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Role of Patient Compliance in Clinical Pharmacokinetics

A Review of Recent Research

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  • Clinical Pharmacokinetic Concepts
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Summary

Until 1986 to 1987, the estimation of patient compliance with prescribed drug regimens in ambulatory care relied on methods that were biased either by their subjectivity or by the improvement in compliance that commonly occurs during the day or two prior to a scheduled examination, so called ‘white-coat compliance’.

In 1986 to 1987, 2 objective methods were developed: electronic monitoring and low-dose, slow-turnover chemical markers (digoxin or phenobarbital [phenobarbitone]) incorporated into dosage forms. While neither method is without limitations, both have enabled major advances in the understanding of patients’ compliance with dosage regimens and, thus, the spectrum of drug exposure in ambulatory care. The new methods have also triggered not only a revival of interest in patient compliance and its determinants, but also new statistical approaches to interpreting the clinical correlates of widely variable drug administration, and thus drug exposure, in drug trials.

The marker methods prove dose ingestion during the 3 to 7 days prior to blood sampling, but do not reveal the timing of doses. The electronic monitoring methods, i.e. time and date-stamping microcircuitry incorporated into drug packages, provide a continuous record of timing of presumptive doses throughout periods of many months, but do not prove dose ingestion. The electronic record has been judged robust enough to detect certain types of investigator fraud, and to support modelling projections of the complete time course of the plasma drug concentration during a trial.

Both marker and electronic methods show that the predominant errors are those of omission, i.e. delays or omissions of scheduled doses. Patient interviews, diaries, and counts of returned, untaken doses have been shown by both marker and electronic monitoring methods to consistently and substantially to overestimate compliance. Monitoring of plasma drug concentrations also overestimates compliance, because white-coat compliance is prevalent, and the pharmacokinetic turnover of most drugs is rapid enough that measured concentrations of drug in plasma reflect only drug administration during the period of white-coat compliance.

Thus, compliance is a great deal poorer in clinical trials than has been revealed by the older methods. The long-standing underestimation of poor compliance in drug trials has many implications for the interpretation of drug trials, for optimal dose estimation, for the interpretation of failed drug therapy, and for accurate labelling of prescription drugs.

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  1. Department of Epidemiology, University of Limburg, PO Box 616, 6200MD, Maastricht, The Netherlands

    John Urquhart

  2. APREX Corporation, 47221 Fremont Boulevard, Fremont, California, 94538, USA

    John Urquhart

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Urquhart, J. Role of Patient Compliance in Clinical Pharmacokinetics. Clin. Pharmacokinet. 27, 202–215 (1994). https://doi.org/10.2165/00003088-199427030-00004

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