| 1. |
- Bergström, Mats, et al.
(författare)
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Blood-brain barrier penetration of zolmitriptan--modelling of positron emission tomography data
- 2006
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 33:1, s. 75-91
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Tidskriftsartikel (refereegranskat)abstract
- Positron emission tomography (PET) with the drug radiolabelled allows a direct measurement of brain or other organ kinetics, information which can be essential in drug development. Usually, however, a PET-tracer is administered intravenously (i.v.), whereas the therapeutic drug is mostly given orally or by a different route to the PET-tracer. In such cases, a recalculation is needed to make the PET data representative for the alternative administration route. To investigate the blood-brain barrier penetration of a drug (zolmitriptan) using dynamic PET and by PK modelling quantify the brain concentration of the drug after the nasal administration of a therapeutic dose. [11C]Zolmitriptan at tracer dose was administered as a short i.v. infusion and the brain tissue and venous blood kinetics of [11C]zolmitriptan was measured by PET in 7 healthy volunteers. One PET study was performed before and one 30 min after the administration of 5 mg zolmitriptan as nasal spray. At each of the instances, the brain radioactivity concentration after subtraction of the vascular component was determined up to 90 min after administration and compared to venous plasma radioactivity concentration after correction for radiolabelled metabolites. Convolution methods were used to describe the relationship between arterial and venous tracer concentrations, respectively between brain and arterial tracer concentration. Finally, the impulse response functions derived from the PET studies were applied on plasma PK data to estimate the brain zolmitriptan concentration after a nasal administration of a therapeutic dose. The studies shows that the PET data on brain kinetics could well be described as the convolution of venous tracer kinetics with an impulse response including terms for arterial-to-venous plasma and arterial-to-brain impulse responses. Application of the PET derived impulse responses on the plasma PK from nasal administration demonstrated that brain PK of zolmitriptan increased with time, achieving about 0.5 mg/ml at 30 min and close to a maximum of 1.5 mg/ml after 2 hr. A significant brain concentration was observed already after 5 min. The data support the notation of a rapid brain availability of zolmitriptan after nasal administration.
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| 2. |
- Kågedal, Matts, et al.
(författare)
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A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
- 2013
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 82, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [C-11]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived fro m each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.
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| 3. |
- Kågedal, Matts, et al.
(författare)
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Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions : extending the simplified reference tissue model
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 80:1, s. 116-127
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extended the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared to other brain regions, could be better explained by a difference in the extent of non-displaceable binding.METHODS: The analysis was based on a PET study in 6 healthy volunteers using the 5-HT1B receptor radioligand [(11) C]AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT1B receptor antagonist AZD3783. Nonlinear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies.RESULTS: The estimate (95% CI) of KiPL was 10.2 ng/ml (5.4-15) and 10.4 ng/ml (8.1-13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference respectively. The estimate (95% CI) of KiPL for caudate relative to other brain regions was 55% ( 48% -62%).CONCLUSIONS: The extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. The AZD3783 affinity appears to be higher in caudate compared with other brain regions.
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| 4. |
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| 5. |
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| 6. |
- Kågedal, Matts, et al.
(författare)
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Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers
- 2012
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 61:4, s. 849-856
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to develop a model simultaneously estimating (11)C-AZD9272 radioligand kinetics and the relationship between plasma concentration of AZD9272 and receptor occupancy in the human brain.AZD9272 is a new chemical entity pharmacologically characterised as a noncompetitive antagonist at the metabotropic glutamate receptor subtype 5 (mGluR5). Positron emission tomography (PET) was used to measure the time course of ((11)C-AZD9272) in the brain. The study included PET measurements in six healthy volunteers where the radioligand was given as a tracer dose alone as well as post oral treatment with different doses of unlabelled AZD9272. Estimation of radioligand kinetics, including saturation of receptor binding was performed by use of non-linear mixed effects modelling. Data from the regions with the highest (ventral striatum) and lowest (cerebellum) radioligand concentrations were included in the analysis. It was assumed that the extent of non-displaceable brain uptake was the same in both regions while the rate of CNS uptake and the receptor density differed.The results of the analysis showed that AZD9272 binding at the receptor is saturable with an estimated plasma concentration corresponding to 50% occupancy of approximately 200nM. The density of the receptor binding sites was estimated to 800nM and 200nM in ventral striatum and cerebellum respectively. By simultaneously analysing data from several PET measurements and different brain regions in a non-linear mixed effects framework it was possible to estimate parameters of interest that would otherwise be difficult to quantify.
