Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Further Considerations Towards an Effective and Efficient Oncology Drug Discovery DMPK Strategy

Author(s): Beth Williamson , Nicola Colclough, Adrian John Fretland, Barry Christopher Jones, Rhys Dafydd Owen Jones and Dermot Francis McGinnity *

Volume 21, Issue 2, 2020

Page: [145 - 162] Pages: 18

DOI: 10.2174/1389200221666200312104837

Price: $65

Abstract

Background: DMPK data and knowledge are critical in maximising the probability of developing successful drugs via the application of in silico, in vitro and in vivo approaches in drug discovery.

Methods: The evaluation, optimisation and prediction of human pharmacokinetics is now a mainstay within drug discovery. These elements are at the heart of the ‘right tissue’ component of AstraZeneca’s ‘5Rs framework’ which, since its adoption, has resulted in increased success of Phase III clinical trials. With the plethora of DMPK related assays and models available, there is a need to continually refine and improve the effectiveness and efficiency of approaches best to facilitate the progression of quality compounds for human clinical testing.

Results: This article builds on previously published strategies from our laboratories, highlighting recent discoveries and successes, that brings our AstraZeneca Oncology DMPK strategy up to date. We review the core aspects of DMPK in Oncology drug discovery and highlight data recently generated in our laboratories that have influenced our screening cascade and experimental design. We present data and our experiences of employing cassette animal PK, as well as re-evaluating in vitro assay design for metabolic stability assessments and expanding our use of freshly excised animal and human tissue to best inform first time in human dosing and dose escalation studies.

Conclusion: Application of our updated drug-drug interaction and central nervous system drug exposure strategies are exemplified, as is the impact of physiologically based pharmacokinetic and pharmacokinetic-pharmacodynamic modelling for human predictions.

Keywords: Drug discovery, ADME, drug metabolism, clearance, volume of distribution, bioavailability, pharmacokinetics, CNS exposure.

