Population Pharmacokinetic Analysis for Simultaneous Determination of B max and K D In Vivo by Positron Emission Tomography

Liefaard, Lia C.; Ploeger, Bart; Molthoff, Carla F. M.; Boellaard, Ronald; Lammertsma, Adriaan A.; Danhof, Meindert; Voskuyl, Rob A.

doi:10.1007/s11307-005-0022-3

Cited by 25 publications

(34 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(27), and 54.5 ngÁmL 21 in rat brain homogenates (28). The K D estimate, 5.9 6 0.9 ngÁmL 21 , obtained in the present study is also in line with previously published studies (17,18,(25)(26)(27)(28). On the basis of time-activity data obtained in a previous study when 11 C-flumazenil was administered without the addition of unlabeled flumazenil (18), the doses used in the present study resulted in approximate occupancy levels of 30%-40% for 4-mg, 60%-70% for 20-mg, 70%-80% for 100-mg, and around 90% for 400-mg dose groups.…”

Section: Discussionsupporting

confidence: 93%

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

et al. 2012

Self Cite

View full text Add to dashboard Cite

The aim of the present study was to investigate if flumazenil blood-brain barrier transport and binding to the benzodiazepine site on the g-aminobutyric acid A (GABA A ) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)-mediated efflux of flumazenil at the blood-brain barrier may confound interpretation of 11 C-flumazenil PET in epilepsy. Methods: The transport of flumazenil across the blood-brain barrier and the binding to the benzodiazepine site on the GABA A receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive 11 C-flumazenil PET scans, each one lasting 30 min. The tracer was mixed with different amounts of isotopically unmodified flumazenil (4, 20, 100, or 400 mg) to cover a wide range of receptor occupancies during the scan. Before the second scan, the rats were pretreated with a 3 or 15 mg/kg dose of the P-gp inhibitor tariquidar. The second scan was then obtained according to the same protocol as the first scan. Results: GABA A receptor density, B max , was estimated as 44 6 2 ngÁmL 21 in the hippocampus and as 33 6 2 ngÁmL 21 in the cerebellum, with intermediate values in the occipital cortex, parietal cortex, and caudate putamen. B max was decreased by 12% in kainate-treated rats, compared with controls. The radiotracer equilibrium dissociation constant, K D , was similar in both rat groups and all brain regions and was estimated as 5.9 6 0.9 ngÁmL 21 . There was no difference in flumazenil transport across the blood-brain barrier between control and kainate-treated rats, and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment also decreased flumazenil transport out of the brain by 73%, increased the volume of distribution in the brain by 24%, and did not influence B max or K D , compared with baseline . Conclusion: B max was decreased in kainate-treated rats, compared with controls, but no alteration in the bloodbrain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but B max estimates were not influenced, suggesting that 11 C-flumazenil scanning is not confounded by alterations in P-gp function.

show abstract

Section: Discussionsupporting

confidence: 93%

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…Population PK modeling is particularly helpful here, because by this approach all data for the entire study population (i.e., all mothers and fetuses) are taken into account. An important feature of population PK modeling is that it enables the analysis of data from studies with unbalanced designs (e.g., unequal groups) and of incomplete data sets (6,9). Specifically, nonlinear mixed-effects (population) modeling can be used to connect the sparse data for umbilical cord and neonatal blood concentrations to the more detailed information on the PKs in the mother (3,11).…”

Section: Discussionmentioning

confidence: 99%

“…To obtain useful information, the PKs (i.e., the concentration-versus-time profile) in the maternal serum, the arterial or venous umbilical cord serum, and the neonatal serum should be known. The use of a population PK approach can be useful for the analysis of such data (6,9,3,11). The objective of this study was to describe the concentration-time profile of amoxicillin in umbilical cord and neonatal serum in relation to the concentration-time profile in maternal serum.…”

