title: Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics.
abstract: In the rat, selective suppression of conditioned avoidance response has been widely reported as a test with high predictive validity for antipsychotic efficacy. Recent studies have shown that the relationship between dopamine D2 receptor occupancy and the suppression of conditioned avoidance response behaviour correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect. The aim of the present study was to evaluate how pharmacokinetic/pharmacodynamic (PK/PD) predictions of therapeutic effective steady-state plasma levels by means of conditioned avoidance response behaviour in rodents, correlate with clinically relevant plasma exposure for the classical antipsychotic drug haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine, including selected metabolites. In order to confirm the validity of the present conditioned avoidance response procedure, in vivo striatal dopamine D2 receptor occupancy was determined in parallel using 3H-raclopride as the radioligand. The PK/PD relationship was established by modelling the time-response and time-plasma concentration data. We found the order of dopamine D2 receptor occupancy required to suppress conditioned avoidance response behaviour according to EC50 measurements to be sertindole (+dehydrosertindole)=dehydrosertindole=paliperidone (the metabolite of risperidone)=haloperidol=olanzapine>risperidone>>clozapine. Overall, a good agreement was observed between the rat dopamine D2 receptor occupancy levels providing 50% response in the conditioned avoidance response test and the dopamine D2 receptor occupancy levels reported from responding schizophrenic patients treated with antipsychotics. Predictions of therapeutically effective steady-state levels for sertindole (+dehydrosertindole) and olanzapine were 3-4-fold too high whereas for haloperidol, clozapine and risperidone the predicted steady-state EC50 in conditioned avoidance responding rats correlated well with the therapeutically effective plasma levels observed in patients. Accordingly, the proposed PK/PD model may act as a guide for determining effective plasma concentrations of potential antipsychotics in the clinical setting and thereby accelerating the overall drug development process.
authors.affiliation: Department of Psychopharmacology, DK-2500 Valby Copenhagen, Denmark. ckol@lundbeck.com
authors.forename: Christina Kurre
authors.initials: CK
authors.lastname: Olsen
authors.forename: Lise Tøttrup
authors.initials: LT
authors.lastname: Brennum
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D001479:Basal Ganglia / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics; D001667:Binding, Competitive; D003024:Clozapine / Q000097:blood / Q000493:pharmacokinetics; D003213:Conditioning, Psychological / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006220:Haloperidol / Q000097:blood / Q000493:pharmacokinetics; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D000077152:Olanzapine; D011485:Protein Binding; D020891:Raclopride / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015203:Reproducibility of Results; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007093:Imidazoles; D007211:Indoles; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D020891:Raclopride; C066304:sertindole; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine