Dose-Related Reference Range as a Tool in Therapeutic Drug Monitoring

Abstract

Background: Therapeutic drug monitoring (TDM) aims to individualize drug therapy. This systematic review provides a state-of-the-art overview of the benefits of adding the dose-related reference range (DRR) as a second reference range to the set of tools used by TDM for measurement and evaluation. It discusses alternative pharmacokinetic approaches for individualization of drug therapy.Methods: Literature was searched in PubMed. Textbooks provided Bateman transformations for calculating expected drug concentrations at various times after drug application in "normal patients," that is, the population of phase II clinical trials. The review compiles conditions and prerequisites for these transformations to be valid.Results: Relating a measured drug concentration to the orienting therapeutic reference range provides pharmacodynamic information for improving the benefit-to-risk ratio of desired drug effects versus adverse drug effects. The discriminating DRR considers a patient's individual pharmacokinetic situation. DRR is statistically based on the pharmacokinetic parameters total clearance, time to reach maximal concentrations, and elimination half-life. Relating the measured drug concentration to a range rather than a particular value, DRR determines if individual patients do or do not belong to the population of "normal patients." Once a patient is identified to be outside the population of "normal patients," the clinical-pharmacological TDM report elaborates the cause. It consists of the measured value, the TDM 9-field-board, the elimination pathways table, and a medication recommendation taking into account clinical information. The internet-based platform KONBEST supports editing of the clinical-pharmacological TDM report. It is personally signed and send to the therapist. Conclusions:The DRR embedded into a clinical-pharmacological TDM report allows adjusting a patient's medication to the patient's individual needs (individualization of drug therapy).

Oxycodone, Morphine, and Fentanyl in Patients With Chronic Pain: Proposal of Dose-Specific Concentration Ranges

“…Thus, an additional tool in TDM has been proposed: dose-related reference ranges calculated from pharmacokinetic patient population data, estimating an expected concentration range for any given medicine dose. [6][7][8] For several drugs, including opioids, neither therapeutic nor dose-related reference ranges have been established. Therapeutic reference ranges seem less suited for opioids because the relationship between blood concentration and effect is highly variable, 9,10 owing to tolerance development, possible drug-drug interactions, and differences in analgesic response.…”