Counterpoint: Is Pharmacokinetic or Pharmacodynamic Monitoring of Calcineurin Inhibition Therapy Necessary?

Abstract

Individual dose adjustment of cyclosporine (CsA)1 and tacrolimus (TAC), which are critical-dose drugs widely used in transplantation, is important not only to prevent acute rejection but also to prolong graft (and patient) survival. New therapeutic regimens such as calcineurin inhibitor (CNI)-sparing strategies have recently strengthened the need for fine individual dose adjustment of these drugs. A good treatment-personalization strategy should employ a marker or a set of markers with (a) strong relationships with therapeutic and/or adverse effects; (b) low intraindividual variability; (c) established, and ideally, validated target values; and (d) easy and fast measurement. So far, dose individualization has mainly been based on pharmacokinetics, which monitors the handling of the drug by the body. Pharmacodynamics (PD), which focuses on the biologic effect of the drug on its target(1), might also be useful as a replacement or an adjunct. Early on in the use of CsA, monitoring of the predose (trough, C) concentration became the standard of care(2). However, no trial has been conducted in transplantation patients to determine whether C monitoring is superior to no therapeutic monitoring with respect to efficacy or toxicity(2), and conducting such a trial now would not be ethically acceptable given the obvious improvements brought to transplantation patients by therapeutic drug monitoring. However, it has long been recognized that the results of C monitoring are suboptimal, and retrospective analysis of transplantation populations monitored on C has shown that the full interdose area under the concentration-time curve (AUC0–12h), abbreviated AUCs (AUC0–6h or AUC0–4h), and Cmax (maximum concentration) have stronger links with the residual inefficacy or toxicity episodes than C. Because of the impracticability of routine AUC0–12h monitoring, limited sampling strategies have been proposed as a more practical approach. In 2002, the CONCERT (Consensus …