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

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 43; no. 5; pp. 573 - 585
• Main Authors: Cantillon, Marc, Ings, Robert, Prakash, Arul, Bhat, Laxminarayan
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2018
• Subjects: Administration, Oral; Adolescent; Adult; Aged; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Biomedical and Life Sciences; Biomedicine; Double-Blind Method; Drug Administration Schedule; Female; Human Physiology; Humans; Male; Medical Biochemistry; Middle Aged; Models, Biological; Organic Chemicals - administration & dosage; Organic Chemicals - blood; Organic Chemicals - pharmacokinetics; Original; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Psychotic Disorders - blood; Psychotic Disorders - diagnosis; Psychotic Disorders - drug therapy; Schizophrenia - blood; Schizophrenia - diagnosis; Schizophrenia - drug therapy; Young Adult
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-018-0472-z

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