Abstract
Once-daily dosing almost invariably shows a slightly higher percentage of prescribed doses taken than does twice-daily dosing. Many pharmaceutical scientists, regulators, and prescribers have considered this finding to signify the therapeutic superiority of once-daily dosing. The therapeutically more relevant question, however, is not the percentage of prescribed doses taken but the comparative impact of missed doses on the pharmacologic effects of a drug under the two dosing regimens. A key point in this regard is that the pharmacokinetic equivalent of a single missed once-daily dose is 2–3 sequentially omitted twice-daily doses. Thus, an important parameter in comparing the two regimens is the probability of two or three twice-daily doses being sequentially omitted, versus the probability of missing a single once-daily dose. Our data indicate that the probability of sequential omission of 2–3 twice daily doses is half the probability of omission of a single once-daily dose. For that reason, a twice-daily regimen could prove to be superior to a once-daily regimen in maintaining drug concentrations within a therapeutically desirable range. A more important consideration, however, is to maintain not just the concentration of drug in plasma, but the drug’s therapeutic action. The duration of therapeutic drug action following a last-taken dose is not only drug-specific, but also, for some drug, dependent on the pharmacodynamic properties. Judging the comparative superiority of one dosing regimen over another requires knowledge of the drug’s duration action after a last-taken dose, plus knowledge of the comparative probabilities of the various patterns of dose omission. When applied to HIV protease inhibitors, a twice-daily regimen appears to be better than an once-daily regimen in maintaining therapeutically effective drug actions.
Similar content being viewed by others
References
Moyle G (2002) The appt-1 study: assessing patients preferred treatments. Program and abstracts of the 6th International Congress on Drug Therapy in HIV Infection. November 17–21, Glasgow, Scotland, Abstract p 90
Hughes D (2006). Less is more: medicines that require less frequent administration improve adherence, but are they better?. Pharmacoeconomics 24(3): 211–213
Claxton AJ, Cramer J and Pierce C (2001). A systematic review of the associations between dose regimens and medication compliance. Clin Ther 23(8): 1296–1310
Vrijens B and Urquhart J (2005). Patient adherence to prescribed antimicrobial drug dosing regimens. J Antimicrob Chemother 55(5): 616–627
Vrijens B, Tousset E, Rode R, Bertz R, Mayer S and Urquhart J (2005). Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models. J Clin Pharmacol 45(4): 461–467
Vrijens B, Tousset E, Gaillard P-A, Metry JM and Urquhart J (2005). Major features of dose omissions in 87 ambulatory drug trials. Clin Pharmacol Ther 77(2): 99
Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, Wagener MM and Singh N (2000). Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 133: 21–30
Paterson DL, Potoski B and Capitano B (2002). Measurement of adherence to antiretroviral medications. J Acquir Immune Defic Syndr 31(Suppl 3): S103–S106
Vrijens B and Goetghebeur E (1997). Comparing compliance patterns between randomized treatments. Control Clin Trials 18(3): 187–203
Bertz R, Renz C, Foit C, Swerdlow J, Ye X, Jasinsky O, Hsu A, Granneman GR, Sun E (2001) Steady-state pharmacokinetics of Kaletra (lopinavir/ritonavir 400/100 mg BID) in HIV-infected subjects when taken with food. Second International Workshop on Clinical Pharmacology of HIV Therapy, Noordwijk, The Netherlands
Kaletra® Prescribing Information, Abbott Laboratories, January (2002)
Urquhart J and Vrijens B (2005). New findings about patient adherence to prescribed drug dosing regimens: an introduction to pharmionics. EJHP 5: 103–106
http://www.labcorp.com/pdf/TheraSure_LabFacet_1451.pdf
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Comté, L., Vrijens, B., Tousset, E. et al. Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics. J Pharmacokinet Pharmacodyn 34, 549–558 (2007). https://doi.org/10.1007/s10928-007-9058-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-007-9058-0