« Previous Next »
Graphical Abstract

[1]
Cook, D.; Brown, D.; Alexander, R.; March, R.; Morgan, P.; Satterthwaite, G.; Pangalos, M.N. Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nat. Rev. Drug Discov., 2014, 13(6), 419-431.
[http://dx.doi.org/10.1038/nrd4309] [PMID: 24833294]
[2]
Morgan, P.; Brown, D.G.; Lennard, S.; Anderton, M.J.; Barrett, J.C.; Eriksson, U.; Fidock, M.; Hamrén, B.; Johnson, A.; March, R.E.; Matcham, J.; Mettetal, J.; Nicholls, D.J.; Platz, S.; Rees, S.; Snowden, M.A.; Pangalos, M.N. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat. Rev. Drug Discov., 2018, 17(3), 167-181.
[http://dx.doi.org/10.1038/nrd.2017.244] [PMID: 29348681]
[3]
Ballard, P.; Brassil, P.; Bui, K.H.; Dolgos, H.; Petersson, C.; Tunek, A.; Webborn, P.J.H. Metabolism and pharmacokinetic optimization strategies in drug discovery. In: Drug Discovery and Development, 2nd ed.;; Hill, R.G.; Rang, H.P.; Eds.; Elsevier Ltd, London. , 2013; pp. 135-155.
[http://dx.doi.org/10.1016/B978-0-7020-4299-7.00010-X]
[4]
Grime, K.H.; Barton, P.; McGinnity, D.F. Application of in silico, in vitro and preclinical pharmacokinetic data for the effective and efficient prediction of human pharmacokinetics. Mol. Pharm., 2013, 10(4), 1191-1206.
[http://dx.doi.org/10.1021/mp300476z] [PMID: 23253040]
[5]
McGinnity, D.F.; Grime, K.H. ADME optimization in drug discovery. In: Comprehensive. Med. Chem., 2017, III, 34-44.
[6]
McGinnity, D.F.; Collington, J.; Austin, R.P.; Riley, R.J. Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs. Curr. Drug Metab., 2007, 8(5), 463-479.
[http://dx.doi.org/10.2174/138920007780866799] [PMID: 17584017]
[7]
Evers, B.; Drost, R.; Schut, E.; de Bruin, M.; van der Burg, E.; Derksen, P.W.B.; Holstege, H.; Liu, X.; van Drunen, E.; Beverloo, H.B.; Smith, G.C.M.; Martin, N.M.B.; Lau, A.; O’Connor, M.J.; Jonkers, J. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res., 2008, 14(12), 3916-3925.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-4953] [PMID: 18559613]
[8]
Rottenberg, S.; Jaspers, J.E.; Kersbergen, A.; van der Burg, E.; Nygren, A.O.H.; Zander, S.A.L.; Derksen, P.W.B.; de Bruin, M.; Zevenhoven, J.; Lau, A.; Boulter, R.; Cranston, A.; O’Connor, M.J.; Martin, N.M.B.; Borst, P.; Jonkers, J. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. USA, 2008, 105(44), 17079-17084.
[http://dx.doi.org/10.1073/pnas.0806092105] [PMID: 18971340]
[9]
Barf, T.; Covey, T.; Izumi, R.; van de Kar, B.; Gulrajani, M.; van Lith, B.; van Hoek, M.; de Zwart, E.; Mittag, D.; Demont, D.; Verkaik, S.; Krantz, F.; Pearson, P.G.; Ulrich, R.; Kaptein, A. Acalabrutinib (ACP-196): a covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J. Pharmacol. Exp. Ther., 2017, 363(2), 240-252.
[http://dx.doi.org/10.1124/jpet.117.242909] [PMID: 28882879]
[10]
Butterworth, S.; Cross, D.A.E.; Finlay, M.R.V.; Ward, R.A.; Waring, M.J. The structure-guided discovery of osimertinib: the first U.S. FDA approved mutant selective inhibitor of EGFR T790M. MedChemComm, 2017, 8(5), 820-822.
[http://dx.doi.org/10.1039/C7MD90012K] [PMID: 30108799]
[11]
Hellriegel, E.T.; Bjornsson, T.D.; Hauck, W.W. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin. Pharmacol. Ther., 1996, 60(6), 601-607.
[http://dx.doi.org/10.1016/S0009-9236(96)90208-8] [PMID: 8988062]
[12]
