Pimozide

Pimozide is an orally active neuroleptic drug which blocks central dopaminergic receptors. Pimozide antagonises many of the actions of amphetamine and apomorphine.

The mean serum elimination half-life in schizophrenic patients is approximately 55 hours. This is highly variable and may be as long as 150 hours in some individuals. There is a 13-fold interindividual difference in the area under the serum pimozide concentration-time curve and an equivalent degree of variation in peak serum levels among patients studied. The significance of this is unclear since there are few correlations between plasma levels and clinical findings.

The results of mutagenic studies indicate no genotoxicity. Carcinogenicity studies revealed no treatment related tumors in rats or male mice, but increased incidences of pituitary adenomas and mammary gland adenocarcinomas in female mice. These histopathology changes in the mammary gland and pituitary are thought to be prolactin-mediated and have been shown in rodents following hyperprolactinaemia by a variety of neuroleptic drugs with the relevance to humans being unknown. Due to the lack of toxicokinetic data in rodents the safety margin cannot be determined. Animal data has shown some embryo-toxicity at dose levels similar to the maximum human use level (MHUL). Fetal growth retardation and fetaltoxicity was observed at dose levels of approximately 6 times the MHUL on an mg/kg basis. Teratogenic effects have not been observed.

Pimozide has been shown in studies in vitro to block the cardiac hERG channel and to prolong the action potential duration in isolated perfused hearts. This effect on the hERG channel may be attenuated by pimozide’s blocking effect on the cardiac calcium L channel. In a number of in vivo animal studies intravenous or oral administration of pimozide has been shown to cause significant QTc prolongation. The doses which prolonged QTc did not cause arrhythmias.