Significant dissociation of brain and plasma kinetics with antipsychotics

Abstract

Current dosing regimens of psychotropic drugs are based on plasma kinetic considerations, although it is unclear whether plasma levels faithfully reflect brain kinetics of drugs. 1,2 To examine this, we compared the kinetics of plasma levels of two widely used antipsychotics, olanzapine and risperidone, vs the time course of their effects in the brain. We used positron emission tomography (PET) and Novel antipsychotics are currently used to treat diverse medical conditions such as schizophrenia, mania, depression, and dementia. It is well established that antagonism of D 2 receptors is critical for antipsychotic efficacy, 3,4 and that at clinical doses antipsychotics block a substantial proportion of D 2 receptors in vivo. 5 Positron emission tomography and selective ligands such as [ 11 C]raclopride have provided valuable insights regarding receptor occupancy during treatment with olanzapine and risperidone. 6,7 However, in most studies PET scans were obtained only at a single time point after medication intake, typically 12 h post-dose. Hence, little is known about the time course of brain receptor blockade with these atypical antipsychotics. This is of particular interest as it has been shown that D 2 receptor occupancy can persist up to 15 days after withdrawal from oral doses of conventional neuroleptics, 8 and up to 6 months after depot injection of haloperidol decanoate. 9 We measured the time course of drug plasma levels and brain D 2 receptor occupancy in healthy volunteers after a single dose of 3-4 mg risperidone (n = 4) or 15 mg olanzapine (n = 4). We used [ 11 C]raclopride as a PET-ligand to estimate central D 2 receptor occupancy in the striatum, 1 and [ 11 C]FLB457 for quantification of extra-striatal D 2 blockade in the thalamus. 10 Additionally, we investigated the time course of plasma levels and striatal D 2 occupancy in five stable patients suffering from schizophrenia. These patients had received a monotherapy with olanzapine 15-20 mg day −1 (n = 3) or risperidone 3 mg day −1 (n = 2) for at least one month. We scanned them immediately after withdrawal from their antipsychotic medication, and again after 24 and 48 h.In the single-dose experiments in healthy volunteers, mean peak olanzapine plasma levels occurred 6 h after intake (23 ng ml −1 ± 4 SD). The plasma elimination half-life time (t 1/2 ) was 24.2 h (95% confidence interval (CI): 21.2-28.1). After 72 h, plasma levels declined on Figure 1 Single dose experiments in controls. Time course of plasma levels (olanzapine: , grey dashed line; risperidone plus 9-OH-risperidone: , grey solid line), and striatal D 2 receptor occupancy (olanzapine: , black dashed line; risperidone: , black solid line). All results are normalized to 100% of their peak value. Error bars denote one standard deviation.

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

“…Consistently, D 2 occupancy stabilized very close to baseline levels (mean occupancy was approximately 60% at 6 months compared with 70% at baseline). This reflects the asymptotic nonlinear relationship that is known to exist between plasma concentrations and D 2 receptor occupancy with atypical and typical antipsychotic drugs, including olanzapine (Tauscher et al, 2002). These changes were mirrored by seven patients receiving oral supplementation within the first four injection cycles, suggesting central D 2 occupancy generally required for antipsychotic efficacy (Nordström et al, 1993) was not attained in these patients until steadystate plasma concentrations were reached.…”

Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John’s wort: an [11C]-harmine PET study

“…Plasma levels alone with affinity measures are not an adequate substitute for in vivo imaging: the nonlinear relation between plasma levels and occupancy is not easily predictable, and sometimes the pharmacokinetics in plasma and the brain differ greatly. 7,8 It cannot be assumed that optimal occupancies for antidepressants are the same across targets. For example, the 5-HTT occupancy of SSRIs is 80% during steady-state treatment of MDD, 6,7,9 and the dopaminergic transporter (DAT) occupancy of bupropion is 14% during steady-state treatment of MDD.…”

Predicting Brain Occupancy from Plasma Levels using PET: Superiority of Combining Pharmacokinetics with Pharmacodynamics while Modeling the Relationship

“…The delayed approach to equilibrium can have clinically important effects: for example the usual clinical doses of some antipsychotic drugs, such as amisulpride and risperidone, are higher than would be predicted from their in vitro pharmacology and plasma PKs because they show poor blood-brain barrier penetration and dissociation between their brain and plasma PKs (Bressan et al, 2004;Kapur et al, 2002). Furthermore, in vivo evidence shows that there is a discrepancy between the time courses of drug plasma concentration and antipsychotic dopamine receptor occupancy (Tauscher et al, 2002). Figure 1B illustrates that applying the E max model without fully modeling the PK-PD relationship can lead to marked discrepancies in estimates where there is a difference between the plasma concentration and drug occupancy curves over time.…”