Introduction and Background of Pharmionics

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Chapter: Pharmacovigilance: Introduction to Pharmionics

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

INTRODUCTION AND BACKGROUND

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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