Info

Effect

ke0

dCe _ kieCVi dt

F CH

Figure 6 PK/PD model used to assess the relationship between YKP1358 and D2 receptor occupancy. (From ref. 27, by permission of Macmillan Publishers Ltd.)

- ke0Ce fits the general profile of an atypical antipsychotic drug [27] . A D2 receptor occupancy study was conducted in healthy volunteers using PET to measure the D2 receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [11C]raclopride. The relationship between plasma concentration and D2 receptor occupancy was analyzed with an indirect link model that included an effect compartment, as well as an equilibrium rate constant (ke0), as presented in Figure 6.

Results of the study demonstrated that YKP1358 possesses potential anti-psychotic effects based on the D2 receptor occupancy data. Considering the D2 receptor occupancy data, effective doses in patients were predicted to be greater than 250 mg twice a day. This is the first study in which the relationship between plasma concentration and the biomarker of D2 receptor occupancy was modeled using nonlinear mixed- effects modeling. It is anticipated that these results will be useful in estimating the initial doses of YKP1358 required to achieve a therapeutically effective range of D2 receptor occupancy in subsequent studies.

Project Management Made Easy

Project Management Made Easy

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