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Modeling and Simulation in the Development of Cardiovascular Agents

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Clinical Trial Simulations

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 1))

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Abstract

Cardiovascular pharmacology encompasses a wide range of diseases. With most agents in this therapeutic area, there are specific therapeutic targets for biomarkers such as systolic blood pressure or LDL cholesterol levels that need to be met to ensure adequate clinical response in patients. Overdoses of these agents may be associated with toxicity. Modeling and simulation have proven to be valuable tools to target and adjust doses in patients. Because most cardiovascular agents are adaptively dosed based on individual response, the dose adjustment strategy must be implemented for model evaluation and simulation. This chapter reviews the cardiovascular pharmacology areas of treatment of hypercholesterolemia, stroke and hypertension, and applications of modeling and simulation in these disease states.

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References

  • Ahn JE, French J (2009) Longitudinal model-based meta-analysis with NONMEM. ACoP Meeting Mystic CT USA. http://www.go-acop.org/sites/all/assets/webform/ahn_1.doc

  • Bailey JM, Lu W, Levy JH, Ramsay JG, Shore-Lesserson L, Prielipp RC, Brister NW, Roach GW, Jolin-Mellgard A, Nordlander M (2002) Clevidipine in adult cardiac surgical patients: a dose-finding study. Anesthesiology 96(5):1086–1094

    Article  PubMed  CAS  Google Scholar 

  • Beal SL, Sheiner LB, Boeckmann AJ (1989–2006) NONMEM Users Guides, ICON Development Solutions, Ellicott City, MD

    Google Scholar 

  • Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A (2000) Non-lipid-related effects of statins. Ann Med 32:164–176

    Article  PubMed  CAS  Google Scholar 

  • Blum CB (1994) Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Am J Cardiol 73:3D–11D

    Article  PubMed  CAS  Google Scholar 

  • Brott T, Adams HP, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V (1989) Measurements of acute cerebral infarction: a clinical examination scale. Stroke 20:864–870

    Article  PubMed  CAS  Google Scholar 

  • Bullock R, Zauner A, Myseros JS, Marmarou A, Woodward JJ, Young HF (1995a) Evidence for prolonged release of excitatory amino acids in severe human head trauma relationship to clinical events. Ann NY Acad Sci 765:290–297

    Article  PubMed  CAS  Google Scholar 

  • Bullock R, Zauner A, Woodward J, Young HF (1995b) Massive persistent release of excitatory amino acids following human occlusive stroke. Stroke 26:2187–2189

    Article  PubMed  CAS  Google Scholar 

  • Chabaud S, Girard P, Nony P, Boissel JP (2002) Clinical trial simulation using therapeutic effect modeling: application to ivabradine efficacy in patients with angina pectoris. J Pharmacokinet Pharmacodyn 29(4):339–363

    Article  PubMed  CAS  Google Scholar 

  • Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1(8):623–634

    Article  PubMed  CAS  Google Scholar 

  • Cote R, Hachinski V, Shurvell B, Norris JW, Wolfson C (1986) The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 17:731–736

    Article  PubMed  CAS  Google Scholar 

  • Dayneka NL, Garg V, Jusko WJ (1993) Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 21(4):457–478

    Article  PubMed  CAS  Google Scholar 

  • Faltaos DW, Urien S, Carreau V, Chauvenet M, Hulot JS, Giral P, Bruckert E, Lechat P (2006) Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients. Fundam Clin Pharmacol 20(3):321–330

    Article  PubMed  CAS  Google Scholar 

  • FDA (1998) Guidance for industry: E9 statistical principles for clinical trials

    Google Scholar 

  • FDA (2007) New labeling information for warfarin (marketed as Coumadin). http://www.fda.gov/cder/drug/infopage/warfarin/default.htm. Accessed 16 Aug 2007

  • FDA (2007) FDA approves updated warfarin (Coumadin) prescribing information [press release]. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed 16 Aug 2007

  • Fiorelli M, Alperovitch A, Argentino C, Sacchetti ML, Toni D, Sette G, Cavalletti C, Gori MC, Fieschi C (1995) Prediction of long-term outcome in the early hours following acute ischemic stroke. Arch Neurol 52:250–255

    Article  PubMed  CAS  Google Scholar 

  • Friberg LE, Karlsson MO (2003) Mechanistic models for myelosuppression. Invest New Drugs 21(2):183–194

    Article  PubMed  CAS  Google Scholar 

  • Gabrielsson J, Jusko WJ, Alari L (2000) Modelling of dose-response-time data: four examples of estimating the turnover parameters and generating kinetic functions from response profiles. Biopharm Drug Dispos 2:41–52

    Article  Google Scholar 

  • Geyskes GG, Boer P, Dorhout Mees EJ (1979) Clonidine withdrawal. Mechanism and frequency of rebound hypertension. Br J Clin Pharmacol 7(1):55–62