Sjögren, E.; Westergren, J.; Grant, I.; Hanisch, G.; Lindfors, L.; Lennernäs, H.; Abrahamsson, B.; Tannergren, C. In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur. J. Pharm. Sci., 2013, 49(4), 679-698.
[http://dx.doi.org/10.1016/j.ejps.2013.05.019] [PMID: 23727464]
[13]
Lin, L.; Wong, H. Predicting oral drug absorption: mini review on physiologically-based pharmacokinetic models. Pharmaceutics, 2017, 9(4), 41.
[http://dx.doi.org/10.3390/pharmaceutics9040041] [PMID: 28954416]
[14]
Heikkinen, A.T.; Baneyx, G.; Caruso, A.; Parrott, N. Application of PBPK modeling to predict human intestinal metabolism of CYP3A substrates - an evaluation and case study using GastroPlus. Eur. J. Pharm. Sci., 2012, 47(2), 375-386.
[http://dx.doi.org/10.1016/j.ejps.2012.06.013] [PMID: 22759901]
[15]
Turner, D.B.; Liu, B.; Patel, N.; Pathak, S.M.; Polak, S.; Jamei, M.; Dressman, J.; Rostami-Hodjegan, A. Comment on: “In silico modeling of gastrointestinal drug absorption: predictive performance of three physiologically-based absorption models. Mol. Pharm., 2017, 14(1), 336-339.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b00469] [PMID: 27392013]
[16]
Fredlund, L.; Winiwarter, S.; Hilgendorf, C. In vitro intrinsic permeability: a transporter-independent measure of caco-2 cell permeability in drug design and development. Mol. Pharm., 2017, 14(5), 1601-1609.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b01059] [PMID: 28329446]
[17]
Artursson, P.; Neuhoff, S.; Matsson, P.; Tavelin, S. assive permeability and active transport models for the prediction of oral absorption. Compr. Med. Chem., 2007, 259-278.
[http://dx.doi.org/10.1016/B0-08-045044-X/00126-7]
[18]
Shugarts, S.; Benet, L.Z. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm. Res., 2009, 26(9), 2039-2054.
[http://dx.doi.org/10.1007/s11095-009-9924-0] [PMID: 19568696]
[19]
Peters, S.A.; Jones, C.R.; Ungell, A.L.; Hatley, O.J.D. Predicting drug extraction in the human gut wall: assessing contributions from drug metabolizing enzymes and transporter proteins using preclinical models. Clin. Pharmacokinet., 2016, 55(6), 673-696.
[http://dx.doi.org/10.1007/s40262-015-0351-6] [PMID: 26895020]
[20]
Department of Health and Human Services, Food and Drug Administration,Center for Evaluation and Research (CDER). Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Guidance for industry. U.S 2017.https://www.fda.gov/media/70963/download
[21]
Miyake, M.; Kondo, S.; Koga, T.; Yoda, N.; Nakazato, S.; Emoto, C.; Mukai, T.; Toguchi, H. Evaluation of intestinal metabolism and absorption using the Ussing chamber system equipped with intestinal tissue from rats and dogs. Eur. J. Pharm. Biopharm., 2018, 122, 49-53.
[http://dx.doi.org/10.1016/j.ejpb.2017.09.015] [PMID: 28974435]
[22]
Rowland, M.; Tozer, T.N. Clinical pharmacokinetics concepts and applications, 2nd ed; Lea and Febiger: Philadelphia, 1989.
[23]
Bolger, M.B.; Lukacova, V.; Woltosz, W.S. Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine. AAPS J., 2009, 11(2), 353-363.
[http://dx.doi.org/10.1208/s12248-009-9111-6] [PMID: 19434502]
[24]
Podoll, T.; Pearson, P.G.; Evarts, J.; Ingallinera, T.; Bibikova, E.; Sun, H.; Gohdes, M.; Cardinal, K.; Sanghvi, M.; Slatter, J.G. Bioavailability, biotransformation, and excretion of the covalent bruton tyrosine kinase inhibitor acalabrutinib in rats, dogs, and humans. Drug Metab. Dispos., 2019, 47(2), 145-154.
