |
Pflanz S.,Biology |
Frey C.R.,Biology |
Hesselgesser J.,Clinical Virology and Medicinal Chemistry |
And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2014
GS-9620 [8-(3-(pyrrolidin-1-ylmethyl)benzyl)-4-amino-2-butoxy-7,8- dihydropteridin-6(5H)-one] is a potent, orally bioavailable small-molecule agonist of Toll-like receptor 7 (TLR7) developed for finite treatment of chronic hepatitis B viral (HBV) infection, with the goal of inducing a liver-targeted antiviral effect without inducing the adverse effects associated with current systemic interferon-a (IFN-a) therapies. We characterized the pharmacodynamic response of GS-9620 in CD-1 mice and cynomolgus monkeys following intravenous or oral administration and showed that GS-9620 induces the production of select chemokines and cytokines, including IFN-a and interferon-stimulated genes (ISGs). It is noteworthy that we also demonstrated that, in animals and healthy human volunteers, oral administration of GS-9620 can induce a type I interferon-dependent antiviral innate immune response, as measured by whole-blood mRNA of the ISGs 2959-oligoadenylate synthetase 1 (OAS1) and myxovirus resistance 1 (MX1), without the induction of detectable systemic IFN-a, i.e., a presystemic response. Additionally, presystemic induction of hepatic OAS1 and MX1 mRNA was observed in CD-1 mice in the absence of detectable systemic IFN-a. We propose that the mechanism of this presystemic response is likely its high intestinal absorption,which facilitates localized activation of TLR7, probably in plasmacytoid dendritic cells at the level of gut-associated lymphoid tissue and/or the liver. This localized response is further supported by data that indicate onlyminimal contributions of systemic immune stimulation to the overall pharmacodynamic response to orally administered GS-9620. These data demonstrate that GS-9620 can induce an antiviral innate immune response without inducing a systemic IFN-a response and thus suggest the therapeutic potential of this approach in the treatment of chronic HBV infection. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Shebley M.,Drug Metabolism |
Shebley M.,Abbvie Inc. |
Liu J.,Drug Metabolism |
Kavetskaia O.,Drug Metabolism |
And 5 more authors.
Drug Metabolism and Disposition | Year: 2017
To assess drug-drug interaction (DDI) potential for the three direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir, and paritaprevir, in vitro studies profiled drug-metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, organic anion-transporting polypeptide (OATP) 1B1/1B3, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp). Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations, but additional physiologically based pharmacokinetic modeling was necessary to achieve the same for drug transporters. When perpetrator interactions were assessed, ritonavir was responsible for the strong increase in exposure of sensitive CYP3A substrates, whereas paritaprevir (an OATP1B1/1B3 inhibitor) greatly increased the exposure of sensitive OATP1B1/1B3 substrates. The 3D regimen drugs are UGT1A1 inhibitors and are predicted to moderately increase plasma exposure of sensitive UGT1A1 substrates. Paritaprevir, ritonavir, and dasabuvir are BCRP inhibitors. Victim DDI predictions were qualitatively in line with the clinical observations. Plasma exposures of the 3D regimen were reduced by strong CYP3A inducers (paritaprevir and ritonavir; major CYP3A substrates) but were not affected by strong CYP3A4 inhibitors, since ritonavir (a CYP3A inhibitor) is already present in the regimen. Strong CYP2C8 inhibitors increased plasma exposure of dasabuvir (a major CYP2C8 substrate), OATP1B1/1B3 inhibitors increased plasma exposure of paritaprevir (an OATP1B1/1B3 substrate), and P-gp or BCRP inhibitors (all compounds are substrates of P-gp and/or BCRP) increased plasma exposure of the 3D regimen. Overall, the comprehensive mechanistic assessment of compound disposition along with mechanistic and PBPK approaches to predict victim and perpetrator DDI liability may enable better clinical management of nonstudied drug combinations with the 3D regimen. Copyright © 2017 by The Author(s).
Lee C.A.,QPS DMPK Hepatic Biosciences |
Kalvass J.C.,Drug Metabolism |
Galetin A.,University of Manchester |
Clinical Pharmacology and Therapeutics | Year: 2014
The "P-glycoprotein" IC 50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC 50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC 50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC 50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.
