The Odds that Clinically Unrecognized Poor or Partial Adherence Confuses Population Pharmacokinetic/Pharmacodynamic Analyses

Authors

  • Bernard Vrijens,

    Corresponding author
    1. AARDEX Ltd., Zug, Switzerland,
    2. Department of Biostatistics and Medical Informatics, University of Liège, Liège, Belgium,
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  • Robert Gross,

    1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, U.S.A.
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  • John Urquhart

    1. AARDEX Ltd., Zug, Switzerland,
    2. Pharmaco-Epidemiology Group, Maastricht University, Maastricht, Netherlands
    3. Department of Biopharmaceutical Sciences, University of California San Francisco Medical Center, San Francisco, CA, U.S.A.
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Author for correspondence: Bernard Vrijens, AARDEX Ltd., Statistical Research Centre, Rue des Cyclistes Frontière, 24, B-4600 Visé, Belgium (fax +32 4 374 86 22, e-mail bernard.vrijens@aardex.net).

Abstract

Abstract: Electronic compilation of ambulatory patients' or trial participants' dosing histories has revealed that a wide range of dosing patterns, markedly skewed toward underdosing, occur in virtually every disease and treatment situation so far studied. In planning ambulatory trials and their analyses, one should recognize that patients' variable exposure to test drugs, created by their diversely erratic execution of protocol-specified dosing regimens, is generally the single largest source of variance in drug responses. Trial subjects' erratic dosing behaviour may, if ignored, weaken the trial's assay sensitivity. In contrast, reliably compiled and soundly analyzed dosing histories may greatly inform the analysis of the trial. Dosing histories found to be associated with suboptimal clinical results can highlight particular dosing patterns that should be avoided. Thus begins the sequence leading from first observations, to repeat observations, to ethically possible experimental designs, to causal inference, i.e., learning and then confirming. With the broadening use of electronic monitoring to estimate longitudinal drug exposure, the need exists for an explicit discipline that concerns itself with `what the patient does with the drug'. It is called Pharmionics.

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