A Population Pharmacokinetic and Pharmacodynamic Analysis of RP5063 Phase 2 Study Data in Patients with Schizophrenia or Schizoaffective Disorder.

BACKGROUND AND OBJECTIVE

RP5063 is a novel multimodal dopamine (D)-serotonin (5-HT) stabilizer possessing partial agonist activity for D and 5-HT, antagonist activity for 5-HT and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships.

METHODS

Pharmacokinetic sample data (175 patients on RP5063; 28 doses/patient) were analyzed, utilized one- and two-compartment models, and evaluated the impact of covariates. Pharmacodynamic analysis involved development of an E model.

RESULTS

The pharmacokinetic analysis identified a one-compartment model incorporating body mass index influence on volume as the optimum construct, with fixed-effect parameters: (1) oral clearance (Cl/F), 5.11 ± 0.11 L/h; (2) volume of distribution (V/F), 328.00 ± 31.40 L; (3) absorption constant (ka) 0.42 ± 0.17 h; (4) lag time (t lag) of 0.41 ± 0.02 h; and (5) a calculated half-life of 44.5 h. Pharmacokinetics were linear related to dose. An E model for total Positive and Negative Syndrome Scale (PANSS) scores as the response factor against cumulative area under the curve (AUC) provided fixed-effect estimates: (1) E = 87.3 ± 0.71 (PANSS Units; pu); (2) E = - 31.60 ± 4.05 (pu); and (3) AUC = 89.60 ± 30.10 (µg·h/mL). The predicted PANSS improvement reflected a clinical dose range of 5-30 mg.

CONCLUSIONS

Pharmacokinetics of RP5063 behaved predictably and consistently. Pharmacodynamics were characterized using an E model, reflecting total PANSS score as a function of cumulative AUC, that showed high predictability and low variability when correlated with actual observations.