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.
Summary:To gain an insight in the regulation of (24jR)-hydroxycalcidiol, we studied the pharmacokinetics of orally administered (24R)-hydroxycalcidiol in 6 healthy subjects without calcium supplementation, in 4 healthy subjects with calcium supplementation and in 6 patients with primary hyperparathyroidism. Various quantities related to calcium and vitamin D metabolism were also monitored.In the healthy subjects without calcium supplementation, the basal (24/?)-hydroxycalcidiol concentration (C b ) in serum was 2.4 ± 0.8 nmol/1 (mean ± SD, n = 5), the terminal serum half-time (t I/2 ) 7.2 ±1.4 days, the production rate 0.05 ± 0.01 nmol/kg · day, and the production rate/[calcidiol] ratio (1.5 ± 0.4 χ 10~3 I/kg • day). In the healthy subjects studied, the serum concentration vs time curves exhibited a second maximum after administration, possibly due to binding by intestinal cells or (partial) uptake by the lymph system. In the calcium-supplemented healthy subjects, the pharmacokinetic quantities were not significantly different while the area under the serum concentration-time curve and the estimated bioavailability were significantly decreased.Basal concentration (C b ), production rate and the production rate/[calcidiol] ratio were significantly lower in patients with primary hyperparathyroidism but ti/ 2 was unchanged.Exogenous (24jR)-hydroxycalcidiol had no clear effect on calcium and vitamin D metabolism.In conclusion, a) exogenous (24JR)-hydroxycalcidiol has no clear effect on calcium and vitamin D metabolism, b) clearance and production rate of (24/?)-hydroxycalcidiol are not affected by calcium supplementation, c) bioavailability is lower in the calcium-supplemented state, d) basal concentration (C b ) and production rate are significantly decreased in patients with hyperparathyroidism.
[11C]‐Flumazenil is a radiopharmaceutical that can be used to quantify benzodiazepine receptor concentrations and drug binding in the human brain using positron emission tomography (PET). In PET studies, arterial blood sampling is required to correct for labelled metabolites in plasma. The metabolite corrected arterial plasma curve of [11C]‐flumazenil is used as the input function for the receptor pharmacokinetic model in clinical PET studies. The main metabolic pathway for flumazenil is conversion to flumazenil ‘acid’ by hepatic carboxylesterases. Interestingly, carboxylesterases are also involved in the bioconversion of other ester‐type drugs such as cocaine, acetylsalicylic acid and many cholesterol synthesis inhibitors. Thus far, little is known about (genetic) differences in carboxylesterase activities. In principle, flumazenil may serve as a marker substrate for carboxylesterase phenotyping and predict metabolism for these kinds of drugs. The aim was to study interindividual differences in flumazenil clearance and flumazenil ‘acid’ formation in healthy volunteers and CNS patients. Healthy volunteers and CNS patients (n=25) participating in different PET protocols were included. During PET scanning, arterial blood samples were collected for ex vivo counting and metabolite analysis at 7 time‐points. The plasma samples were analysed by reversed phase h.p.l.c. with radioactivity detection, as previously described [1]. The data were fitted by a commercially available and previously validated pharmacokinetic computer program (MW\Pharm, MediWare BV, Groningen, The Netherlands). The total body clearance (CL), volume of distribution (Vd) and the elimination rate constant (k10) were calculated for flumazenil pharmacokinetics. Parent flumazenil clearance from the plasma compartment was best fitted with a 2‐compartment model (r2>0.98). The plasma clearance ranged from 48–139 l h−1. The flumazenil ‘acid' curve was fitted by an extravascular, 1‐compartment model (r2>0.98). The rate constant of metabolite formation (km) ranged from 2.4–24 h−1, indicating pronounced interindividual differences in flumazenil ‘acid' formation. The total body clearance of this tracer dose of flumazenil is in the range of earlier reported pharmacological doses ([2]; Table 1). The estimated hepatic extraction ratio (EH) was 0.6–0.8 (assuming a hepatic blood flow of 60–90 l h−1). The rate of flumazenil ‘acid' formation correlated with the clearance of flumazenil, suggesting a major role of hepatic carboxylesterases in flumazenil clearance. Pharmacokinetics of parent [11C]‐flumazenil. Tracer dose Pharmacological dose Range Mean Clearance (l h−1)48–13976 ± 2330–78 Vd (l kg−1)n.d.0.78 (n.d.)0.6–1.1 k 10 (h−1)1.7–254.6 ± 4.6n.d.EH0.6–0.8n.d.0.6 The plasma pharmacokinetics of [11C]‐flumazenil show pronounced interindividual variation. The relative high hepatic extraction ratio implicates that the formation of flumazenil ‘acid' depends on the functional status of liver cells (carboxylesterase activity) and also on hepatic blood flow. Input curves ...
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