mentioning

confidence: 99%

Pharmacokinetics of Amoxicillin in Maternal, Umbilical Cord, and Neonatal Sera

Muller

Oostvogel

DeJongh

et al. 2009

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The pharmacokinetics of amoxicillin were studied in umbilical cord and neonatal sera relative to maternal concentrations in prevention of neonatal group B streptococcus infection. The subjects were 44 pregnant women receiving amoxicillin as 1 or 2 g as an intravenous infusion. To measure the concentrations, blood samples were obtained from the mother, the arterial and venous umbilical cord, and the neonate. The pharmacokinetics were characterized by a five-compartment model by using nonlinear mixed-effects (population) modeling. The population estimates for the clearance, central volume of distribution, and the two peripheral maternal volumes of distribution were 19.7 ؎ 0.99 liters/h, 6.40 ؎ 0.61 liters, and 5.88 ؎ 0.83 liters (mean ؎ standard error), respectively. The volume of distribution of the venous umbilical cord and the neonatal volume of distribution were 3.40 liters and 11.9 liters, respectively. The pharmacokinetic parameter estimates were used to simulate the concentration-time profiles in maternal, venous umbilical cord, and neonatal sera. The peak concentration in the venous umbilical cord serum was 18% of the maternal peak concentration. It was reached 3.3 min after the maternal peak concentration. The concentration-time profile in neonatal serum was determined by the profile in venous umbilical cord serum, which in turn depended on the profile in maternal serum. Furthermore, the simulated concentrations in maternal, venous umbilical cord, and neonatal sera exceeded the MIC for group B streptococcus for more than 90% of the 4-h dosing interval. In a first approximation, the 2-g infusion to the mother appears to be adequate for the prevention of group B streptococcal disease. However, to investigate the efficacy of the prophylaxis, further studies of the interindividual variability in pharmacokinetics are indicated.Amoxicillin (amoxicilline), a penicillin derivative, is an antibiotic used for the prevention of neonatal group B streptococcal (GBS) disease. Neonates from mothers colonized with GBS are at risk for vertical transmission, because they might be exposed to GBS in utero or in the vagina during delivery. While protection of the fetus is the actual objective of the prophylaxis, the procedure used for the prophylaxis of GBS is administration of antibiotics to the pregnant woman. Since antibiotics reach the fetus only after transport over the placenta via the umbilical cord, adequate concentrations in maternal serum are a prerequisite, but no guarantee, for adequate venous and arterial umbilical cord and fetal serum concentrations. While data on ampicillin concentrations in umbilical cord blood have been reported (2, 4), data for amoxicillin are not available. The pharmacokinetics (PKs) of amoxicillin in pregnant women before labor have been described previously and have been shown to exceed the MIC for an adequate percentage of the dosing interval for treatment of the infection in the mother (7). To assess whether the administration of amoxicillin also protects the fetus from GBS infection, d...

show abstract

“…In this method the entire range of possible receptor occupancies (i.e. 0-100%) is covered within one single scan [2]. Data are then analysed using population modelling, yielding population estimates of B max and K D , whilst also taking into account interindividual variability in the different parameter estimates.…”

mentioning

confidence: 99%

“…The full saturation approach, using a 2-compartment-plasma-2-compartment-brain population model [2], yielded B max and K D values of 37 ± 5 ng mL −1 and 6.8 ± 1.4 ng mL −1 , respectively. The model was also applied without including interindividual variation, as it did not further improve the goodness of fit.…”

mentioning

confidence: 99%

Comparison of two methods for estimating Bmax and KD of [11C]flumazenil in rat brain

et al. 2010

Self Cite

View full text Add to dashboard Cite

Population Pharmacokinetic Analysis for Simultaneous Determination of B max and K D In Vivo by Positron Emission Tomography

Abstract: The proposed population PK model allowed for simultaneous estimation of B (max) and K (D) for a group of animals using single injection PET experiments per animal.

Cited by 25 publications

References 40 publications

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

Pharmacokinetics of Amoxicillin in Maternal, Umbilical Cord, and Neonatal Sera

Comparison of two methods for estimating Bmax and KD of [11C]flumazenil in rat brain

Contact Info

Product

Resources

About

Population Pharmacokinetic Analysis for Simultaneous Determination of B max and K D In Vivo by Positron Emission Tomography

Abstract: The proposed population PK model allowed for simultaneous estimation of B (max) and K (D) for a group of animals using single injection PET experiments per animal.

Cited by 25 publications

References 40 publications

Altered GABAA Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using 11C-Flumazenil and PET

Altered GABAA Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using 11C-Flumazenil and PET

Pharmacokinetics of Amoxicillin in Maternal, Umbilical Cord, and Neonatal Sera

Comparison of two methods for estimating Bmax and KD of [11C]flumazenil in rat brain

Contact Info

Product

Resources

About

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET