Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone

Preliminary in vitro findings indicated that the novel anxiolytic drug, deramciclane is a substrate for the cytochrome P(450) (CYP) 3A4 isoenzyme. Moreover, its co-administration with buspirone, another anxiolytic drug, is likely in clinical practice. The primary objective of the present study was to evaluate the in vivo effects of deramciclane on CYP3A4 activity as measured by buspirone pharmacokinetics. The secondary objective was to study the possible pharmacodynamic interaction between these two anxiolytic drugs. Sixteen healthy subjects received 60 mg deramciclane or matched placebo for 8 days in this randomized, double-blind, cross-over study. On day 8 of both phases, the subjects received a 20-mg single dose of buspirone. Buspirone and its active metabolite, 1-pyrimidylpiperazine (1-PP), concentrations were measured for 24 h. Pharmacodynamic testing and measurement of plasma prolactin concentrations were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane and buspirone co-administration. Repeated administration of deramciclane had no effect on CYP3A4 activity as measured by buspirone pharmacokinetics. However, deramciclane administration caused an inhibition of the further, not CYP3A4-dependent, metabolism of 1-PP as evidenced by 84% increase in the AUC ( P