Minimization of the Preanalytical Error in Pharmacokinetic Analyses and Therapeutic Drug Monitoring

Abstract

The conduct of multicenter pharmacokinetic (PK) analyses for long-established drugs entails specific problems, because samples have to be obtained within daily clinical practice. Practices for intravenous (IV) drug administration vary between hospitals, including the use of different infusion devices, the use of infusion line systems with different line volumes, and different priming and rinsing procedures. Variables of IV drug administration that could influence concentration data obtained in PK analyses were evaluated. Kinetics of drug delivery during initiation and cessation of IV infusions were simulated in vitro for a drop-counter and a syringe-driven infusion system at different flow rates. Furthermore, the percentages of the target drug dosage remaining in the infusion line after different rinsing periods were investigated in vitro and in clinical practice. Varying times required for the drug to migrate from the bag/syringe to the cannula and to reach a steady-state drug administration rate were observed. Time to steady state ranged from almost immediate to 48 minutes depending on the infusion system and flow rate. The longest times were seen for the drop-counter system at low flow rates and were associated with large drug concentration gradients in the infusion line, which makes it difficult to accurately determine start and end of the infusion. For most systems, when rinsing at the end of infusion was performed with once the volume of the infusion line, <5% of the total drug dosage was discarded. Larger variability was seen for slow infusion rates and small infusion volumes. The choice of the infusion apparatus, standardized infusion systems, and standardized operating procedures for drug administration are important when performing postmarketing PK analyses in multicentric studies.