Key points are not available for this paper at this time.
When an aptly prescribed medicine has not worked as expected, the potential explanations logically fall among three categories: pharmacodynamic, pharmacokinetic, and pharmionic. Pharmacodynamic reasons include problems in drug reception created by deficient or absent receptors, when disease or comorbidities are too severe for the agent's usual therapeutic benefits to express themselves, when unusually strong physiological counter-regulatory actions attenuate or nullify the drug's usual actions, and others – obviously a whole topic in its own right. Pharmacokinetic reasons include problems with drug absorption or unusually high rates of presystemic or systemic drug metabolism, or of other clearance mechanisms, resulting in unusually low concentrations of drug in plasma and other body fluids arising from the usually satisfactory, recommended dosage regimen. Pharmionic reasons include failure of the medicine to be taken in the doses, at the times, and in keeping with other dosing instructions that are needed, ceteris paribus, for satisfactory therapeutic action. 'Pharmionic' is the adjectival form of the name of a nascent discipline, pharmionics, which is concerned with factors that measure and control the use of prescription pharmaceuticals. The suffix 'ionic' comes from the Greek verb 'to go'1. Pharmionics is akin to 'avionics', which is the discipline and technologies concerned with the measuring and controlling of flight in aircraft – 'the going' of the airplane. Avionics began and grew in importance as advances in aircraft pushed speed and acceleration past the point that pilots could safely rely on direct vision, a compass, an altimeter, and 'seat of the pants' sensations for controlling flight. Today's means of measurement, communication, and control have superseded the simple approaches that can suffice when flight is slow, low, and in ideal weather. Analogously, one can reasonably say that pharmacotherapeutics has reached or passed the point where the power and complexity of medicines require formalization into disciplinary terms of the methods of measurement, communication, and control needed to improve the likelihood, if not assure, that powerful medicines are administered in appropriate doses, at appropriate times, under appropriate circumstances. These are the topics that comprise the subject matter of pharmionics. The etymology of 'pharmionics' indicates its basic concern with 'the going of the prescription drug – 'going' in the sense that a manufactured dosage form must, if it is to play its therapeutic role, travel from the package in which it is dispensed by a pharmacy into the patient's mouth, and down the oesophagus to the stomach. At that point, the discipline of pharmacokinetics takes centre-stage, dealing with subsequent conversion of drug into metabolites and movement into the bloodstream, toward receptors or other sites of action, which fall under the discipline of pharmacodynamics. The distances that the drug travels under the purview of pharmionics are a few metres more than the meter or so that drug travels under the purview of pharmacokinetics. One can envision a further spatial compression from metres to the angstroms involved in the receptor docking/undocking that could reasonably be considered the domain of pharmacodynamics, beyond which receptor-generated message(s), but usually not the drug molecules themselves, may travel locally or in some cases systemically. Undocked drug molecules return to the domain of pharmacokinetics, for metabolism and/or excretion. In terms of what can go wrong in ambulatory pharmacotherapy, history shows that things can go wrong at every point along the medicine's travels from pharmaceutical factory to drug receptor. Most errors occur, however, after the dispensing of the prescription, when the patient becomes responsible for the penultimate steps in the whole chain from factory to receptor. Errors made at any point in, or segment of, those travels can nullify or otherwise pervert therapeutic intentions of manufacturers, prescribers, and pharmacists. This view was nicely codified by Carl Peck and the late John Harter in a valuable paper in 1991 2, recently fine-tuned 3. But given that errors at any point can nullify, thwart, or confound therapeutic intent, it might seem odd to a visitor from outside the pharmaceutical-medical world that attention is so markedly focused on just the pharmacokinetic phase of the overall process. This imbalance reflects probably several factors. One, of course, has been the phenomenal advances in analytical chemical methods during the past 3 decades, which have greatly facilitated studies of the disposition of ingested or otherwise administered drug within the body – 'what the body does to the drug'. In contrast, pharmacodynamics – 'what the drug does to the body' – has been vexed by the methodologic difficulties of reliably quantifying the manifold types of drug action, many of which cannot be expressed in the numerical terms that most scientists have been trained to seek, but which must instead be quantified in clinimetric terms that relatively few scientists have been educated to develop and apply to clinically pressing problems. Against the foregoing two backdrops, the nascent discipline of pharmionics could hardly begin to be contemplated until the integration of time-stamping microcircuitry into pharmaceutical packages made it possible to compile reliable data on ambulatory patients' dosing histories 4–7. That development, which by now has compiled an extensive range of published applications 8, represents the 'technological push' side of the story, as important to pharmionics as the advances in analytical chemistry since 1960 have been to pharmacokinetics. The medical need, or 'pull' for pharmionics, arises from the increasing power and specificity of drug actions, reflected by the increasing use of patients' responses to certain prescribed drugs as bases for medical decision-making. This aspect of medical practice is exemplified by, but certainly not limited to, the 'stepped-care' approach to treating arterial hypertension 9. Stepped-care management includes the concept of first-, second-, and third-line agents. In general, a patient's failure to respond to treatment