2008 - Marseille - France

PAGE 2008: Applications- CNS
Gianluca Nucci

A sparse sample PK & PKPD approach to estimate the time course of antipsychotic-induced D2 occupancy

Gianluca Nucci (1), Ana M. Catafau (2), María M. Penengo (3), Santiago Bullich (3), Emilio Merlo-Pich (2) and Roberto Gomeni (1)

(1) Clinical Pharmacokinetics Modeling & Simulation, GlaxoSmithKline, Verona, Italy

Background: Blockade of dopamine D2 receptors (D2RO) is a common feature of all antipsychotics (AP) and is a predictor of clinical response and of side effects of AP [1-3]. However, the degree of D2RO associated with efficacy, the relationships with AP plasma concentration (CP), the influence of the scanning time and the D2RO profile over time required for symptom control are still poorly understood. 

Objectives: A sparse-sample design and Pop PK and PKPD modelling approach were used: (a) to define the relationship between CP and striatal D2RO measured by SPECT in stabilized schizophrenic patients on risperidone (r), olanzapine (o), clozapine (c) and quetiapine (q) (PK-D2RO relationship), (b) to evaluate the time-course of the D2RO profile, and (c) to compare the profiles of D2RO and CP over time for these four AP.

Methods: A total of 46 patients with diagnosis of schizophrenia and responding to monotherapy with the four AP were included. Each treatment group was subdivided in four subgroups of n = 2-3 and allocated to undergo the SPECT scan at one time point during the interdose interval, defined based on the known PK for each AP. Blood samples were drawn during SPECT scanning for AP PK measurement. Each patient received only one tracer injection and was scanned once due to dosimetry limitations. A non-linear mixed effects modelling was applied to the population data to estimate the average time-course. Then an empirical Bayesian approach was used to estimate the individual PK, and the individual D2RO time course.

Results: Pop-PK modelling was undertaken using non-linear mixed-effect modelling as implemented in NONMEM VI to assess population PK of the four AP tested. Empirical Bayesian methods were used to estimate individual PK parameters using as a prior the information reported in the literature on each AP [4-7]. PK/D2RO modelling was best described by a direct link model between CP and D2RO (Emax model). PK and D2RO profiles over time were compared. Using the PK-PD model parameters, simulated D2RO curves were generated for representative doses of each AP.

Conclusions: A wide range of both observed CP and D2RO were obtained at therapeutic doses of r, o, c and q in stabilized patients. Our results suggest that clinical response to APs may be maintained with D2RO values below 65% SPECT. The relationship between PK and striatal D2RO was adequately described by a PK-D2RO Emax model. D2RO patterns over time differ between AP, being stabilized and dissociated from PK for r and o, variable and PK-associated for q and somewhat intermediate for c. These results were considered for the interpretation of D2RO measurements and design / optimization of new AP trials.

[1] Nordstrom et al., Central D2-Dopamine Receptor Occupancy in Relation to Antipsychotic Drug Effects: A  Double-Blind PET Study of Schizophrenic Patients. Biol. Psychiatry; 33:227-235, 1993
[2] Kapur et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157: 514-520, 2000
[3] Agid et al., Striatal Vs Extrastriatal Dopamine D2 Receptors in Antipsychotic Response: A Double-Blind PET Study in Schizophrenia. Neuropsychopharmacology.  32, 1209-1215, 2007
[4] Kimko et al. Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model. Clin Pharmacol Ther 68: 568-577, 2000.
[5] Callaghan J T, et al.  Olanzapine Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 37: 177-193, 1999
[6] Huang M L, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 54: 257-268, 1993
[7] Jerling M, et al. Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. Br J Clin Pharmacol 44: 447-453, 1997

Reference: PAGE 17 (2008) Abstr 1388 [www.page-meeting.org/?abstract=1388]
Poster: Applications- CNS