Wen B.,Drug Metabolism |
Wen B.,Glaxosmithkline |
Roongta V.,Hoffmann-La Roche |
Liu L.,Drug Metabolism |
Moore D.J.,Drug Metabolism
Drug Metabolism and Disposition | Year: 2014
Evodiamine and rutaecarpine are the main active indoloquinazoline alkaloids of the herbal medicine Evodia rutaecarpa, which is widely used for the treatment of hypertension, abdominal pain, angina pectoris, gastrointestinal disorder, and headache. Immunosuppressive effects and acute toxicity were reported in mice treated with evodiamine and rutaecarpine. Although the mechanism remains unknown, it is proposed that metabolic activation of the indoloquinazoline alkaloids and subsequent covalent binding of reactive metabolites to cellular proteins play a causative role. Liquid chromatography-tandem mass spectrometry analysis of incubations containing evodiamine and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed formation of a major GSH conjugate which was subsequently indentified as a benzylic thioether adduct on the C-8 position of evodiamine by NMR analysis. Several other GSH conjugates were also detected, including conjugates of oxidized and demethylated metabolites of evodiamine. Similar GSH conjugates were formed in incubations with rutaecarpine. These findings are consistent with a bioactivation sequence involving initial cytochrome P450-catalyzed dehydrogenation of the 3-alkylindole moiety in evodiamine and rutaecarpine to an electrophile 3-methyleneindolenine. Formation of the evodiamine and rutaecarpine GSH conjugates was primarily catalyzed by heterologously expressed recombinant CYP3A4 and, to a lesser extent, CYP1A2 and CYP2D6, respectively. It was found that the 3-methyleneindolenine or another reactive intermediate was a mechanism- based inactivator of CYP3A4, with inactivation parameters KI = 29 μM and kinact = 0.029 minute-1, respectively. In summary, these findings are of significance in understanding the bioactivation mechanisms of indoloquinazoline alkaloids, and dehydrogenation of evodiamine and rutaecarpine may cause toxicities through formation of electrophilic intermediates and lead to drug-drug interactions mainly via CYP3A4 inactivation. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
Locatelli G.,Nerviano Medical science S.r.l |
Bosotti R.,Nerviano Medical science S.r.l |
Ciomei M.,Nerviano Medical science S.r.l |
Brasca M.G.,Nerviano Medical science S.r.l |
And 12 more authors.
Molecular Cancer Therapeutics | Year: 2010
A transcriptional signature of the pan-cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors.
News Article | August 22, 2016
The Center for Environmental Health Sciences (CEHS) at MIT held its annual poster session on May 4 in the Walker Memorial Building. The session highlighted the work of the environmental health research communities of MIT and some peer institutions. Approximately 50 posters were presented from the science and engineering laboratories affiliated with CEHS. The CEHS has an overall mission to study the biological effects of exposure to environmental agents in order to understand and predict how such exposures affect human health. Moreover, by uncovering the chemical, biochemical, and genetic bases for environmental disease, sometimes researchers are able to leverage that understanding to delay or even prevent the development of disease in human populations. To that end, the center brings together 39 MIT faculty members from a total of nine MIT departments in both the School of Science and the School of Engineering, plus one Harvard University faculty member from the Harvard School of Public Health. This year’s CEHS cash prizes were awarded in two categories, graduate students and postdocs. For each category, the prize for first-place was $1,000; second-place was $500, and third-place was $200 plus CEHS memorabilia. The cash prizes were made possible by the Myriam Marcelle Znaty Research Fund, which was established over 30 years ago to support the research of young scientists at MIT. Graduate students, postdocs, and research staff presented the results of their research at MIT's Morss Hall. Anthony R. Soltis from Professor Ernest Fraenkel’s lab won first place in the graduate student category. Soltis presented his work on the “Multi-Omic Data Collection and Integrative Modeling of High-Fat Diet-Induced Obesity Reveals Features of Hepatic Insulin Resistance.” In second place was Joseph M. Azzarelli and Rong Zhu from Professor Timothy Swager’s lab, who presented their work on “Wireless Hazard Badges for Organophosphate Acetylcholinesterase Inhibitors.” Finally, in third place was Chen Gu, from Professor Peter Dedon’s lab, presenting his work on “Phosphorylation of Human TRM9L Modulates its Functions in Oxidative Stress Management and Tumor Growth Suppression.” In the postdoc category, first place went to Collin Edington and Xin Wang from professors Linda Griffith and Steven R. Tannenbaum labs (respectively), presenting on “Construction and Evaluation of the In Vitro Central Nervous System Models.” Second place went to Renan Escalante-Chong, from Professor Ernest Fraenkel's lab, who presented his work on “Integrative Approaches for Cell Signature Generation in ALS Patients at NeuroLINCS.” And Nikolaos Tsamandouras, from Professor Linda Griffith’s lab, took third place after presenting his work on “Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused 3-D human Liver Bioreactor Along with Modeling and Simulation Techniques.”
Yang C.,Georgia State University |
Gundala S.R.,Georgia State University |
Mukkavilli R.,Drug Metabolism |
Mukkavilli R.,Manipal University India |
And 3 more authors.
