Population plasma pharmacokinetics of ¹¹C‐flumazenil at tracer concentrations

Abstract

ObjectiveThe objectives of the study were to develop a population pharmacokinetic model for 11 C-flumazenil at tracer concentrations, to assess the effects of patient-related covariates and to derive an optimal sampling protocol for clinical use. MethodsA population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received ~ 370 MBq (1-4 m g) of 11 C-flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established. ResultsThe population pharmacokinetics of tracer quantities of 11 C-flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates ( P < 0.002). Mean population pharmacokinetic parameters (percent coefficient of variation) were: CL 1530 mL min -1 (6.6%), V 1 24.8 ¥ 10 3 mL (3.8%), V 2 27.3 ¥ 10 3 mL (5.4%), and Q 2510 mL min -1 (6.5%). CL was 20% lower in patients with epilepsy, and the influence of weight on V 1 was 0.55% kg -1 . For the prediction of the AUC, a combination of two time points at t = 30 and 60 min post injection was considered optimal (bias -0.7% (95% CI -2.2 to 0.8%), precision 5.7% (95% CI 4.5-6.9%)). The optimal sampling strategy was cross-validated (observed AUC = 296 MBql -1 min -1 (95% CI 102-490), predicted AUC = 288 MBql -1 min -1 (95% CI 70-506)). ConclusionsThe population pharmacokinetics of tracer quantities of 11 C-flumazenil are well described by a two-compartment model. Inclusion of weight and type of disease as covariates significantly improved the model. Furthermore, an optimal sampling procedure may increase the feasibility and applicability of 11 C-flumazenil PET.C. M. van Rij et al.

HRRT Versus HR+ Human Brain PET Studies: An Interscanner Test–Retest Study

“…After each sample was collected, the arterial line was flushed with heparinized sterile and isotonic saline. These manual sample data were used for calibrating the (online) blood sampler, measuring plasma and whole-blood ratios, and determining metabolite fractions (17,18). The fractions of metabolized and unchanged 11 C-flumazenil corresponded with a previous report (19), and deviations between metabolite fractions on the HR1 and HRRT scanners were not statistically different (2-sided paired t test, P .…”

[11C]Flumazenil PET in Temporal Lobe Epilepsy: Do We Need an Arterial Input Function or Kinetic Modeling?

“…Of note is that the variability (CV) in the VD images of the patients and controls was comparable. This suggests that factors which are removed from the parametric VD images account for much of the higher variability in ADD images, namely delivery, blood flow, and metabolism (van Rij et al, 2005), rather than receptor number or affinity. The comparison of parametric images of R I values (ratio of the delivery in the tissue ROI compared with that in the reference region, dominated by blood flow (Gunn et al, 1997)), further supports this view: As would be expected from the above, while the means of global average R I values were identical, their CV in patients was nearly four times higher than in controls (15% versus 4%), indicating much greater heterogeneity of blood flow and/or tracer delivery between subjects in patients.…”

Accuracy of 3-Dimensional Reconstruction Algorithms for the High-Resolution Research Tomograph

“…At set times (5,10,15,20,30,40, and 60 min after injection), continuous blood sampling was interrupted to collect manual blood samples. These manual sample data were used for calibrating the (online) blood sampler, for measuring plasma or whole-blood ratios, and for determining metabolite fractions (27). The metabolite-corrected arterial plasma time-activity curve was used as an input function for kinetic analysis.…”