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| 7. |
- Kågedal, Matts, 1968-
(författare)
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Nonlinear Mixed Effects Methods for Improved Estimation of Receptor Occupancy in PET Studies
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Receptor occupancy assessed by Positron Emission Tomography (PET) can provide important translational information to help bridge information from one drug to another or from animal to man. The aim of this thesis was to develop nonlinear mixed effects methods for estimation of the relationship between drug exposure and receptor occupancy for the two mGluR5 antagonists AZD9272 and AZD2066 and for the 5HT1B receptor antagonist AZD3783. Also the optimal design for improved estimation of the relationship between drug exposure and receptor occupancy as well as for improved dose finding in neuropathic pain treatment, was investigated.Different modeling approaches were applied. For AZD9272, the radioligand kinetics and receptor occupancy was simultaneously estimated using arterial concentrations as input function and including two brain regions of interest. For AZD2066, a model was developed where brain/plasma partition coefficients from ten different brain regions were included simultaneously as observations. For AZD3783, the simplified reference tissue model was extended to allow different non-specific binding in the reference region and brain regions of interest and the possibility of using white matter as reference was also evaluated. The optimal dose-selection for improved precision of receptor occupancy as well as for improved precision of the minimum effective dose of a neuropathic pain treatment was assessed, using the D-optimal as well as the Ds-optimal criteria.Simultaneous modelling of radioligand and occupancy provided a means to avoid simplifications or approximations and provided the possibility to tests or to relax assumptions. Inclusion of several brain regions of different receptor density simultaneously in the analysis, markedly improved the precision of the affinity parameter. Higher precision was achieved in relevant parameters with designs based on the Ds compared to the D-optimal criterion. The optimal design for improved precision of the relationship between dose and receptor occupancy depended on the number of brain regions and the receptor density of these regions.In conclusion, this thesis presents novel non-linear mixed effects models estimating the relationship between drug exposure and receptor occupancy, providing useful translational information, allowing for a better informed drug-development.
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| 8. |
- Lindhe, Örjan, et al.
(författare)
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Autoradiographic mapping of 5-HT1B/1D binding sites in the Rhesus monkey brain using [carbonyl-11C]zolmitriptan
- 2011
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Ingår i: International Journal of Molecular Imaging. - : Hindawi Publishing Corporation. - 2090-1712 .- 2090-1720.
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Tidskriftsartikel (refereegranskat)abstract
- Zolmitriptan is a serotonin 5-HT1B/1D receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [11C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95–5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT1 receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1B and 5-HT1D ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1A receptor antagonist.
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| 9. |
- Wall, Anders, et al.
(författare)
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Distribution of zolmitriptan into the CNS in healthy volunteers : a positron emission tomography study
- 2005
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Ingår i: Drugs in R&D. - 1174-5886 .- 1179-6901. ; 6:3, s. 139-147
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Triptans are highly effective in the treatment of migraine. Both central and peripheral mechanisms of action have been suggested. Until now, firm data about the passage of triptans into the CNS in humans have been lacking. The aim of the current study was to evaluate, using positron emission tomography (PET), the uptake and distribution of zolmitriptan into the CNS after intranasal administration. Subjects and methods: Eight healthy volunteers, five males and three females (mean ages 23 and 26 years, respectively), were included. Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions: once alone, and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5mg. PET was used to measure the concentration of labelled zolmitriptan in the brain, from the start of the tracer infusion for 90 minutes. Regional cerebral blood volume was determined with [15O]carbon monoxide. In addition, an MRI scan was performed to obtain anatomical information. The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data. Results: PET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain. Significant concentrations of [11C]zolmitriptan were found in all brain regions studied. Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase, reaching about 2nM (0.5 μg/L) 30 minutes after administration and 3.5nM (1.0 μg/L), or one-fifth of the plasma concentration, 1 hour after administration. Five minutes after zolmitriptan administration, the mean CNS concentration had already reached 0.5nM, which is higher than in vitro values for initiation of the agonistic action on 5-HT1B/1D receptors. Conclusion: This study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans, achieving an uptake rate and concentration compatible with a central mode of action.
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| 10. |
- Zingmark, Per-Henrik, et al.
(författare)
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Modelling a spontaneously reported side effect by use of a Markov mixed-effects model.
- 2005
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 32:2, s. 261-281
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To present a method for analyzing side-effect data where change in severity is spontaneouslyreported during the experiment. Methods: A clinical study in 12 healthy volunteers aimed toinvestigate the concentration-response characteristics of a CNS-specific side-effect was conducted.After an open session where the subjects experienced the side-effect and where the individualpharmacokinetic parameters were evaluated they were randomized to a sequence of three differentinfusion rates of the drug in a double-blinded crossover way. The infusion rates were individualizedto achieve the same target concentration in all subjects and different drug input rates wereselected to mimic absorption profiles from different formulations. The occurrence of the specificside-effect and any subsequent change in severity was self-reported by the subjects. Severity wasrecorded as 0 = no side-effect, 1 = mild side-effect and 2 = moderate or severe side-effect.Results: The side-effect data were analyzed using a mixed-effects model for ordered categoricaldata with and without Markov elements. The former model estimated the probability of having acertain side-effect score conditioned on the preceding observation and drug exposure. The observednumbers of transitions between scores were from 0 ->1: 24, from 0 ->2: 11, from 1 ->2: 23, from2 ->1: 1, from 2 ->0: 32 and from 1 ->0: 2. The side-effect model consisted of an effect-compartmentmodel with a tolerance compartment. The predictive performance of the Markov model wasinvestigated by a posterior predictive check (PPC), where 100 datasets were simulated from thefinal model. Average number of the different transitions from the PPC was from 0 ->1: 26, from0 ->2: 11, from 1 ->2: 25, from 2 ->1: 1, from 2 ->0: 35 and from 1 ->0: 1. A similar PPCfor the model without Markov elements was at considerable disparity with the data. Conclusion:This approach of incorporating Markov elements in an analysis of spontaneously reported categoricalside-effect data could adequately predict the observed side-effect time course and could beconsidered in analyses of categorical data where dependence between observations is an issue.
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