Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ 18 F]Fallypride PET Study

Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
American Journal of Psychiatry (Impact Factor: 13.56). 05/2008; 165(8):988-95. DOI: 10.1176/appi.ajp.2008.07101574
Source: PubMed

ABSTRACT Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia.
Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole.
Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142).
Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

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    • "The influence of hysteresis characteristics on EC 50 also suggests that if PD modeling is used alone, the concentration–occupancy relationship described by the model will vary according to the time points when the data are measured. For example, another study, which measured plasma concentration and receptor occupancy by aripiprazole at the times similar to ours, reported similar EC 50 (10±4(s.d.) ng/mL in putamen) (Grunder et al, 2008). In contrast, another study by the same group reported that a single ziprasidone dose resulted in occupancies exceeding the 95% prediction limits of the occupancy versus plasma concentrations for chronic doses, suggesting different concentration–occupancy relationship between single and chronic doses (Vernaleken et al, 2008). "
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    • "Aripiprazole has been recently approved for treating psychiatric disorders and requires 90% receptor occupancy to achieve efficacy in preclinical animal models (Natesan et al., 2006) as well as in patients with schizophrenia (Grü nder et al., 2008). Unlike other D 2 -partial agonists that failed in clinical development, aripiprazole has high affinity for D 2 /D 3 receptors and a long plasma half-life, which leads to high-receptor occupancy over a long period time (Grü nder et al., 2008). The difference in receptor occupancy required for these two partial agonists is probably related to differences in the role of dopaminergic transmission in psychosis and nicotinic cholinergic transmission in cognitive function. "
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