Using pharmacokinetic–pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics

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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.

Introduction

Schizophrenia research is guided by a range of preclinical in vivo pharmacological tests predicting antipsychotic potential (Arnt et al., 1997). These include the well established conditioned avoidance response paradigm in which antipsychotic drugs decrease the number of avoidances to an aversive unconditioned stimulus such as footshock in doses that do not affect the escape response (Arnt, 1982, Ogren and Archer, 1994, Wadenberg and Hicks, 1999). This selective disruption is common for both classical dopamine D2 receptor antagonists such as haloperidol and chlorpromazine as well as second generation antipsychotics such as olanzapine, risperidone and clozapine (Moore et al., 1992, Wadenberg et al., 2001). Several hypotheses have been raised in order to explain the nature behind the suppression of avoidances ranging from a general disruption of motor performance, impaired motor initiation response, deficit in associative learning, or as more recently proposed, a deficit in incentive motivation that drives the animal to actively pursue the goal (Beninger et al., 1980, Li et al., 2004). Nevertheless, suppression of conditioned avoidance response behaviour is a characteristic effect of all clinically effective antipsychotics. In addition, human positron emission tomography (PET) has shown that the level of striatal dopamine D2 receptor occupancy is predictive of clinical efficacy as well as side effects of antipsychotics (Farde et al., 1992, Kapur et al., 1999, Nyberg et al., 1999, Kapur and Remington, 2001, Bressan et al., 2001, Abi-Dargham and Laruelle, 2005). This is mirrored in recent studies, showing that the relationship between dopamine D2 receptor occupancy and conditioned avoidance response effects correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect (Wadenberg et al., 2001, Natesan et al., 2005). The conditioned avoidance response paradigm therefore is considered to possess a high degree of predictive validity (Wadenberg and Hicks, 1999).

To optimize bridging between preclinical and clinical researches, predictions of clinical therapeutically effective plasma levels contribute to the design of rational dosage regimes in clinical pharmacology (Breimer and Danhof, 1997, Perez-Urizar et al., 2000). The relationship between the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the drug can be described mathematically as PK/PD modelling. The PK encompasses the processes of absorption, distribution, metabolism and elimination of a drug and describes the quantitative relationship between dose and exposure levels whereas PD describes the quantitative relationship between exposure level and the pharmacological effect. PK/PD modelling describes the temporal relationship between PK and PD profiles and thereby provides an assessment of effect onset/duration relative to the plasma PK profile. Furthermore, estimate of the steady-state relationship between drug exposure and pharmacological effect can be obtained by PK/PD modelling of data from an acute single dose study, which for antipsychotic drugs is the most clinically relevant.

The present study investigated how well PK/PD modelling applies to the antipsychotics and the conditioned avoidance response paradigm by evaluating the degree of correlation between PK/PD predictions of therapeutically effective steady-state plasma levels in rodents with clinically relevant plasma exposure levels for the classical antipsychotic haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine. This includes the evaluation of dehydrosertindole and paliperidone, the metabolites of sertindole and risperidone, respectively. 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. 3H-raclopride was chosen because of its high affinity and selectivity for the dopamine D2 receptor and its analogy to human PET occupancy studies (Farde et al., 1988).

Section snippets

Animals

Male Wistar rats (Harlan, Netherlands) weighing approximately 200 g at the beginning of the training were used. For binding purposes rats were used at 175–230 g. Rats were housed under controlled laboratory conditions (temperature: 21 ± C; humidity: 55 ± 5% relative) on a 12:12 h light–dark cycle (lights on at 06:00). The animals were kept on a restricted diet in order to keep them to 80% of their free-feeding weight. Water was available ad libitum. All experiments were performed in accordance

Results

Relatively simple PK and PD models were evaluated to be sufficient for modelling of the sparse data sets. Raw data along with fitted PK and PK/PD curves for haloperidol (0.08 mg/kg, s.c.), sertindole (10 mg/kg, p.o.), dehydrosertindole (10 mg/kg, p.o.), clozapine (10 mg/kg, s.c.), risperidone (0.63 mg/kg, s.c.), paliperidone (1.3 mg/kg, s.c.) and olanzapine (2.5 mg/kg, s.c.) are presented in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7A, respectively. Data were recorded for at least

Discussion

This is the first report to describe the time course of drug plasma levels, brain dopamine D2 receptor occupancy and conditioned avoidance response behaviour in the rodent following single doses of antipsychotics. The main objectives were to evaluate the PK/PD relationship of antipsychotics using the suppression of conditioned avoidance response behaviour and dopamine D2 receptor occupancy as markers and correlate the PD responses in rats to clinically relevant plasma levels of the drugs for

Acknowledgements

The authors thank Susanne Herskind-Hansen, Marlene Q. Jørgensen, J. Lisbeth Petri, Mona Elster, Mette Lund Pedersen and Hanne Søndergård for their excellent technical assistance, and to Rebecca Dias for critical proof-reading of the manuscript.

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