with a first-line agent is an indication to escalate the strength of the prescribed treatment. Escalation can variously be done by raising the dose of the already-prescribed agent(s), by adding a further first-line agent, by combining a first- and second-line agent, or by switching completely to a second-line agent. Persistent nonresponse is interpreted as an indication to proceed toward so-called 'triple therapy', i.e. three concomitantly prescribed drugs drawn mainly from 2nd and 3rd line agents. Similar ideas that nonresponse should drive progression through 1st, 2nd, and 3rd line agents toward a 3-drug 'ultimate' regimen is found in epilepsy, glaucoma, and other chronic diseases for which numerous choices of drug are available. Lip-service is, of course, given to the possibility that nonresponse may be consequent to poor compliance, but that sensible advice is nullified by the fact that, in the absence of electronic monitoring, the clinical ascertainment of patient compliance is aptly described as no better than a coin-toss 10. Views about the impact and pervasiveness of poor compliance with prescribed or, in trials, protocol-specified drug regimens did not have to await the development of electronic monitoring methods. Four seminal studies presaged the growing importance of the topic with usually unreliable methods that were pushed by extraordinary efforts to a state of what might be called 'marginal reliability'. Jointly considered, these studies give a foretaste of the explanatory power of reliable data on ambulatory patients' actual exposure to prescription drugs 11–14. These studies are reviewed in 15. With the advent, first of low-dose, slow turnover chemical markers 16–18, and then of electronic monitoring methods, the methodologic foundation has been laid for pharmionics to flourish. Its logic rests on the fact that, as the disciplinary home for reliable measurement and interpretation of patient compliance with prescribed drug regimens, pharmionics can claim to concern itself with one of the two biggest single sources of variability in drug response, the other being pharmacokinetics 2. Therein, of course, lies the basis of my title 'the odds of the three nons'. I use the lay sense of the term 'odds', to mean the probabilities that a disappointing response to a rationally prescribed drug will find its explanation as a problem in pharmionics, in pharmacokinetics, in pharmacodynamics, or in some combination thereof. An essential feature of the story is that prescription drugs now provide greater, more specifically focused interventional power than ever before. This evolution has occurred gradually, as a logical outcome of the highly competitive, economically attractive marketplace in which pharmaceuticals compete for share. Among all the varied attributes of a pharmaceutical product, therapeutic efficacy is naturally a principal focus in the quest for competitive advantage. The imposition, four decades ago, of the need to prove efficacy as a condition for product registration has assured that each pharmaceutical product enters the marketplace with an explicit claim of efficacy. Efficacy claims of course serve many purposes, one of which is to be a competitive target for future products. Efficacy can be proven in a few hundred or a few thousand patients in a circumscribed period of time. In contrast, the other principal focus of pharmaceutical development – defining the risk of harm that patients incur in using the product – is an open-ended, methodologically uncertain process involving several orders of magnitude more patients and much longer periods of observation than are involved in the proof of effectiveness. With progressively more power and specifically acting pharmaceuticals have come new understanding of disease, facilitation of previously impossible surgical procedures, previously impossible (and unthinkable) preventive manoeuvres, reliable family planning, reduced mortality rates at all ages of life (although the death rate ultimately remains at one per person), and improved management of many diseases. Two natural concomitants of these benefits are increased usage and increased prices of prescription drugs, as natural extensions of the basic economic principle – applicable both inside and outside the healthcare arena – that effective products command wider usage and higher prices than ineffective products. The steadily increasing power and pricing of pharmaceuticals are, together with the dose and time dependencies of drug actions, the four factors that have jointly brought patient compliance with prescribed drug regimens from a trivial to a key role in ambulatory care. In effect, then, the need for the discipline of pharmionics is a de facto tribute to the success of medicinal chemistry, pharmaceutical development, and pharmacologic and pharmaceutical science since the origins of these disciplines roughly a century ago. A natural consequence of the present role of prescription drugs is that, when aptly prescribed, correctly taken, and continued for a sufficiently long period of time, they are more likely than not to have beneficial medical consequences. How much more likely depends upon the dynamics of the underlying disease and for how long the treatment persists. The proof of efficacy carries the corollary that prescribing the drug increases the odds of a good outcome, but there is a set of provisos. The main provisos are that the patient: (a) is properly diagnosed (b) rationally treated (c) complies satisfactorily with the prescribed drug regimen, and (d) persists with the treatment regimen for an adequately long period of time. Proviso (b) includes a regimen that assures adequate absorption and effective concentrations of drug at sites of action, and satisfactory reception of drug. If these provisos are not met, the outcome may still be good if the disease is one from which patients recover without treatment. If not, however, then each of the provisos approaches the status of being a conditio sine qua non for a good outcome. In contrast, when prescribing is inept, or otherwise inappropriate, or when a properly prescribed drug regimen is ineptly executed (i.e. poorly complied with), or if persistence with the regimen is too brief, patients are likely to have bad outcomes, which may be