Abstract
Introduction For a small number of drugs circadian variability has been shown to modify efficacy, safety, or pharmacokinetics. Objective of the study We aimed to develop a database containing optimum timing of drug administration and to test how well such information is considered in daily practice. Setting University hospital providing primary and tertiary care. Methods We included data of randomised controlled trials collected from Embase and Medline studying the impact of the timing of drug administration on pharmacodynamics, pharmacokinetics, and adverse events. Data were analysed and weighed according to an algorithm considering trial design and assessed endpoints. Each branch of the algorithm led to a specific recommendation as to the time of the day the drug should be administered. A second algorithm was used to establish a recommendation if studies differed in their conclusion. Subsequently we retrospectively analysed the dosing time in consecutive electronic prescriptions issued at our institution in 2007. Results For 30 active compounds randomised controlled trials were published assessing optimum timing of their administration. In 33% of them timing had no impact on clinical endpoints while the administration at a certain time of the day significantly improved the outcome of another 64% no clear statement was made for one drug (ketoprofen). We then analysed 478864 electronic prescriptions. Two percent of them contained drugs with known circadian variability. Only in 14% the suggested time was considered with a range between 0% for telmisartan (bedtime administration) and 85% for perindopril (morning administration). Conclusion Thus far, dedicated studies on circadian responsiveness to drugs are sparse and for the few drugs with unequivocal evidence this information is only rarely considered in daily practice. Integration of circadian dosing information into a clinical decision support system linked to electronic prescribing may be one promising way to make this information widely accessible.
Similar content being viewed by others
References
Smolensky MH, Portaluppi F. Chronopharmacology and chronotherapy of cardiovascular medications relevance to prevention and treatment of coronary heart disease. Am Heart J. 1999;137:14–24.
Lemmer B. The clinical relevance of chronopharmacology in therapeutics. Pharmacol Res. 1996;33:107–15.
Goo RH, Moore JG, Greenberg E, Alazraki NP. Circadian variation in gastric emptying of meals in humans. Gastroenterology. 1987;93:515–8.
Lemmer B, Nold G. Circadian changes in estimated hepatic blood flow in healthy subjects. Br J Clin Pharmacol. 1991;32:627–9.
Shaw GL, Falk RT, Caporaso NE, Issaq HJ, Kase RG, Fox SD, et al. Effect of diurnal variation on debrisoquine metabolic phenotyping. J Natl Cancer Inst. 1990;82:1573–5.
Bleyzac N, Allard-Latour B, Laffont A, Mouret J, Jelliffe R, Maire P. Diurnal changes in the pharmacokinetic behavior of amikacin. Ther Drug Monit. 2000;22:307–12.
Kitahara Y, Saito F, Akao M, Fujita H, Takahashi A, Taguchi H, et al. Effect of morning and bedtime dosing with cilnidipine on blood pressure, heart rate, and sympathetic nervous. J Cardiovasc Pharmacol. 2004;43:68–73.
Hermida RC, Calvo C, Ayala DE, López JE, Rodríguez M, Chayán L, et al. Dose- and administration time-dependent effects of nifedipine gits on ambulatory blood pressure in hypertensive subjects. Chronobiol Int. 2007;24:471–93.
White WB, Mansoor GA, Pickering TG, Vidt DG, Hutchinson HG, Johnson RB, et al. Differential effects of morning and evening dosing of nisoldipine ER on circadian blood pressure and heart rate. Am J Hypertens. 1999;12:806–14.
Usher RW, Beasley CM Jr, Bosomworth JC. Efficacy and safety of morning versus evening fluoxetine administration. J Clin Psychiatry. 1991;52:134–6.
Vashi V, Chung M, Dias N, Phillips K. Effect of time of administration on the pharmacokinetics and tolerance of doxazosin in healthy male volunteers. J Clin Pharmacol. 1996;36:325–31.
Kirby RS, Chapple CR, Sethia K, Flannigan M, Milroy EJ, Abrams P. Morning vs evening dosing with doxazosin in benign prostatic hyperplasia: efficacy and safety. Prostate Cancer Prostatic Dis. 1998;1:163–71.
Khasawneh SM, Affarah HB. Morning versus evening dose: a comparison of three H2-receptor blockers in duodenal ulcer healing. Am J Gastroenterol. 1992;87:1180–2.
Hongo M, Ohara S, Hirasawa Y, Abe S, Asaki S, Toyota T. Effect of lansoprazole on intragastric pH. Comparison between morning and evening dosing. Dig Dis Sci. 1992;37:882–90.
