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RESEARCH ARTICLE – Pharmacokinetics, Pharmacodynamics and Drug Transport and Metabolism| Volume 104, ISSUE 9, P3101-3119, September 01, 2015

A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment

      ABSTRACT:

      Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug substances. Although the pharmacokinetics of toxic drug degradation products may impact product safety, these data are frequently unavailable. The objective of this study is to incorporate the prediction capability of physiologically based pharmacokinetic (PBPK) models into a rational drug degradation product risk assessment procedure using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of experimental and literature data and computational methods. The impact of model parameter uncertainty was incorporated into stochastic risk assessment procedure for estimating human safe exposure levels based on the novel use of a statistical metric called “PROB” for comparing probability that a human toxicity-target tissue exposure exceeds the rat exposure level at a critical no-observed-adverse-effect level. When compared with traditional risk assessment calculations, this novel PBPK approach appeared to provide a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

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      REFERENCES

        • Raillard S.P.
        • Bercu J.
        • Baertschi S.W.
        • Riley C.M.
        Prediction of drug degradation pathways leading to structural alerts for potential genotoxic impurities.
        Org Process Res Dev. 2010; 14: 1015
        • Raman N.V.V.S.S.
        • Prasad A.V.S.S.
        • Ratnakar Reddy K.
        Strategies for the identification, control and determination of genotoxic impurities in drug substances: A pharmaceutical industry perspective.
        J Pharm Biomed Anal. 2011; 55: 6/25
        • International Conference on Harmonization (ICH)
        Guidance for industry Q3A impurities in new drug substances. 2008
        • International Conference on Harmonization (ICH)
        Impurities in new products Q3B (R2). 2006
        • Ashby J.
        Fundamental structural alerts to potential carcinogenicity or noncarcinogenicity.
        Environ Mutagen. 1985; 7: 919-921
        • Zambon E.
        • Giovanetti R.
        • Cotarca L.
        • Pasquato L.
        Mechanistic investigation on 2-aza-spiro[4,5]decan-3-one formation from 1-(aminomethyl)cyclohexylacetic acid (gabapentin).
        Tetrahedron. 2008; 64: 7/7
        • Pharmacopeial Convention U.S.
        United States Pharmacopeia and National Formulary (USP 32-NF 27). 2009 (Rockville, Maryland)
        • Zour E.
        • Lodhi S.A.
        • Nesbitt R.U.
        • Silbering S.B.
        • Chaturvedi P.R.
        Stability studies of gabapentin in aqueous solutions.
        Pharm Res. 1992; 9: 595-600
        • FDA U.S.
        Guidance for industry ANDAs: Impurities in drug products.
        Center for Drug Evaluation and Research (CDER). 2010 (U.S., Washington, D.C)
      1. Curtis D.K. Casarett and Doull’s toxicology the basic science of poisons. McGraw Hill Professional, New York2008
      2. Kannan Krishnan Melvin Andersen E. Quantitative modeling in toxicology. John Wiley & Sons, New Jersey2010
        • WHO
        Characterization and application of physiologically based pharmacokinetic models in risk assessment. IPCS Harmonization Project, Ottawa, Canada2010
        • Clewell R.A.
        • Clewell III, H.J.
        Development and specification of physiologically based pharmacokinetic models for use in risk assessment.
        Regul Toxicol Pharmacol. 2008; 50: 2
        • U.S. EPA
        Approaches for the application of physiologically) based pharmacokinetic (PBPK) models and supporting data in risk assessment (final report). U.S. Environmental Protection Agency, Washington, D.C2006 (EPA/600/R-05/043 F)
        • Bois F.Y.
        • Jamei M.
        • Clewell H.J.
        PBPK modelling of interindividual variability in the pharmacokinetics of environmental chemicals.
        Toxicology. 2010; 278: 256-267
        • Bois F.Y.
        Ananlysis of PBPK models for risk characterization.
        Ann N Y Acad Sci. 1999; 895: 317-337
        • Clewell III, H.J.
        • Andersen M.E.
        Use of physiologically based pharmacokinetic modeling to investigate individual versus population risk.
        Toxicology. 1996; 111: 7/17
        • Zhixin Z.
        • Kirsch L.E.
        Studies on the instability of chlorhexidine, part I: Kinetics and mechanisms.
        J Pharm Sci. 2012; 101: 2417-2427
        • Powell M.F.
        Stability of lidocaine in aqueous solution: Effect of temperature, pH, buffer, and metal ions on amide hydrolysis.
        Pharm Res. 1987; 4: 42-45
        • Fijałek Z.
        • Baczynski E.
        • Piwonska A.
