Approaches to clear residual chemotherapeutics from indwelling catheters in children with cancer

Abstract

Objectives: To develop a method for drug dosing and pharmacokinetic (PK) sampling in children with cancer from a single indwelling central venous catheter that minimized drug contamination.

Methods: A benchtop system was designed to simulate dosing and clearing actinomycin-D (AMD) and vincristine (VCR) from central venous catheters. The authors evaluated the effects of flush volume, composition and pH, timed drug instillation, and number of blood-draw return cycles on residual drug concentrations. A proof-of-principle study was conducted in three pediatric patients with cancer with paired PK samples obtained by both central and peripheral catheters.

Results: Nearly complete removal of drug from the catheter was obtained after five blood-draw return cycles consisting of 5 mL of whole blood. Residual concentration of AMD was 0.18 ± 0.02 ng/mL or 0.16% of the initial infusion concentration. VCR exhibited lower propensity for catheter adsorption than AMD with residual concentrations undetectable after three blood-draw return cycles. In patients in which the clearance procedure was used, higher drug concentrations were generally observed from centrally cleared samples at most time points, but differences relative to peripherally obtained samples were not statistically significant for either AMD or VCR. Two of three patients had higher exposure for AMD based on PK samples obtained from central catheters, whereas exposure for VCR was similar for both sampling catheters in all patients.

Conclusions: A reliable procedure to efficiently reduce AMD and VCR contamination during PK sampling has been established and is currently being used in a PK study being conducted by the Children's Oncology Group.

Figure 1

Design of the in vitro sampling apparatus. The internal diameter of the catheter was 5 french, or 1.67 mm. This corresponded to a volume of approximately 200 μL. Modifications to the types of catheters and stopcock were implemented in later experiments.

Figure 2

Schematic of experimental design and procedures for the in vitro catheter studies. Dosing and sampling of AMD or VCR were carried out using several configurations of the catheter apparatus. Various clearing conditions were tested to minimize residual drug adsorption to the catheter. Each experiment was repeated 2 to 3 times as indicated by n.

Figure 3

Effect of clearing conditions on residual AMD concentration. Following the dosing of AMD, the catheter fragment was flushed with (A) varying volumes of normal saline; (B) normal saline with varying pH values; (C) normal saline followed by a second flush of varying compositions; (D) normal saline preceded by varying drug contact time in the catheter lumen; (E) 3 mL 0.9% normal saline flush followed by 3, 5, or 10 mL of blood draw return cycles. Results are plotted as means or means ± SD from 2 or 3 independent experiments, respecively.

Figure 4

Effect of clearing conditions on residual VCR concentration. Following the dosing of VCR, the catheter fragment was flushed with (A) varying volumes of normal saline; (B) normal saline with varying pH values; (C) normal saline followed by a second flush of varying compositions; (D) normal saline preceded by varying drug contact time in the catheter lumen. (E) 3 mL 0.9% normal saline flush followed by 5 or 10 mL of blood draw return cycles. Results are plotted as means or means ± SD from 2 or 3 independent experiments, respectively.

Figure 5

Plasma concentration time profiles of (A) AMD and (B) VCR in three patients in a pediatric pilot study. Following intravenous administration of AMD and VCR through a central venous line, blood samples were collected from both the dosing catheter and a newly placed peripheral venous catheter. Areas under the curve (AUC, hr•ng/mL) were derived using noncompartmental analysis method.