Scharnagl H, Vogel M, Abletshauser C, Freisinger F, Stojakovic T, März W. Efficacy and safety of fluvastatin-extended release in hypercholesterolemic patients: morning administration is equivalent to evening administration. Cardiology. 2006;106:241–8.
Fogari R, Malacco E, Tettamanti F, Gnemmi AE, Milani M. Evening vs. morning isradipine sustained release in essential hypertension: a double-blind study with 24 h ambulatory monitoring. Br J Clin Pharmacol. 1993;35:51–4.
Kuroda T, Kario K, Hoshide S, Hashimoto T, Nomura Y, Saito Y, et al. Effects of bedtime vs. morning administration of the long-acting lipophilic angiotensin-converting enzyme inhibitor trandolapril on morning blood pressure in hypertensive patients. Hypertens Res. 2004;27:15–20.
Postma DS, Sevette C, Martinat Y, Schlösser N, Aumann J, Kafé H. Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Eur Respir J. 2001;17:1083–8.
Deedwania PC, Pool PE, Thadani U, Eff J. Effect of morning versus evening dosing of diltiazem on myocardial ischemia detected by ambulatory electrocardiographic monitoring in chronic stable angina pectoris. Dilacor XR Ambulatory Ischemia Study Group. Am J Cardiol. 1997;80:421–5.
Glass-Marmor L, Paperna T, Galboiz Y, Miller A. Immunomodulation by chronobiologically-based glucocorticoids treatment for multiple sclerosis relapses. J Neuroimmunol. 2009;210:124–7.
Lund TM, Torsvik H, Falch D, Christophersen B, Skårdal R, Gullestad L. Effect of morning versus evening intake of simvastatin on the serum cholesterol level in patients with coronary artery disease. Am J Cardiol. 2002;90:784–6.
Wallace A, Chinn D, Rubin G. Taking simvastatin in the morning compared with in the evening: randomised controlled trial. BMJ. 2003;327:788.
Pehlivanov ND, Olyaee M, Sarosiek I, McCallum RW. Comparison of morning and evening administration of rabeprazole for gastro-oesophageal reflux and nocturnal gastric acid breakthrough in patients with reflux disease: a double-blind, cross-over study. Aliment Pharmacol Ther. 2003;18:883–90.
Kerr DJ, Lewis C, O’Neil B, Lawson N, Blackie RG, Newell DR, et al. The myelotoxicity of carboplatin is influenced by the time of its administration. Hematol Oncol. 1990;8:59–63.
Palatini P, Racioppa A, Raule G, Zaninotto M, Penzo M, Pessina AC. Effect of timing of administration on the plasma ACE inhibitory activity and the antihypertensive effect of quinapril. Clin Pharmacol Ther. 1992;52:378–83.
Levi F, Le Louarn C, Reinberg A. Timing optimizes sustained-release indomethacin treatment of osteoarthritis. Clin Pharmacol Ther. 1985;37:77–84.
Ozaydin M, Dede O, Dogan A, Aslan SM, Altinbas A, Ozturk M, et al. Effects of morning versus evening intake of atorvastatin on major cardiac event and restenosis rates in patients undergoing first elective percutaneous coronary intervention. Am J Cardiol. 2006;97:44–7.
Cilla DD Jr, Gibson DM, Whitfield LR, Sedman AJ. Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening. J Clin Pharmacol. 1996;36:604–9.
Portaluppi F, Vergnani L, Manfredini R, degli Uberti EC, Fersini C. Time-dependent effect of isradipine on the nocturnal hypertension in chronic renal failure. Am J Hypertens. 1995;8:719–26.
Busse WW, Bush RK. Comparison of morning and evening dosing with a 24-hour sustained-release theophylline, Uniphyl, for nocturnal asthma. Am J Med. 1985;79:62–6.
Su YM, Cheng TP, Yeh TW, Wen CY, Wang DI. Influence of morning or evening administration on absorption of theophylline. Zhonghua Yi Xue Za Zhi. 2000;63:113–8.
Nold G, Strobel G, Lemmer B. Morning versus evening amlodipine treatment: effect on circadian blood pressure profile in essential hypertensive patients. Blood Press Monit. 1998;3:17–25.
Qiu YG, Chen JZ, Zhu JH, Yao XY. Differential effects of morning or evening dosing of amlodipine on circadian blood pressure and heart rate. Cardiovasc Drugs Ther. 2003;17:335–41.
Kuwajima I, Suzuki Y, Shimosawa T, Kanemaru A, Hoshino S, Kuramoto K. Diminished nocturnal decline in blood pressure in elderly hypertensive patients with left ventricular hypertrophy. Am Heart J. 1992;123:1307–11.