[http://dx.doi.org/10.1124/dmd.118.084459] [PMID: 30442651]
[25]
Flecknell, P. Replacement, reduction and refinement. ALTEX, 2002, 19(2), 73-78.
[PMID: 12098013]
[26]
Smith, D.A.; Beaumont, K.; Maurer, T.S.; Di, L. Clearance in drug design. J. Med. Chem., 2019, 62(5), 2245-2255.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01263] [PMID: 30281973]
[27]
Thummel, K.E.; Shen, D.D.; Isoherranen, N. Design and optimization of dosage regimens: pharmacokinetic data. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed.;; Brunton, L.L.;Hilal-Dandan, R.; Knollmann, B.C.; Eds; McGraw Hill Education,Lange,. , 2011; pp. 1891-990.
[28]
Hosey, C.M.; Broccatelli, F.; Benet, L.Z. Predicting when biliary excretion of parent drug is a major route of elimination in humans. AAPS J., 2014, 16(5), 1085-1096.
[http://dx.doi.org/10.1208/s12248-014-9636-1] [PMID: 25004821]
[29]
Cerny, M.A. Prevalence of non-cytochrome P450-mediated metabolism in food and drug administration-approved oral and intravenous drugs: 2006-2015. Drug Metab. Dispos., 2016, 44(8), 1246-1252.
[http://dx.doi.org/10.1124/dmd.116.070763] [PMID: 27084892]
[30]
Grime, K.; Riley, R.J. The impact of in vitro binding on in vitro-in vivo extrapolations, projections of metabolic clearance and clinical drug-drug interactions. Curr. Drug Metab., 2006, 7(3), 251-264.
[http://dx.doi.org/10.2174/138920006776359266] [PMID: 16611020]
[31]
Ito, K.; Houston, J.B. Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes. Pharm. Res., 2004, 21(5), 785-792.
[http://dx.doi.org/10.1023/B:PHAM.0000026429.12114.7d] [PMID: 15180335]
[32]
Riley, R.J.; McGinnity, D.F.; Austin, R.P. A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metab. Dispos., 2005, 33(9), 1304-1311.
[http://dx.doi.org/10.1124/dmd.105.004259] [PMID: 15932954]
[33]
Sohlenius-Sternbeck, A.K.; Jones, C.; Ferguson, D.; Middleton, B.J.; Projean, D.; Floby, E.; Bylund, J.; Afzelius, L. Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes. Xenobiotica, 2012, 42(9), 841-853.
[http://dx.doi.org/10.3109/00498254.2012.669080] [PMID: 22509824]
[34]
Jones, B.C.; Srivastava, A.; Colclough, N.; Wilson, J.; Reddy, V.P.; Amberntsson, S.; Li, D. An investigation into the prediction of in vivo clearance for a range of flavin-containing monooxygenase substrates. Drug Metab. Dispos., 2017, 45(10), 1060-1067.
[http://dx.doi.org/10.1124/dmd.117.077396] [PMID: 28784689]
[35]
Reddy, V.P.; Jones, B.C.; Colclough, N.; Srivastava, A.; Wilson, J.; Li, D. An investigation into the prediction of the plasma concentration-time profile and its interindividual variability for a range of flavin-containing monooxygenase substrates using a physiologically based pharmacokinetic modeling approach. Drug Metab. Dispos., 2018, 46(9), 1259-1267.
[http://dx.doi.org/10.1124/dmd.118.080648] [PMID: 29895591]
[36]
Pike, K.G.; Barlaam, B.; Cadogan, E.; Campbell, A.; Chen, Y.; Colclough, N.; Davies, N.L.; de-Almeida, C.; Degorce, S.L.; Didelot, M.; Dishington, A.; Ducray, R.; Durant, S.T.; Hassall, L.A.; Holmes, J.; Hughes, G.D.; MacFaul, P.A.; Mulholland, K.R.; McGuire, T.M.; Ouvry, G.; Pass, M.; Robb, G.; Stratton, N.; Wang, Z.; Wilson, J.; Zhai, B.; Zhao, K.; Al-Huniti, N. The Identification of potent, selective, and orally available inhibitors of ataxia telangiectasia mutated (ATM) kinase: The discovery of AZD0156 (8-6-[3-(dimethylamino)propoxy]pyridin-3-yl-3-methyl-1-(tetrahydro-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one). J. Med. Chem., 2018, 61(9), 3823-3841.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01896] [PMID: 29683659]
