Introduction to Pharmionics: The Vagaries in Ambulatory Patients’ Adherence to Prescribed Drug Dosing Regimens, and Some of Their Clinical and Economic Consequences
Introduction to
Pharmionics: The Vagaries in Ambulatory Patients’ Adherence to Prescribed Drug
Dosing Regimens, and Some of Their Clinical and Economic Consequences
The
general topic of this chapter is very old. Hippocrates is said to have
complained that some of his patients did not take the medicines he prescribed,
and then blamed him for a poor outcome. Given the state of therapeutics at that
time, it is unlikely that many of the medicines that Hippocrates prescribed
were very effective or free from toxicity. Thus, patients who declined to take
his prescribed medicine(s) were perhaps more likely than not to be making the
better choice.
The
situation today is radically different. Begin-ning in the mid-1930s with the
advent of the sulfa drugs, and catalyzed after 1945 by the advent of
peni-cillin, the pharmaceutical industry has transformed itself from a minor to
a major industry by discovering drugs and developing them into pharmaceutical
prod-ucts of increasing therapeutic and prophylactic power, whilst meeting
increasingly rigorous standards for acceptable hazard. Since 1961, with the
introduction of oral steroidal contraceptives, a growing number of medicines
have been developed for long-term prophy-lactic use by either completely normal
individuals (as is the case with oral contraceptives) or individuals who have
certain precursor conditions (e.g., uncom-plicated, mild hypertension; elevated
lipid levels; decreased bone mineral density) that are deemed risk factors for
the subsequent development of overt disease. A further transition in the use of
pharmaceu-ticals has been the increasing use of drug response vs. non-response
as diagnostic information. A still further change, which will foreseeably
continue, has been increasingly ability to see disease in its earliest stages,
thus moving backwards the somewhat fuzzy bound-ary between prophylaxis of
disease and treatment of disease. This last point is illustrated by the
continually more aggressive efforts during the past two decades to modify by
increasingly intense pharmacological means the concentrations of various lipids
in blood, steadily lowering the risk of coronary arterial disease.
In
the arena of infectious disease, the period 1945– 2005 have seen an intense
race between the emer-gence of micro-organismal resistance to anti-infective
agents in clinical use and the emergence of new anti-infective agents from the
pharmaceutical indus-try’s research and development efforts. There is a broad
consensus that patients’ erratic exposure to anti-infective agents, either
through erratic execution of drug dosing regimens or early discontinuation of
treat-ment, creates conditions that foster the emergence of drug resistant
micro-organisms. Most infectious disease experts recognize that either form of
under-treatment can drop the concentrations of anti-infective agents in blood
or tissues to a point low enough to allow high rates of micro-organismal
replication, whilst still being high enough to exert so-called ‘selec-tion
pressure’. Thus, mutant micro-organisms, carry-ing mutations that confer drug
resistance, are selected for, as they are believed to thrive better in an
envi-ronment of partial exposure to anti-microbial drug action than wild-type
micro-organisms, which lack these mutations.
How
soon after the onset of clinical use is a newly introduced anti-infective agent
likely to begin to be confronted by drug-resistant micro-organisms? There is
great variability in the answer to this question. At one end of the spectrum is
the continuing sensitiv-ity of Treponema
pallidum, the infective agent for syphilis. Treponema pallidum has never developed resistance to penicillin in
almost 60 years of use to cure syphilis – a disease that, in the preceding
several centuries, was pandemic in the western world, rival-ing tuberculosis as
the leading infectious disease and cause of mortality and major morbidity at
all ages of human life. In contrast, other micro-organisms, for example Staphylococcus aureus, Pseudomonas
aerug-inosa and Bacillus proteus,
have each more or less rapidly
achieved resistance to successively introduced anti-infective agents. So have
tubercle bacilli and the human immunodeficiency virus (HIV). Clearly the topic
of emergent drug resistance of anti-infective agents has many aspects that are
specific to the drugs and the micro-organisms involved. Such detail goes beyond
the scope of this chapter, but suffice it to say that erratic exposure of
infecting micro-organisms to anti-infective agents, either due to erratic
dosing or early cessation of dosing, is generally accepted as a crucial factor
in the emergence of micro-organismal resistance to anti-microbial drug
resistance.
For
many reasons that are beyond the scope of this chapter, prices of prescription
drugs, which for many years lagged behind the Consumer Price Index in the
United States, have risen steeply since the early 1990s.
Thus
the advent of medicines with unprecedented therapeutic power and economic cost,
some of which are indicated for multi-year or lifelong use, and some of which
are beset by the problem of emergent drug-resistance, has put increasing
emphasis on the ques-tion of how well or poorly patients actually use
prescribed medicines. That growing emphasis has led to the formation of a new
subdiscipline of biopharma-ceutical science, called pharmionics (Urquhart 2002), which concerns itself with learning
what patients actually do with prescribed drugs and analysing the clinical and
economic consequences of the various temporal patterns of drug exposure that
arise from patients’ variable adherence to prescribed drug dosing regimens. A
natural by-product of this focus is an ongoing challenge to the optimality of
recommended drug dosing regimens.
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