Predicting brain concentrations of drug using positron emission tomography and venous input: modeling of arterial-venous concentration differences.
OBJECTIVE
In a positron emission tomography (PET) study, the concentrations of the labeled drug (radiotracer) are often different in arterial and venous plasma, especially immediately following administration. In a PET study, the transfer of the drug from plasma to brain is usually described using arterial plasma concentrations, whereas venous sampling is standard in clinical pharmacokinetic studies of new drug candidates. The purpose of the study was to demonstrate the modeling of brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform (T(av)).


METHODS
Brain kinetics (C(br)) was described as the convolution of arterial plasma kinetics (C(ar)) with an arterial-to-brain impulse response function (T(br)). The arterial plasma kinetics was obtained as venous plasma kinetics (C(ve)) convolved with the inverse of the arterio-venous transform (T(av) (-1)). The brain kinetics was then given by C(br)=C(ve)*T(av) (-1)*T(br). This concept was applied on data from a clinical PET study in which both arterial and venous plasma sampling was done in parallel to PET measurement of brain drug kinetics. The predictions of the brain kinetics based on an arterial input were compared with predictions using a venous input with and without an arterio-venous transform.


RESULTS
The venous based models for brain distribution, including a biexponential arterio-venous transform, performed comparably to models based on arterial data and better than venous based models without the transform. It was also shown that three different brain regions with different shaped concentration curves could be modeled with a common arterio-venous transform together with an individual brain distribution model.


CONCLUSIONS
We demonstrated the feasibility of modeling brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform. Such a model can in turn be used for the calculation of brain kinetics resulting from an arbitrary administration mode by applying this model on venous plasma pharmacokinetics. This would be an important advantage in the development of drugs acting in the brain, and in other circumstances when the effect is likely to be closer related to the brain than the plasma concentration.
Syvänen
Stina
S
Uppsala Imanet, Box 967, 75109, Uppsala, Sweden. stina.syvanen@uppsala.imanet.se
Blomquist
Gunnar
G
Appel
Lieuwe
L
Hammarlund-Udenaes
Margareta
M
Långström
Bengt
B
Bergström
Mats
M
D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D004364:Pharmaceutical Preparations