further complicated by hazards arising not only from failure to treat in an effective and timely way, but also from the holiday pattern of drug exposure, which can trigger hazardous rebound effects or recurrent first-dose effects 19–23. Thus, the achievement of a good or poor outcome of treatment correspondingly tilts the retrospectively assessed odds of the status of the various provisos. Good outcomes are not likely in patients who have complied poorly or who have persisted only a short while with their prescribed treatment. Conversely, patients who have had a good outcome are likely to have complied satisfactorily and persisted with prescribed treatment for an adequate period of time. These outcome-dependent probabilities can be considered as therapeutically pertinent biases when patients are selected for some new therapeutic adventure based on the outcomes they have had from prior treatment. When recognized as such, these biases may be used to advantage when, e.g. one seeks to assemble a cohort of unusually uniformly compliant and persistent patients. Conversely, they may complicate a trial designed to show that a new medicine can satisfactorily treat patients who had failed to respond to a competing agent. If a substantial fraction of such patients failed to respond to a prior treatment because of inadequate compliance with the prescribed drugs, then it is likely that they will carry their poor compliance over into the new trial or treatment program. If their prevailing level of compliance is too poor for the new medicine to work, then it, too, will fail, as will any medicine, however, powerful. These tendencies to select for unusually good or unusually poor compliance need to be seen in the context of the usual patterns of good, partial, and poor compliance found in medically unselected patients, exemplified by patients who have only recently embarked on a first course of primary preventive treatment, without special attention having been paid to their compliance with the prescribed regimen(s). The dosing patterns observed in such patients by unobtrusive electronic monitoring, without any attempt to feed results back to patients or otherwise influence their dosing patterns, is approximately as follows 24: One-sixth of the patients execute the regimen with strict punctuality. One-sixth of the patients take virtually all the prescribed doses but with some fluctuations in dose-timing. One-sixth of the patients occasionally omit a single day's doses, with fluctuations in dose-timing. One-sixth of the patients have a drug holiday (the sequential omission of 3 or more days' doses) 3–4 times per year, together with occasional omissions of 1–2 days' doses. One-sixth of the patients have a drug holiday monthly or more often, together with frequent omissions of 1–2 day's doses. One-sixth of the patients take few or no doses, while maintaining the appearance of satisfactory, if not perfect, compliance. These categories are, of course, approximations, but this 'rule of sixes' is a useful approximation of what to expect of drug exposure when dosing histories are compiled by electronic monitoring methods in medically unselected patients. These approximate the dosing patterns that, e.g. underlie the 50-fold higher conception rates characteristic of 'typical' to use of and the fact that only about of treated patients in the satisfactory control of their 9. An of for unusually compliant patients is by the of de and who compliance in patients who had a found virtually compliance in over of the patients. These with the 'rule of sixes' described in medically unselected patients, in which only one in about patients are The patients by de had been selected as for on the basis of their having severe then had to in a for some an available. failure is a medically with a naturally and high mortality in which treatment can in and One naturally to data on both prescribing and the patients' compliance with prescribed drug regimens through the period of an cohort of patients selected as for all have at the present are data on the compliance patterns of patients In any the high of compliance naturally the did the of their medical condition many patients to to compliance, or, did most of those compliance was fall by the during their long in the or too to be an surgical the is medically but it remains for future studies to show which is the more of are an compliant and I compliance in patients of a of who had prescribed, through the pharmacy with the receptor as first-line treatment for their Most of the agents used were of the that from the were patients hypertension was as by of their medical and of their prescription dispensing The only the patients could and still be in the was a any patient who had previously or a was from the patients after based on a explanation that the of the special package was to a of their doses, given their receptor in an package An high of compliance was found in this of patients, raising the of how this from the usual of compliance with prescribed drugs of course, were (a) that these patients and their a and that naturally good compliance with prescribed drug regimens, or (b) about the their usual compliance A explanation was by the which had not been when the was that, several prior to the this of had using receptor as first-line treatment for and had to other mainly Thus, the patients in this had been on their present treatment prior to that in prescribing and were of treatment with receptor This the of compliant patients, to in dosing who have been to hazardous rebound were selected of the cohort by is that in dosing with receptor trigger hazardous rebound effects that include disease 19–23. This is usually in to of treatment, but it must also be so that the of drug among about a of medically unselected patients, who are a of risk of In the course of time, these of risk could be to take their in terms of the done by and the of disease, and of the of drug who had course, receptor are prescribed to the overall risk of disease, with from of an 9. The of in the is not with the adding in a of patients dosing patterns to recurrent of created by recurrent rebound effects that for a few to a or on the of drug and the dynamics of the rebound such as this are one of the reasons reliably compliance with protocol-specified