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Population plasma pharmacokinetics of 11 C‐flumazenil at tracer concentrations
Author(s) -
Van Rij Catharina M.,
Huitema Alwin D. R.,
Swart Eleonora L.,
Greuter Henricus N. J. M.,
Lammertsma Adriaan A.,
Van Loenen Arie C.,
Franssen Eric J. F.
Publication year - 2005
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02487.x
Subject(s) - nonmem , pharmacokinetics , population , medicine , population pharmacokinetics , flumazenil , coefficient of variation , covariate , chemistry , mathematics , statistics , chromatography , benzodiazepine , receptor , environmental health
Objective The 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. Methods 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 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. Results The 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)). Conclusions The 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.