Antipsychotic Dosing in Preclinical Models Is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on in Vivo Occupancy (original) (raw)
Research ArticleNEUROPHARMACOLOGY
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 625-631; DOI: https://doi.org/10.1124/jpet.102.046987
Abstract
What is the appropriate dose of an antipsychotic in an animal model? The literature reveals no standard rationale across studies. This study was designed to use in vivo dopamine D2 receptor occupancy as a cross-species principle for deriving clinically comparable doses for animal models. The relationship between dose, plasma levels, and in vivo dopamine D2 receptor occupancy was established in rats for a range of doses administered as a single dose or multiple doses (daily injections or osmotic minipump infusions) for five of the most commonly used antipsychotics. As a single dose, haloperidol (0.04–0.08 mg/kg), clozapine (5–15 mg/kg), olanzapine (1–2 mg/kg), risperidone (0.5–1 mg/kg), and quetiapine (10–25 mg/kg) reached clinically comparable occupancies. However, when these “optimal” single doses were administered as multiple doses, either by injection or by a mini-pump, it led to no or inappropriately low trough (24-h) occupancies. This discrepancy arises because the half-life of antipsychotics in rodents is 4 to 6 times faster than in humans. Only when doses 5 times higher than the optimal single dose were administered by pump were clinically comparable occupancies obtained (e.g., haloperidol, 0.25 mg/kg/day; olanzapine, 7.5 mg/kg/day). This could not be achieved for clozapine or quetiapine due to solubility and administration constraints. The study provides a rationale as well as clinically comparable dosing regimens for animal studies and raises questions about the inferences drawn from previous studies that have used doses unrepresentative of the clinical situation.
Footnotes
S.K. is supported by a Canada Research Chair in Schizophrenia and Therapeutic Neuroscience, and this work was supported by a grant from the Canadian Institutes of Health Research. The authors have in the past received grant support from some of the pharmaceutical companies whose products are discussed—however, there was no direct support for this project and the data have been collected and reported independent of any pharmaceutical company input.
DOI: 10.1124/jpet.102.046987
Abbreviation:
D2BP
D2 receptor binding potential- Received November 25, 2002.
- Accepted February 14, 2003.
The American Society for Pharmacology and Experimental Therapeutics
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