        • Warowna-Grzeskiewicz M.
        Determination of local anaesthetics and their impurities in pharmaceutical preparations using HPLC method with amperometric detection.
        J Pharm Biomed Anal. 2005; 37 (4/29): 913-918
        • Koshy K.T.
        • Lach J.L.
        Stability of aqueous solutions of N-acetyl-p-aminophenol.
        J Pharm Sci. 1961; 50: 113-118
        • Khan M.F.
        • Boor P.J.
        • Gu Y.
        • Nancy W.A.
        • Ansari G.A.S.
        Oxidative stress in the splenotoxicity of aniline.
        Toxicol Sci 35:22–30. 1997;
        • Jenkins F.P.
        • Robinson J.A.
        • Gellatly J.B.M.
        • Salmond G.W.A.
        The no-effect dose of aniline in human subjects and a comparison of aniline toxicity in man and the rat.
        Food Cosmet Toxicol. 1972; 10: 671-679
        • National Cancer Institute
        Bioassay of aniline hydrochloride for possible carcinogenicity. US Department of Health, Education, and Welfare, NIH1978 (Tech. Rep. No 130)
        • Newton J.F.
        • Kuo C.H.
        • Gemborys M.W.
        • Mudge G.H.
        • Hook J.B.
        Nephrotoxicity of p-aminophenol, a metabolite of acetaminophen, in the Fischer 344 rat.
        Toxicol Appl Pharmacol. 1982; 65: 9/15
        • Kao J.
        • Faulkner J.
        • Bridges J.W.
        Metabolism of aniline in rats, pigs and sheep.
        Drug Metab Dispos. 1978; 6 (September 01): 549-555
        • Chhabra R.S.
        • Thompson M.
        • Elwell M.R.
        • Gerken D.K.
        Toxicity of p-chloroaniline in rats and mice.
        Food Chem Toxicol. 1990; 28: 717-722
        • Dial L.D.
        • Anestis D.K.
        • Kennedy S.R.
        • Rankin G.O.
        Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-chloroaniline in Fischer 344 rats.
        Toxicology. 1998; 131: 11/16
        • Schanker L.S.
        • Tocco D.J.
        • Brodie B.B.
        • Hogben C.A.M.
        Absorption of drugs from the rat small intestine.
        J Pharmacol Exp Ther. 1958; 123: 158
        • Brown R.P.
        • Delp M.D.
        • Lindstedt S.L.
        • Rhomberg L.R.
        • Beliles R.P.
        Physiological parameter values for physiologically based pharmacokinetic models.
        Toxicol Ind Health. 1997; 13 (July 01): 407-484
        • Delp M.D.
        • Manning R.O.
        • Bruckner J.V.
        • Armstrong R.B.
        Distribution of cardiac output during diurnal changes of activity in rats.
        Am J Physiol Heart Circ Physiol. 1991; 261 (November 01): H1487-H1493
        • MacPherson J.
        • Tothill P.
        Bone blood flow and age in the rat.
        Clin Sci Mol Med. 1978; 54: 111-113
        • Bernareggi A.
        • Rowland M.
        Physiologic modeling of cyclosporin kinetics in rat and man.
        J Pharmacokinet Pharmacodyn. 1991; 19: 21-50
        • Idvall J.
        • Aronsen K.
        • Stenberg P.
        Tissue perfusion and distribution of cardiac output during ketamine anesthesia in normovolemic rats.
        Acta Anaesthesiol Scand. 1980; 24: 257-263
        • Sasaki Y.
        • Wagner Jr., H.N.
        Measurement of the distribution of cardiac output in unanesthetized rats.
        J Appl Physiol. 1971; 30 (Jun): 879-884
        • Valentin J.
        Basic anatomical and physiological data for use in radiological protection: Reference values: ICRP Publication 89.
        Ann ICRP. 2002; 32: 12
        • de la Grandmaison G.L.
        • Clairand I.
        • Durigon M.
        Organ weight in 684 adult autopsies: New tables for a Caucasoid population.
        Forensic Sci Int. 2001; 119: 6/15
        • Sheila Annie Peters
        Evaluation of a generic physiologically based pharmacokinetic model for lineshape analysis.
        Clin Pharmacokinet. 2008; 47: 261-275
        • Pytela O.
        • Otyepka M.
        • Kulhánek J.
        • Otyepková E.
        • Nevecná T.
        Correlation of dissociation constants of 2-and 2, 6-substituted anilines in water by methods based on the similarity principle and quantum-chemistry calculations.
        J Phys Chem A. 2003; 107: 11489-11496
        • Albert A.
        • Serjeant E.P.
        Ionization constants of acids and bases: A laboratory manual. 1962 (London: Methuen)
        • Biggs A.
        • Robinson R.
        The ionisation constants of some substituted anilines and phenols: A test of the Hammett relation.
        J Chem Soc (Resumed). 1961; : 388-393
        • Serjeant E.P.
        • Dempsey B.
        Ionisation constants of organic acids in aqueous solution. Pergamon Oxford, England1979
        • Leo A.
        • Hansch C.
        • Elkins D.
        Partition coefficients and their uses.
        Chem Rev. 1971; 71: 525-615
        • Rodgers T.
        • Rowland M.
        Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions.
        J Pharm Sci. 2006; 95: 1238-1257