[37]
Pike, K.G. Discovery of AZD0156: the first potent and selective inhibitor of ATM kinase for clinical evaluation. Compr. Med. Chem., 2017, 161-177.
[http://dx.doi.org/10.1016/B978-0-12-409547-2.13801-6]
[38]
Pryde, D.C.; Dalvie, D.; Hu, Q.; Jones, P.; Obach, R.S.; Tran, T.D. Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J. Med. Chem., 2010, 53(24), 8441-8460.
[http://dx.doi.org/10.1021/jm100888d] [PMID: 20853847]
[39]
Hutzler, J.M.; Yang, Y.S.; Albaugh, D.; Fullenwider, C.L.; Schmenk, J.; Fisher, M.B. Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes. Drug Metab. Dispos., 2012, 40(2), 267-275.
[http://dx.doi.org/10.1124/dmd.111.042861] [PMID: 22031625]
[40]
Jensen, K.G.; Jacobsen, A.M.; Bundgaard, C.; Nilausen, D.Ø.; Thale, Z.; Chandrasena, G.; Jørgensen, M. Lack of exposure in a first-in-man study due to aldehyde oxidase metabolism: investigated by use of 14C-microdose, humanized mice, monkey pharmacokinetics, and in vitro methods. Drug Metab. Dispos., 2017, 45(1), 68-75.
[http://dx.doi.org/10.1124/dmd.116.072793] [PMID: 27737930]
[41]
Sanoh, S.; Tayama, Y.; Sugihara, K.; Kitamura, S.; Ohta, S. Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy. Drug Metab. Pharmacokinet., 2015, 30(1), 52-63.
[http://dx.doi.org/10.1016/j.dmpk.2014.10.009] [PMID: 25760530]
[42]
Lepri, S.; Ceccarelli, M.; Milani, N.; Tortorella, S.; Cucco, A.; Valeri, A.; Goracci, L.; Brink, A.; Cruciani, G. Structure-metabolism relationships in human-AOX: Chemical insights from a large database of aza-aromatic and amide compounds. Proc. Natl. Acad. Sci. USA, 2017, 114(16), E3178-E3187.
[http://dx.doi.org/10.1073/pnas.1618881114] [PMID: 28373537]
[43]
Zientek, M.; Jiang, Y.; Youdim, K.; Obach, R.S. In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab. Dispos., 2010, 38(8), 1322-1327.
[http://dx.doi.org/10.1124/dmd.110.033555] [PMID: 20444863]
[44]
Rosen, A.S.; Fournié, P.; Darwish, M.; Danjou, P.; Troy, S.M. Zaleplon pharmacokinetics and absolute bioavailability. Biopharm. Drug Dispos., 1999, 20(3), 171-175.
[http://dx.doi.org/10.1002/(SICI)1099-081X(199904)20:3<171:AID-BDD169>3.0.CO;2-K] [PMID: 10211871]
[45]
Pilla Reddy, V.; Bui, K.; Scarfe, G.; Zhou, D.; Learoyd, M. Physiologically based pharmacokinetic modeling for olaparib dosing recommendations: bridging formulations, drug interactions, and patient populations. Clin. Pharmacol. Ther., 2019, 105(1), 229-241.
[http://dx.doi.org/10.1002/cpt.1103] [PMID: 29717476]
[46]
Grime, K.; Paine, S.W. Species differences in biliary clearance and possible relevance of hepatic uptake and efflux transporters involvement. Drug Metab. Dispos., 2013, 41(2), 372-378.
[http://dx.doi.org/10.1124/dmd.112.049312] [PMID: 23139379]
[47]
Paine, S.W.; Ménochet, K.; Denton, R.; McGinnity, D.F.; Riley, R.J. Prediction of human renal clearance from preclinical species for a diverse set of drugs that exhibit both active secretion and net reabsorption. Drug Metab. Dispos., 2011, 39(6), 1008-1013.
[http://dx.doi.org/10.1124/dmd.110.037267] [PMID: 21357702]
[48]