Morgan T, Anderson A, Jones E. The effect on 24 h blood pressure control of an angiotensin converting enzyme inhibitor (perindopril) administered in the morning or at night. J Hypertens. 1997;15:205–11.
Prichard PJ, Yeomans ND, Mihaly GW, Jones DB, Buckle PJ, Smallwood RA, et al. Omeprazole: a study of its inhibition of gastric pH and oral pharmacokinetics after morning or evening dosage. Gastroenterology. 1985;88:64–9.
Müssig S, Witzel L, Lühmann R, Schneider A. Morning and evening administration of pantoprazole: a study to compare the effect on 24-hour intragastric pH. Eur J Gastroenterol Hepatol. 1997;9:599–602.
Hermida RC, Ayala DE, Calvo C, López JE, Mojón A, Rodríguez M, et al. Differing administration time-dependent effects of aspirin on blood pressure in dipper and non-dipper hypertensives. Hypertension. 2005;46:1060–8.
Moore JG, Goo RH. Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man. Chronobiol Int. 1987;4:111–6.
Hermida RC, Calvo C, Ayala DE, Domínguez MJ, Covelo M, Fernández JR, et al. Administration time-dependent effects of valsartan on ambulatory blood pressure in hypertensive subjects. Hypertension. 2003;42:283–90.
Hermida RC, Calvo C, Ayala DE, Fernández JR, Covelo M, Mojón A, et al. Treatment of non-dipper hypertension with bedtime administration of valsartan. J Hypertens. 2005;23:1913–22.
Hermida RC, Calvo C, Ayala DE, Mojón A, Rodríguez M, Chayán L, et al. Administration time-dependent effects of valsartan on ambulatory blood pressure in elderly hypertensive subjects. Chronobiol Int. 2005;22:755–76.
Hermida RC, Ayala DE, Fernández JR, Calvo C. Comparison of the efficacy of morning versus evening administration of telmisartan in essential hypertension. Hypertension. 2007;50:715–22.
Hermida RC, Ayala DE, Chayan L, Mojon A, Fernandez JR. Administration-time-dependent effects of olmesartan on the ambulatory blood pressure of essential hypertension patients. Chronobiol Int. 2009;26:61–79.
Myburgh DP, Verho M, Botes JH, Erasmus TP, Luus HG. 24-Hour blood pressure control with ramipril: comparison of once-daily morning and evening administration. Current Ther Res. 1995;56:1298–306.
Hermida RC, Ayala DE. Chronotherapy with the angiotensin-converting enzyme inhibitor ramipril in essential hypertension: improved blood pressure control with bedtime dosing. Hypertension. 2009;54:40–6.
Calvo C, Hermida RC, Ayala DE, López JE, Rodríguez M, Chayán L, et al. Chronotherapy with torasemide in hypertensive patients: increased efficacy and therapeutic coverage with bedtime administration. Med Clin. 2006;127:721–9.
Reinberg A, Gervais P, Chaussade M, Fraboulet G, Duburque B. Circadian changes in effectiveness of corticosteroids in eight patients with allergic asthma. J Allergy Clin Immunol. 1983;71:425–33.
Vinje O, Fagertun HE, Laerum E, Lund H, Larsen S. Ketoprofen controlled release (CR) in the treatment of osteoarthrosis; a double blind, randomized multicentre study of single morning versus evening dose. Norwegian Study Group of General Practitioners. Scand J Prim Health Care. 1993;11:91–7.
Perpoint B, Mismetti P, Simitsidis S, Hocquart J, Rambaud C, Buchmuller A, et al. Dosing time optimizes sustained-release ketoprofen treatment of osteoarthritis. Chronobiol Int. 1994;11:119–25.
Poondru S, Devaraj R, Boinpally RR, Yamasani MR. Chronopharmacokinetics of sumatriptan in healthy human subjects. J Pharm Pharmacol. 2000;52:1085–90.
Kesselheim AS, Misono AS, Lee JL, Stedman MR, Brookhart MA, Choudhry NK, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008;300:2514–26.
Funding
This study was supported by the University of Heidelberg. Arwa Hassan’s work was funded by an unrestricted educational grant from Syria.
Conflict of Interest
The authors have no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hassan, A., Haefeli, W.E. Appropriateness of timing of drug administration in electronic prescriptions. Pharm World Sci 32, 162–171 (2010). https://doi.org/10.1007/s11096-009-9362-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11096-009-9362-4