Carcinogenesis | Year: 2015
Phytochemical complexity of plant extracts may offer health-promoting benefits including chemotherapeutic and chemopreventive effects. Isolation of 'most-active fraction' or single constituents from whole extracts may not only compromise the therapeutic efficacy but also render toxicity, thus emphasizing the importance of preserving the natural composition of whole extracts. The leaves of Annona muricata, commonly known as Graviola, are known to be rich in flavonoids, isoquinoline alkaloids and annonaceous acetogenins. Here, we demonstrate phytochemical synergy among the constituents of Graviola leaf extract (GLE) compared to its flavonoid-enriched (FEF) and acetogenin-enriched (AEF) fractions. Comparative quantitation of flavonoids revealed enrichment of rutin (~7-fold) and quercetin-3-glucoside (Q-3-G, ~3-fold) in FEF compared to GLE. In vivo pharmacokinetics and in vitro absorption kinetics of flavonoids revealed enhanced bioavailability of rutin in FEF compared to GLE. However, GLE was more effective in inhibiting in vitro prostate cancer proliferation, viability and clonogenic capacity compared to FEF. Oral administration of 100 mg/kg bw GLE showed ~1.2-fold higher tumor growth-inhibitory efficacy than FEF in human prostate tumor xenografts although the concentration of rutin and Q-3-G was more in FEF. Contrarily, AEF, despite its superior in vitro and in vivo efficacy, resulted in death of the mice due to toxicity. Our data indicate that despite lower absorption and bioavailability of rutin, maximum efficacy was achieved in the case of GLE, which also comprises of other phytochemical groups including acetogenins that make up its natural complex environment. Hence, our study emphasizes on evaluating the nature of interactions among Graviola leaf phytochemcials for developing favorable dose regimen for prostate cancer management to achieve optimal therapeutic benefits. © The Author 2015. Published by Oxford University Press.
PubMed | Manipal University India, Emory University, Georgia State University and Drug Metabolism
Type: Journal Article | Journal: Carcinogenesis | Year: 2015
Phytochemical complexity of plant extracts may offer health-promoting benefits including chemotherapeutic and chemopreventive effects. Isolation of most-active fraction or single constituents from whole extracts may not only compromise the therapeutic efficacy but also render toxicity, thus emphasizing the importance of preserving the natural composition of whole extracts. The leaves of Annona muricata, commonly known as Graviola, are known to be rich in flavonoids, isoquinoline alkaloids and annonaceous acetogenins. Here, we demonstrate phytochemical synergy among the constituents of Graviola leaf extract (GLE) compared to its flavonoid-enriched (FEF) and acetogenin-enriched (AEF) fractions. Comparative quantitation of flavonoids revealed enrichment of rutin (~7-fold) and quercetin-3-glucoside (Q-3-G, ~3-fold) in FEF compared to GLE. In vivo pharmacokinetics and in vitro absorption kinetics of flavonoids revealed enhanced bioavailability of rutin in FEF compared to GLE. However, GLE was more effective in inhibiting in vitro prostate cancer proliferation, viability and clonogenic capacity compared to FEF. Oral administration of 100mg/kg bw GLE showed ~1.2-fold higher tumor growth-inhibitory efficacy than FEF in human prostate tumor xenografts although the concentration of rutin and Q-3-G was more in FEF. Contrarily, AEF, despite its superior in vitro and in vivo efficacy, resulted in death of the mice due to toxicity. Our data indicate that despite lower absorption and bioavailability of rutin, maximum efficacy was achieved in the case of GLE, which also comprises of other phytochemical groups including acetogenins that make up its natural complex environment. Hence, our study emphasizes on evaluating the nature of interactions among Graviola leaf phytochemcials for developing favorable dose regimen for prostate cancer management to achieve optimal therapeutic benefits.
Piparia R.,Abbott Laboratories |
Ouellette D.,Abbott Laboratories |
Stine W.B.,Abbott Laboratories |
Grinnell C.,Drug Metabolism |
And 3 more authors.
mAbs | Year: 2012
Therapeutic proteins circulating in blood are in a highly crowded, redox environment at high temperatures of ~37° C. These molecules circulate in the presence of enzymes and other serum proteins making it difficult to predict from in vitro studies the stability, aggregation or pharmacokinetics of a therapeutic protein in vivo. Here, we describe use of a high throughput capillary electrophoresis based microfluidic device (LabChip GXII) to obtain pharmacokinetics (PK) of a fluorescently labeled human mAb directly from serum. The non-labeled and labeled mAbs were evaluated in single dose rat PK studies using a traditional ELISA method or LabChip GXII, respectively. The fluorescent dye did not significantly alter clearance of this particular mAb, and PK parameters were comparable for labeled and unlabeled molecules. Further, from the CE profile we concluded that the mAb was resistant to fragmentation or aggregation during circulation. In a follow-up experiment, dimers were generated from the mAb using photo-induced cross-linking of unmodified proteins (PICUP) and labeled with the same fluorophore. The extent of dimerization was incomplete and some monomer and higher molecular weight species were found in the preparation. In rat PK studies, the serum concentration-time profile of the three entities present in the dimer preparation could be followed simultaneously with the GXII technology. While further studies are warranted, we believe this method could be adapted to obtain PK of different forms of antibodies (oxidized, deamidated or various glycosylated species) and other proteins. © 2012 Landes Bioscience.