RP5063 is a novel multimodal dopamine (D)–serotonin (5-HT) stabilizer possessing partial agonist activity for D 2/3/4 and 5-HT 1A/2A, antagonist activity for 5-HT 2B/2C/7, 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.
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 max model.
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 c/ F), 328.00 ± 31.40 L; (3) absorption constant ( ka) 0.42 ± 0.17 h −1; (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 max 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 o = 87.3 ± 0.71 (PANSS Units; pu); (2) E max = − 31.60 ± 4.05 (pu); and (3) AUC 50 = 89.60 ± 30.10 (µg·h/mL). The predicted PANSS improvement reflected a clinical dose range of 5–30 mg.