        • Harrison J.H.
        • Jollow D.J.
        Role of aniline metabolites in aniline-induced hemolytic anemia.
        J Pharmacol Exp Ther. 1986; 238: 1045-1054
        • Nohynek G.J.
        • Duche D.
        • Garrigues A.
        • Meunier P.
        • Toutain H.
        • Leclaire J.
        Under the skin: Biotransformation of para-aminophenol and para-phenylenediamine in reconstructed human epidermis and human hepatocytes.
        Toxicol Lett. 2005; 158: 9/15
        • R Core Team
        R: A language and environment for statistical computing. 2012
        • Soetaert K.
        • Petzoldt T.
        Inverse modelling, sensitivity and Monte Carlo analysis in R using package FME.
        J Stat Softw. 2010; 33
        • Soetaert K.
        • Petzoldt T.
        • Setzer W.
        Solving differential equations.
        in: Package deSolve R. J Stat Softw. 33. 2010: 1-25
        • Hou T.J.
        • Zhang W.
        • Xia K.
        • Qiao X.B.
        • Xu X.J.
        ADME evaluation in drug discovery. 5. Correlation of Caco-2 permeation with simple molecular properties.
        J Chem Inf Comput Sci. 2004; 44 (2014/01): 09/01
        • Nordqvist A.
        • Nilsson J.
        • Lindmark T.
        • Eriksson A.
        • Garberg P.
        • Kihlén M.
        A general model for prediction of Caco-2 cell permeability.
        QSAR Comb Sci. 2004; 23: 303-310
        • Schwarz G.
        Estimating the dimension of a model.
        Ann Stat. 1978; 6: 461-464
        • Alsenz J.
        • Haenel E.
        Development of a 7-day, 96-well Caco-2 permeability assay with high-throughput direct UV compound analysis.
        Pharm Res. 2003; 20: 12/01
        • Fagerholm U.
        • Johansson M.
        • Lennernäs H.
        Comparison between permeability coefficients in rat and human jejunum.
        Pharm Res. 1996; 13: 1336-1342
        • Agoram B.
        • Woltosz W.S.
        • Bolger M.B.
        Predicting the impact of physiological and biochemical processes on oral drug bioavailability.
        Adv Drug Deliv Rev. 2001; 50: S41-S67
        • Yu L.X.
        • Amidon G.L.
        A compartmental absorption and transit model for estimating oral drug absorption.
        Int J Pharm. 1999; 186: 119-125
        • Harrison Jr., J.H.
        • Jollow D.J.
        Contribution of aniline metabolites to aniline-induced methemoglobinemia.
        Mol Pharmacol. 1987; 32 (Sep): 423-431
        • Barter Z.E.
        • Bayliss M.K.
        Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: Reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver.
        Curr Drug Metab. 2007; 8: 33-45
        • Gastwirth J.L.
        Statistical measures of earnings differentials.
        Am Stat. 1975; 29: 32-35
        • National Toxicology Program (NTP)
        Toxicology and carcinogenesis studies of 2,6-xylidine (2,6-dimethylaniline) in charles river CD rats (feed studies). US Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda1990 (Tech. Rep. No. 278)
        • Caroline English J.
        • Bhat V.S.
        • Ball G.L.
        • McLellan C.J.
        Establishing a total allowable concentration of o-toluidine in drinking water incorporating early lifestage exposure and susceptibility.
        Regul Toxicol Pharmacol. 2012; 64: 11
        • Cheng Y.
        • Ho E.
        • Subramanyam B.
        • Tseng J.
        Measurements of drug–protein binding by using immobilized human serum albumin liquid chromatography–mass spectrometry.
        J Chromatogr B. 2004; 809: 9/25
        • Poulin P.
        • Theil F.-P.
        Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution.
        J Pharm Sci. 2002; 91: 129-156
        • Rodgers T.
        • Rowland M.
        Mechanistic approaches to volume of distribution predictions: Understanding the processes.
        Pharm Res. 2007; 24: 918-933
        • Lombardo F.
        • Obach R.S.
        • Shalaeva M.Y.
        • Gao F.
        Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data.
        J Med Chem. 2002; 45: 2867-2876
        • McCarthy D.J.
        • Waud W.R.
        • Struck R.F.
        • Hill D.L.
        Disposition and metabolism of aniline in Fischer 344 rats and C57BL/6×C3H F1 mice.
        Cancer Res. 1985; 45 (January 01): 174-180
        • Bidlack W.R.
        • Lowery G.L.
        Multiple drug metabolism: p-Nitroanisole reversal of acetone enhanced aniline hydroxylation.
        Biochem Pharm. 1982; 31: 2/1
        • Bois F.Y.
        • Gelman A.
        • Jiang J.
        • Maszle D.R.
        • Zeise L.
        • Alexeef G.
        Population toxicokinetics of tetrachloroethylene.
        Arch Toxicol. 1996; 70: 347-355
        • Yanga Y.
        • Xu X.
        • Georgopoulo P.G.
        A Bayesian population PBPK model for multiroute chloroform exposure.
        J Exp Sci Environ Epidemiol. 2009; 20: 326-341