drug regimens in should be used to develop if which such is used as a primary of efficacy The need for reliable measurement of compliance in is a story that I have such one obviously to be to the story in an cohort of patients, from the first of through the to treatment, and by reliable data on compliance with prescribed as patients respond or treatment. and their in that, among the patients to their for of over to be clinically all of the patients had been to 'triple in the of persistent had a of nonresponse to any prescribed agents. When seen at the the patients were that, the usual were they first a new which was a period of electronic monitoring of their dosing with their three prescribed that be reviewed with and be the basis on which the be taken to with more which a a for a and an of were then with three electronic each one of their three prescribed the of which is a of explanations are one could reasonably that and other are not when persistent drug regimen is which is as by electronic were to about of their clinically to execute their prescribed regimens to their for the first time, into satisfactory The occurred in two of the patients, on the importance which the to the of the prescribed their compliance, and with a of good compliance for the first time, satisfactorily several had difficulties with as was more treatment than they needed, given satisfactory compliance. of patients with a of poor compliance and persistent about of were to improve their compliance, after a of their dosing together with of what a dosing should was a further to just under of the of patients, who with a of good compliance with persistent hypertension – a which to about in of the clinically who were or to improve their compliance, and so this is a for future the overall results if an important in the management of the of about of the for an fraction of otherwise patients into satisfactory control of their and some prescribing to be and in the or of prescribed drugs can the of the electronic which at for a that has a 3 One or two of the for the of course, be used for monitoring to for of among patients who have been to good compliance. is that the are not in having satisfactory compliance in a substantial of patients with a medical need for drug at have of compliance in a of compliance had roughly their prescribed doses of they were to satisfactory compliance in about of a of such patients it is beyond the of this paper to on for compliance, the two key in both studies have been the of by dosing times, which can be interpreted by most patients, and the fact that the monitoring is with with the prescribing a or a The term for this new approach is and is a with past to improve compliance based on methods of measurement that patients the to their compliance. In contrast, electronic monitoring it a to a of good the of the electronic the patient to execute the with the drug package at each dosing time in to a of good compliance. not it the of two relatively (a) strict and (b) of course remains to be done to these the in the of compliant patients as one from the medically to those selected on the basis of a outcome of prior treatment with prescription drugs, and those selected on the basis of an outcome of prior treatment. 3 show how a of medically unselected patients, roughly and compliance too poor and for a satisfactory outcome of treatment, when as having had a satisfactory or outcome of treatment. of how the of satisfactory and from the roughly in medically unselected patients, to a high of good found among patients who have not only but their status as an surgical risk during a long period of for a in the of severe The other is by patients who have failed to respond to doses of are in the of how the of satisfactory to the success or failure of an treatment. shows this represents how an cohort of patients in the two compliance might be to on success of a rationally prescribed course of ambulatory drug The are to be interpreted not of how the of to the failure of an treatment. shows this represents how an cohort of patients in the two compliance might be to on failure of a rationally prescribed course of ambulatory drug The are to be interpreted not in their to therapeutic in the of occasional omissions of or more doses. can the and good compliance for a satisfactory outcome. The of maintaining therapeutic in the of doses is called and has been previously but suffice it to say that a drug of is longer than the prescribed doses, e.g. for the with a doses is of doses. In contrast, with its several of is of doses in its dosing regimen is in an important in the of compliance with prescribed drug time since a dose is a in when drug will to the of without therapeutic will influence outcomes of treatment with on drug and disease, e.g. periods of hypertension and their effects on and other an of by a of with the possibility of of a or of and in also several when hazardous recurrent first or effects occur, periods of The longer a period of risk the more likely it is that the patient will incur harm from treatment time time for drug to each such period of risk the patient through a risk within which the patient may or may not incur of a of patients through a risk can be to patients from the of but at to the of time the of the but at risk to or to some of or on how one to include or patients from a and on how long the have been at work, a resulting may be as have of of good or poor Thus, the of of good or poor should trigger into the of prior that may have been in exposure times may also be to the of the by certain risk factors to for longer or periods of time. one might expect compliance problems after to to be as frequent with as they are with if the time to a were a time for the of poor or compliance with failure treatment regimens to such patients' their of a At the of the matter is the power of prescription The their the the of and the the potential in the odds of the as a at work, The is to the of the on at which of this paper were as the over a have been in on various of drug the history of medicine, and and many other topics of I also to my long in the development of electronic monitoring for measuring drug exposure in ambulatory patients. and have many in a new of clinical measurement into
John Urquhart (Thu,) studied this question.