Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ 18 F]Fallypride PET Study
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). "
ABSTRACT: Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic-PD (PK-PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration-occupancy relationship. To determine the effect of time on the concentration-occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [(11)C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK-PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration-occupancy relationship and the value of EC(50) was different according to the analysis approach (EC(50) derived from PD modeling alone=11.1 ng/mL (95% confidence interval (CI)=10.1 to 12.1); while that derived from combined PK-PD modeling=8.63 ng/mL (95% CI=7.75 to 9.51)). This finding suggests that PK-PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2011; 32(4):759-68. DOI:10.1038/jcbfm.2011.180 · 5.34 Impact Factor
Psychopharmacology 05/2011; 217(2):297-300. DOI:10.1007/s00213-011-2319-z · 3.99 Impact Factor
- "If one considers that there also is a saturable concentration–effect relationship for SSRIs with respect to one of SSRI's most problematic side effect, i.e., serotonin syndrome severity (Hegerl et al. 1998), TDM could help to titrate the plasma levels of patients toward the minimum effective plasma concentrations to reduce side effect risk of the medication with almost no loss of effectiveness. Having expanded at length on an essentially monophasic hyperbolic relationship between plasma concentration– response relationship that most PET studies (Gründer et al. 2008; Meyer et al. 2004) also focus on, we hasten to add that at the upper end of the plasma concentration–response relationship, there may be a decrease a compound's overall therapeutic effect again, resulting in a biphasic plasma concentration–response relationship that may look like an inverted U. The paroxetine data shown in Fig. 5 may be considered as such an example, although the number of patients per 10 ng/ml bin at and above 105 ng/ml is far too small to allow any meaningful interpretation. "
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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. "
ABSTRACT: Neuronal acetylcholine nicotinic receptors (nAChRs) are targets for the development of novel treatments of brain diseases. However, adverse effects (for example, emesis or nausea) associated with high drug maximal exposures or C(max) at nAChRs often hinder the advancement of experimental compounds in clinical trials. Therefore, it is essential to explore the feasibility of maintaining exposures below a predetermined C(max) while sustaining targeted CNS effects. By use of a [¹²³I]5-IA [5-[¹²³I]iodo-3-[2(S)-azetidinylmethoxy]pyridine] displacement SPECT imaging paradigm in nonhuman primates, we compared brain nAChR binding activity elicited by either a bolus injection or by slow infusion of an identical dose of a novel neuronal nicotinic agonist, ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], where the slow infusion scheme was derived from a two-compartment pharmacokinetic modeling designed to limit the C(max). We determined [¹²³I]5-IA displacement using doses of ABT-089 (0.04, 0.4, and 1.0 mg/kg i.v.) that encompassed efficacious drug exposures in nonhuman primates and examined the relationship between ABT-089 displacement ratios and plasma exposures. Our results indicated that calculated displacement ratios were quite similar between the two different dosing regimens despite substantial differences in C(max). In addition, displacement ratios correlated well with drug exposures calculated as the area-under-curve (AUC) of plasma concentration and varied in a dose-dependent manner, suggesting that displacement ratios are driven by the AUC of drug plasma exposure but not C(max). Our data demonstrate the feasibility of predicting plasma exposures using a two-compartment pharmacokinetic model and its potential for optimizing dosing regimens.Journal of Pharmacology and Experimental Therapeutics 03/2011; 336(3):716-23. DOI:10.1124/jpet.110.173609 · 3.86 Impact Factor