Abstract
Evaluation of the effects of a drug on arterial blood pressure is important in nonclinical safety pharmacology assessment. Detecting large and obvious changes in blood pressure is an unchallenging task. Detecting small changes is more difficult, and interpretation of findings requires careful risk/benefit evaluation. Detecting subtle and small changes in blood pressure is important in particular with respect to increases, since blood pressure above the normal range is associated with increased risk of stroke and sudden cardiac death. Cardiovascular safety pharmacology has been preoccupied with drug-induced changes in the electrocardiogram, and by comparison, there has been little in the way of contemporaneous improvements in the level of complexity and sophistication involved in blood pressure assessment. Thus, it is important to understand the nature of drug-induced changes in blood pressure, appreciate the plethora of agents currently used clinically (and over the counter) that alter blood pressure and understand safety pharmacology study design in order to optimize assessment of a new chemical entity (NCE) or biologic agent in this context.
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References
Anon (2001) ICH S7A: Safety pharmacology studies for human pharmaceuticals Fed Reg 66:36791 − 36792. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074959.pdf
Anon (2010) ICH S9: Nonclinical evaluation for anticancer pharmaceuticals guidance Fed Reg 75:10487–10488. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm085389.pdf
Authier S, Tanguay JF, Fournier S, Gauvin D, Legaspi M, Chaurand F, Breault C, Troncy E (2008) Conscious and anesthetized non-human primate safety pharmacology models: hemodynamic sensitivity comparison. J Pharmacol Toxicol Methods 58:94–98
Biaggioni I, Zygmunt D, Haile V, Robertson D (1990) Pressor effect of inhaled ergotamine in orthostatic hypotension. Am J Cardiol 65:89–92
Borysenko M, Beringer T (1984) Functional histology. Little, Brown and Company Inc., Boston, pp 195–208
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee (2003) The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289:2560–2572
Clyburn EB, DiPette DJ (1995) Hypertension induced by drugs and other substances. Semin Nephrol 15:72–86
Curwen JO, Musgrove HL, Kendrew J, Richmond GH, Ogilvie DJ, Wedge SR (2008) Inhibition of vascular endothelial growth factor-a signaling induces hypertension: examining the effect of cediranib (recentin; AZD2171) treatment on blood pressure in rat and the use of concomitant antihypertensive therapy. Clin Cancer Res 14:3124–3131
Di Lorenzo G, Autorino R, Bruni G, Cartenì G, Ricevuto E, Tudini M, Ficorella C, Romano C, Aieta M, Giordano A, Giuliano M, Gonnella A, De Nunzio C, Rizzo M, Montesarchio V, Ewer M, De Placido S (2009) Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol 20:1535–1542
Ewart L, Milne A, Adkins D, Benjamin A, Bialecki R, Chen Y, Ericsson AC, Gardner S, Grant C, Lengel D, Lindgren S, Lowing S, Marks L, Moors J, Oldman K, Pietras M, Prior H, Punton J, Redfern WS, Salmond R, Skinner M, Some M, Stanton A, Swedberg M, Finch J, Valentin JP (2013) A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions. J Pharmacol Toxicol Methods 68:30–43
Ewer MS, Suter TM, Lenihan DJ, Niculescu L, Breazna A, Demetri GD, Motzer RJ (2014) Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: A comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events. Eur J Cancer 50:2162–2170
Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, Hershey JC, Keller WJ, Ma X, McPherson HE, Messina E, Peterson LB, Sharif-Rodriguez W, Siegl PK, Sinclair PJ, Sparrow CP, Stevenson AS, Sun SY, Tsai C, Vargas H, Walker M III, West SH, White V, Woltmann RF (2008) Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 154:1465–1473
Grossman E, Messerli FH (2008) Secondary hypertension: interfering substances. J Clin Hypertens (Greenwich) 10:556–566
Hamlin RL, del Rio C (2012) dP/dt(max)—a measure of ‘baroinometry’. J Pharmacol Toxicol Methods 66:63–65
Hirschi KK, D’Amore PA (1996) Pericytes in the microvasculature. Cardiovasc Res 32:687–698
Howes LG, Kostner K (2007) The withdrawal of torcetrapib from drug development: implications for the future of drugs that alter HDL metabolism. Expert Opin Investig Drugs 16:1509–1516
Isobe T, Komatsu R, Honda M, Kuramoto S, Shindoh H, Tabo M (2014) Estimating the clinical risk of hypertension from VEGF signal inhibitors by a non-clinical approach using telemetered rats. J Toxicol Sci 39:237–242
Johns DG, Duffy J, Fisher T, Hubbard BK, Forrest MJ (2012) On- and off-target pharmacology of torcetrapib: current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors. Drugs 72:491–507
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R (2002) Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360:1903–1913
Ng A, Smith G (2002) Anesthesia and the gastrointestinal tract. J Anesth 16:51–64
Nwankwo T, Yoon SS, Burt V, Gu Q (2013) Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief 133:1–8
Polakowski JS, King AJ, Campbell TJ, Nelson RA, Preusser LC, Kempf-Grote AJ, Marsh KC, Gintant GA, Cox BF, Mittelstadt SW (2009) Cardiovascular effects of torcetrapib in conscious and pentobarbital-anesthetized dogs. J Cardiovasc Pharmacol 54:543–551
Psaty BM, Lumley T (2008) Surrogate end points and FDA approval: a tale of 2 lipid-altering drugs. JAMA 299:1474–1476
Pugsley MK, Tabrizchi R (2000) The Vascular System: an overview of structure and function. J Pharmacol Toxicol Methods 44:333–340
Pugsley MK, Authier S, Curtis MJ (2008) Principles of safety pharmacology. Br J Pharmacol 154:1382–1399
Pugsley MK, Authier S, Curtis MJ (2010) Cardiovascular disease: drug development struggles against a global epidemic. Pharmacol Matters 3:25–30
Sarazan RD (2014) Cardiovascular pressure measurement in safety assessment studies: technology requirements and potential errors. J Pharmacol Toxicol Methods 70:210–223
Sethuraman V, Sun Q (2009) Impact of baseline ECG collection on the planning, analysis and interpretation of ‘thorough’ QT trials. Pharm Stat 8:113–124
Sivarajah A, Collins S, Sutton MR, Regan N, West H, Holbrook M, Edmunds N (2010) Cardiovascular safety assessments in the conscious telemetered dog: utilization of super-intervals to enhance statistical power. J Pharmacol Toxicol Methods 62:12–19
Soloviev MV, Hamlin RL, Shellhammer LJ, Barrett RM, Wally RA, Birchmeier PA, Schaefer GJ (2006) Variations in hemodynamic parameters and ECG in healthy, conscious, freely moving telemetrized beagle dogs. Cardiovasc Toxicol 6:51–62
Torjman MC, Joseph JI, Munsick C, Morishita M, Grunwald Z (2005) Effects of isoflurane on gastrointestinal motility after brief exposure in rats. Int J Pharm 294:65–71
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Authier, S., Pugsley, M.K., Curtis, M.J. (2015). Haemodynamic Assessment in Safety Pharmacology. In: Pugsley, M., Curtis, M. (eds) Principles of Safety Pharmacology. Handbook of Experimental Pharmacology, vol 229. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46943-9_9
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