    Article  PubMed  CAS  Google Scholar 

  • Green B, Duffull SB (2003) Development of a dosing strategy for enoxaparin in obese patients. Br J Clin Pharmacol 56(1):96–103

    Article  PubMed  CAS  Google Scholar 

  • Grotta J (1997) Lubeluzole treatment of Acute Ischemic Stroke. Stroke 28:2338–2346

    Article  PubMed  CAS  Google Scholar 

  • Guyton AC (1991) Blood pressure control—special role of the kidneys and body fluids. Science 252:1813–1816

    Article  PubMed  CAS  Google Scholar 

  • Hamberg AK, Dahl ML, Barban M, Scordo MG, Wadelius M, Pengo V, Padrini R, Jonsson EN (2007) A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy. Clin Pharmacol Ther 81(4):529–538

    Article  PubMed  CAS  Google Scholar 

  • Hammer GB, Verghese ST, Drover DR, Yaster M, Tobin JR (2008) Pharmacokinetics and pharmacodynamics of fenoldopam mesylate for blood pressure control in pediatric patients. BMC Anesthesiol 8:6

    Article  PubMed  Google Scholar 

  • Holford NH (2005) The visual predictive check – superiority to standard diagnostic (Rorschach) plots PAGE. http://www.page-meeting.org/page/page2005/PAGE2005P105.pdf

  • Hunninghake DB (1992) HMG-CoA reductase inhibitors. Curr Opin Lipidol 3:22–28

    Article  CAS  Google Scholar 

  • Jackson SP, Nesbitt WS, Kulkarni S (2003) Signaling events underlying thrombus formation. J Thromb Haemost Jul 1(7):1602–1612

    Article  CAS  Google Scholar 

  • Jacqmin P, Gieschke R, Jordan P, Steimer JL, Goggin T, Pillai G (2001) Modeling drug induced changes in biomarkers without using drug concentrations: introducing the K-PD model. 10th Population Approach Group Conference, Basel, Switzerland, http://www.page-meeting.org

  • Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B (2002) Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 346:913–923

    Article  PubMed  CAS  Google Scholar 

  • Johnson K, Shah A, Jaw J, Baxter J, Prakash C (2003) Metabolism, pharmacokinetics, and excretion of a highly selective NMDA receptor antagonist, traxoprodil, in human cytochrome P450 2D6 extensive and poor metabolizers. Drug Metab Dispos 31:76–87

    Article  PubMed  CAS  Google Scholar 

  • Jonsson F, Marshall S, Krams M, Jonsson E (2005) A longitudinal model for non-monotonic clinical assessment scale data. J Pharmacokinet Pharmacodyn 32(5–6):795–815 (21)

    Article  PubMed  Google Scholar 

  • Karlsson MO, Sheiner LB (1993) The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 21:735–750

    Article  PubMed  CAS  Google Scholar 

  • Kearon C, Hirsh J (1997) Management of anticoagulation before and after elective surgery. N Engl J Med 336(21):1506–1511

    Article  PubMed  CAS  Google Scholar 

  • Lalonde RL, Kowalski KG, Hutmacher MM, Ewy W, Nichols DJ, Milligan PA, Corrigan BW, Lockwood PA, Marshall SA, Benincosa LJ, Tensfeldt TG, Parivar K, Amantea M, Glue P, Koide H, Miller R (2007) (2007) Model-based drug development. Clin Pharmacol Ther 82(1):21–32

    Article  PubMed  CAS  Google Scholar 

  • LaRosa JC, He J, Vupputuri S (1999) Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA, J Am Med Assoc 282(24):2340–2346

    Article  CAS  Google Scholar 

  • Laurent S, Kingwell B, Bank A, Weber M, Struijker-Boudier H (2002) Clinical applications of arterial stiffness: therapeutics and pharmacology. Am J Hypertens 15(5):453–458

    Article  PubMed  Google Scholar 

  • Lennernäs H, Fager G (1997) Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences\. Clin Pharmacokinet 32(5):403–425

    Article  PubMed  Google Scholar 

  • Lindenstrom E, Boysen G, Christiansen LW, Hansen BR, Nielsen PW (1991) Reliability of Scandinavian Stroke Scale. Cerebrovasc Dis 1:103–107

    Article  Google Scholar 

  • Mason RP, Walter MF, Day C, Jacob RF (2006) Active metabolite of atorvastatin inhibits membrane cholesterol domain formation by an antioxidant mechanism. J Biol Chem 281:9337–9345

    Article  PubMed  CAS  Google Scholar 

  • McConnaughey MM, McConnaughey JS, Ingenito AJ (1999) Practical considerations of the pharmacology of angiotensin receptor blockers. J Clin Pharmacol 39:547–559

    Article  PubMed  CAS  Google Scholar 

  • Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD (1994) Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90(1):61–68

    Article  PubMed  CAS  Google Scholar 

  • Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217–1221

    Article  PubMed  CAS  Google Scholar 

  • Mould D (2007) Developing models of disease progression. In: Ette EI, Williams PJ (eds) Pharmacometrics: the science of quantitative pharmacology. Wiley, Hoboken, NJ, pp 547–581

