Population plasma pharmacokinetics of 11C-flumazenil at tracer concentrations
Article first published online: 15 AUG 2005
British Journal of Clinical Pharmacology
Volume 60, Issue 5, pages 477–485, November 2005
How to Cite
Van Rij, C. M., Huitema, A. D. R., Swart, E. L., Greuter, H. N. J. M., Lammertsma, A. A., Van Loenen, A. C. and Franssen, E. J. F. (2005), Population plasma pharmacokinetics of 11C-flumazenil at tracer concentrations. British Journal of Clinical Pharmacology, 60: 477–485. doi: 10.1111/j.1365-2125.2005.02487.x
- Issue published online: 15 AUG 2005
- Article first published online: 15 AUG 2005
- Received 8 October 2004 Accepted 9 June 2005
The objectives of the study were to develop a population pharmacokinetic model for 11C-flumazenil at tracer concentrations, to assess the effects of patient-related covariates and to derive an optimal sampling protocol for clinical use.
A 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 µg) of 11C-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.
The population pharmacokinetics of tracer quantities of 11C-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%), V1 24.8 × 103 mL (3.8%), V2 27.3 × 103 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 V1 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)).
The population pharmacokinetics of tracer quantities of 11C-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 11C-flumazenil PET.