E-DRUG: Fixed dose combinations and compliance
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Dear E-druggers,
Be cautious in accepting the often-repeated slogan that patient
compliance is best with once-daily dosing. It has been a marketing slogan
for so long that even many skeptics believe it to be true. From a decade
of studies using electronic monitoring , however, one can confidently say
that once-daily regimens do not solve the "compliance problem", because
they do not prevent omission of doses. For documentation of that point,
see the bibliographies posted at the websites of the two sources of
electronically monitored packages for solid, oral dosage forms:
www.aprex.com and www.aardexus.com
An almost invariably consistent finding has been that the percentage of
prescribed doses taken with once-daily regimens is, on average, slightly
higher than with twice-daily regimens. Not only is the difference very
small, but one must also consider the length of time that elapses before
dosing resumes. Consider these words of Wolfgang Kruse, who, together
with the late Prof. Ellen Weber of Heidelberg, has done some of the
important pioneering work with the electronic monitoring method:
"Days without any dosing events were twice as often with the QD than
the BID regimen. ... Episodes of 3 or more subsequent days without dosing
events ... were also observed more often with the QD than the BID regimen.
... Doses were omitted more frequently on weekends than on any other day
of the week ... (p<0.001). Evening doses were omitted about twice as often
as ... morning doses [in] ... patients prescribed the BID regimen
(p<0.001)"
The reference is: Kruse W, Rampmaier J, Ullrich G, Weber E. Patterns of
drug compliance with medication to be taken once and twice daily assessed
by continuous electronic monitoring in primary care. Int J Clin Pharmacol
Ther 32: 453-7, 1994.
The clinical importance of omission of some doses in either a once-daily
(QD) or BID regimen depends on how long therapeutically useful drug
action persists after the last-taken dose. Since the most common
compliance error is the omission of a single dose, the first question to
consider is: what happens to drug action when the evening dose of a BID
regimen is forgotten: is drug action still satisfactorily maintained by the
time of the following morning's dose? Unfortunately, we lack information
on that point for most drugs. It is a question whose answer is not only
drug-specific, but pharmaceutical-specific, because dosage form properties
can, in some instances, markedly modify the duration of drug action.
A contribution to the answer can come from pharmacokinetic studies, but
not the definitive answer, because the question is ultimately a
pharmacodynamic one, answered by measurements of the persistence of drug
action after a last taken dose, which obviously is far more easily said
than done, and probably well-nigh impossible in many instances. For the
vast majority of drugs (except those that develop tolerance during
sustained exposure, e.g. nitroglycerine), one can be reasonably certain
that the drug is still acting if the concentration(s) of drug and/or active
metabolite(s) in plasma are within the range that can, on the basis of
evidence, be said to be the "therapeutic range".
However, there are many instances in which drug and known metabolite
concentrations have faded to undetectable levels with drug action still
in full sway. Thus, there may be some BID drugs that allow one to miss
an occasional single dose and still have continuing drug action to a
therapeutically sufficient extent. Conversely, there may some
once-daily drugs that scarcely act longer than 24 hrs and so lose their
activity within a few hours after missed dose.
(Examples of two widely used, once-daily agents that lose their therapeutic
activity soon after the 24th hour are atenolol and the combined
estrogen-progestagen oral contraceptives. References are:
a) Johnson BF, Whelton A. A study design for comparing the effects
of missing daily doses of antihypertensive drugs. Am J Therapeutics 1:
260-7, 1994.
b) Guillebaud J. Any questions. Brit Med J 307: 617. 1993.)
The upshot of all this is that doses are missed in both once-daily and
BID regimens, that longer lapses in dosing may be more common with once
than with twice daily regimens, and that the clinical consequences of a
lapse in dosing are specific to drug and dosage form -- a difficult point
to quantify and which in many instances will have to be based on
observational data rather than controlled trials.
John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology, Maastricht University, Maastricht NL
Chief Scientist, AARDEX Ltd/APREX, Zug, CH and Union City, California
USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
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