    Chapter  Google Scholar 

  • Muir KW, Weir CJ, Murray GD, Povey C, Lees KR (1996) Comparison of neurological scales and scoring systems for acute stroke prognosis. Stroke 27:1817–1820

    Article  PubMed  CAS  Google Scholar 

  • Pillai G, Gieschke R, Goggin T, Jacqmin P, Schimmer RC, Steimer JL (2004) A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis. Br J Clin Pharmacol 58(6):618–631

    Article  PubMed  Google Scholar 

  • Porchet HC, Piletta P, Dayer P (1992) Pharmacokinetic-pharmacodynamic modeling of the effects of clonidine on pain threshold, blood pressure, and salivary flow. Eur J Clin Pharmacol 42(6):655–661

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg PA, Aizenman E (1989) Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci Lett 103:162–168

    Article  PubMed  CAS  Google Scholar 

  • Salinger DH, Shen DD, Thummel K, Wittkowsky AK, Vicini P, Veenstra DL (2009) Pharmacogenomic trial design: use of a PK/PD model to explore warfarin dosing interventions through clinical trial simulation. Pharmacogenet Genomics 19(12):965–971

    Article  PubMed  CAS  Google Scholar 

  • Scandinavian Stroke Study Group (1985) Multicenter trial of hemodilution in ischemic stroke: background and study protocol. Stroke 16:885–890

    Article  Google Scholar 

  • Schachter M (2004) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 19(1):117–125

    Article  Google Scholar 

  • Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, Kim RB, Roden DM, Stein CM (2008) Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 358(10):999–1008

    Article  PubMed  CAS  Google Scholar 

  • Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106:2329–2333

    Article  PubMed  CAS  Google Scholar 

  • Seiler SM, Bernatowicz MS (2003) Peptide-derived protease-activated receptor-1 (PAR-1) antagonists. Curr Med Chem 1:1–11

    CAS  Google Scholar 

  • Sharma A, Ebling WF, Jusko WJ (1998) Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena. J Pharm Sci 87(12):1577–1584

    Article  PubMed  CAS  Google Scholar 

  • Stancu C, Sima A (2001) Statins: mechanism of action and effects. J Cell Mol Med 5(4):378–387

    Article  PubMed  CAS  Google Scholar 

  • Steinhubl SR, Moliterno DJ (2005) The role of the platelet in the pathogenesis of atherothrombosis. Am J Cardiovasc Drugs 5(6):399–408

    Article  PubMed  CAS  Google Scholar 

  • Stergiou GS (2004) Angiotensin receptor blockade in the challenging era of systolic hypertension. J Human Hypertens 18:837–847

    Article  CAS  Google Scholar 

  • Theilmeier G, Michiels C, Spaepen E, Vreys I, Collen D, Vermylen J, Hoylaerts MF (2002) Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia. Blood 99(12):4486–4493

    Article  PubMed  CAS  Google Scholar 

  • Unadkat JD, Sheiner LB, Hennis PJ, Cronnelly R, Miller RD, Sharma M (1986) An integrated model for the interaction of muscle relaxants with their antagonists. J Appl Physiol 61(4):1593–1598

    PubMed  CAS  Google Scholar 

  • Verotta D, Beal SL, Sheiner LB (1989) Semi parametric approach to pharmacokinetic-pharmacodynamic data. Am J Physiol 256(4 Pt 2):R1005–R1010

    PubMed  CAS  Google Scholar 

  • Whelan HT, Cook JD, Amlie-Lefond CM, Hovinga CA, Chan AK, Ichord RN, Deveber GA, Thall PF (2008) Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children. Stroke 39(9):2627–2636

    Article  PubMed  Google Scholar 

  • Williams D, Feely J (2002) Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 41(5):343–370

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Professor Stuart Beal for his suggestion of the “indescribable” mixture model, and Ms. Tracey Thomas for help in formatting and preparing this chapter.

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Authors and Affiliations

  1. Projections Research Inc., 535 Springview Lane, Phoenixville, PA, 19460, USA

    Diane R. Mould

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  1. Diane R. Mould
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  2. Bill Frame
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  3. Timothy Taylor
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Corresponding author

Correspondence to Diane R. Mould .

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Editors and Affiliations

  1. Department of Advanced Modeling & Simula, Janssen Research & Development, LLC, Route 202 S. 920, Raritan, 08869, New Jersey, USA

    Holly H. C. Kimko

  2. Dept. Biopharmaceutical Sciences, University of California, San Francisco, Parnassus Ave. 513, San Francisco, 94143-0446, California, USA

    Carl C. Peck

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Mould, D.R., Frame, B., Taylor, T. (2011). Modeling and Simulation in the Development of Cardiovascular Agents. In: Kimko, H., Peck, C. (eds) Clinical Trial Simulations. AAPS Advances in the Pharmaceutical Sciences Series, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7415-0_10

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