Bonn, B.; Svanberg, P.; Janefeldt, A.; Hultman, Ia.; Grime, K. Determination of human hepatocyte intrinsic clearance for slowly metabolized compounds: comparison of a primary hepatocyte/stromal cell co-culture with plated primary hepatocytes and HepaRG. Drug Metab. Dispos., 2016, 44(4), 527-533.
[http://dx.doi.org/10.1124/dmd.115.067769] [PMID: 26851239]
[49]
Lancett, P.; Williamson, B.; Barton, P.; Riley, R.J. Development and characterization of a human hepatocyte low intrinsic clearance assay for use in drug discovery. Drug Metab. Dispos., 2018, 46(8), 1169-1178.
[http://dx.doi.org/10.1124/dmd.118.081596] [PMID: 29880630]
[50]
Poulin, P.; Theil, F.P. Development of a novel method for predicting human volume of distribution at steady-state of basic drugs and comparative assessment with existing methods. J. Pharm. Sci., 2009, 98(12), 4941-4961.
[http://dx.doi.org/10.1002/jps.21759] [PMID: 19455625]
[51]
Rodgers, T.; Rowland, M. Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm. Res., 2007, 24(5), 918-933.
[http://dx.doi.org/10.1007/s11095-006-9210-3] [PMID: 17372687]
[52]
Øie, S.; Tozer, T.N. Effect of altered plasma protein binding on apparent volume of distribution. J. Pharm. Sci., 1979, 68(9), 1203-1205.
[http://dx.doi.org/10.1002/jps.2600680948] [PMID: 501558]
[53]
Yates, J.W.T.; Arundel, P.A. On the volume of distribution at steady state and its relationship with two-compartmental models. J. Pharm. Sci., 2008, 97(1), 111-122.
[http://dx.doi.org/10.1002/jps.21089] [PMID: 17705153]
[54]
Vishwanathan, K.; So, K.; Thomas, K.; Bramley, A.; English, S.; Collier, J. Absolute bioavailability of osimertinib in healthy adults. Clin. Pharmacol. Drug Dev., 2019, 8(2), 198-207.
[http://dx.doi.org/10.1002/cpdd.467] [PMID: 29683562]
[55]
Dickinson, P.A.; Cantarini, M.V.; Collier, J.; Frewer, P.; Martin, S.; Pickup, K.; Ballard, P. Metabolic disposition of osimertinib in rats, dogs, and humans: insights into a drug designed to bind covalently to a cysteine residue of epidermal growth factor receptor. Drug Metab. Dispos., 2016, 44(8), 1201-1212.
[http://dx.doi.org/10.1124/dmd.115.069203] [PMID: 27226351]
[56]
Goodwin, R.J.A.; Bunch, J.; McGinnity, D.F. Mass spectrometry imaging in oncology drug discovery. In: Advances in Cancer Research; Fisher, P.B.; Tew, K.D., Eds.; Elsevier Science: Amsterdam, 2017; pp. 133-171.
[http://dx.doi.org/10.1016/bs.acr.2016.11.005]
[57]
Smith, D.A.; Rowland, M. Intracellular and intraorgan concentrations of small molecule drugs: theory, uncertainties in infectious diseases and oncology, and promise. Drug Metab. Dispos., 2019, 47(6), 665-672.
[http://dx.doi.org/10.1124/dmd.118.085951] [PMID: 30910784]
[58]
Colclough, N.; Chen, K.; Johnström, P.; Fridén, M.; McGinnity, D.F. Building on the success of osimertinib: achieving CNS exposure in oncology drug discovery. Drug Discov. Today, 2019, 24(5), 1067-1073.
[http://dx.doi.org/10.1016/j.drudis.2019.01.015] [PMID: 30710641]
[59]
Durant, S.T.; Zheng, L.; Wang, Y.; Chen, K.; Zhang, L.; Zhang, T.; Yang, Z.; Riches, L.; Trinidad, A.G.; Fok, J.H.L.; Hunt, T.; Pike, K.G.; Wilson, J.; Smith, A.; Colclough, N.; Reddy, V.P.; Sykes, A.; Janefeldt, A.; Johnström, P.; Varnäs, K.; Takano, A.; Ling, S.; Orme, J.; Stott, J.; Roberts, C.; Barrett, I.; Jones, G.; Roudier, M.; Pierce, A.; Allen, J.; Kahn, J.; Sule, A.; Karlin, J.; Cronin, A.; Chapman, M.; Valerie, K.; Illingworth, R.; Pass, M. The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci. Adv, 2018, 4(6) eaat1719
[http://dx.doi.org/10.1126/sciadv.aat1719] [PMID: 29938225]
[60]
Ward, R.A.; Anderton, M.J.; Ashton, S.; Bethel, P.A.; Box, M.; Butterworth, S.; Colclough, N.; Chorley, C.G.; Chuaqui, C.; Cross, D.A.E.; Dakin, L.A.; Debreczeni, J.E.; Eberlein, C.; Finlay, M.R.; Hill, G.B.; Grist, M.; Klinowska, T.C.M.; Lane, C.; Martin, S.; Orme, J.P.; Smith, P.; Wang, F.; Waring, M.J. Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). J. Med. Chem., 2013, 56(17), 7025-7048.
[http://dx.doi.org/10.1021/jm400822z] [PMID: 23930994]
[61]
Lonsdale, R.; Burgess, J.; Colclough, N.; Davies, N.L.; Lenz, E.M.; Orton, A.L.; Ward, R.A. Expanding the armory: predicting and tuning covalent warhead reactivity. J. Chem. Inf. Model., 2017, 57(12), 3124-3137.
[http://dx.doi.org/10.1021/acs.jcim.7b00553] [PMID: 29131621]
[62]
Di, L.; Umland, J.P.; Trapa, P.E.; Maurer, T.S. Impact of recovery on fraction unbound using equilibrium dialysis. J. Pharm. Sci., 2012, 101(3), 1327-1335.
[http://dx.doi.org/10.1002/jps.23013] [PMID: 22161810]
[63]
Jones, B.C.; Rollison, H.; Johansson, S.; Kanebratt, K.P.; Lambert, C.; Vishwanathan, K.; Andersson, T.B. Managing the risk of CYP3A induction in drug development: a strategic approach. Drug Metab. Dispos., 2017, 45(1), 35-41.
[http://dx.doi.org/10.1124/dmd.116.072025] [PMID: 27777246]
[64]
Pilla Reddy, V.; Walker, M.; Sharma, P.; Ballard, P.; Vishwanathan, K. Development, verification, and prediction of osimertinib drug-drug interactions using PBPK modeling approach to inform drug label. CPT Pharmacometrics Syst. Pharmacol., 2018, 7(5), 321-330.
[http://dx.doi.org/10.1002/psp4.12289] [PMID: 29468841]
[65]
Edmondson, S.D.; Yang, B.; Fallan, C. Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: recent progress and future challenges. Bioorganic Med. Chem. Lett; , 2019, 29(13), 1555-1564.
[http://dx.doi.org/10.1016/j.bmcl.2019.04.030] [PMID: 31047748]
[66]
Choo, E.F.; Boggs, J.; Zhu, C.; Lubach, J.W.; Catron, N.D.; Jenkins, G.; Souers, A.J.; Voorman, R. The role of lymphatic transport on the systemic bioavailability of the Bcl-2 protein family inhibitors navitoclax (ABT-263) and ABT-199. Drug Metab. Dispos., 2014, 42(2), 207-212.
[http://dx.doi.org/10.1124/dmd.113.055053] [PMID: 24212376]
[67]
Zgair, A.; Wong, J.C.M.; Lee, J.B.; Mistry, J.; Sivak, O.; Wasan, K.M.; Hennig, I.M.; Barrett, D.A.; Constantinescu, C.S.; Fischer, P.M.; Gershkovich, P. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines. Am. J. Transl. Res., 2016, 8(8), 3448-3459.
[PMID: 27648135]
[68]
Choi, G.W.; Lee, Y.B.; Cho, H.Y. Interpretation of non-clinical data for prediction of human pharmacokinetic parameters: in vitro-in vivo extrapolation and allometric scaling. Pharmaceutics, 2019, 11(4), 168.
[http://dx.doi.org/10.3390/pharmaceutics11040168] [PMID: 30959827]
[69]
Hamman, J.H.; Demana, P.H.; Olivier, E.I. Targeting receptors, transporters and site of absorption to improve oral drug delivery. Drug Target Insights, 2007, 2, 71-81.
[http://dx.doi.org/10.1177/117739280700200003] [PMID: 21901064]
[70]
Abet, V.; Filace, F.; Recio, J.; Alvarez-Builla, J.; Burgos, C. Prodrug approach: An overview of recent cases. Eur. J. Med. Chem., 2017, 127, 810-827.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.061] [PMID: 27823878]

Rights & Permissions Print Cite
Article Metrics
77
© 2024 Bentham Science Publishers | Privacy Policy