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

Abstract

Background and ObjectiveRP5063 is a novel multimodal dopamine (D)–serotonin (5-HT) stabilizer possessing partial agonist activity for D2/3/4 and 5-HT1A/2A, antagonist activity for 5-HT2B/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.MethodsPharmacokinetic 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 Emax model.ResultsThe 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 (Vc/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 Emax 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) Eo = 87.3 ± 0.71 (PANSS Units; pu); (2) Emax = − 31.60 ± 4.05 (pu); and (3) AUC50 = 89.60 ± 30.10 (µg·h/mL). The predicted PANSS improvement reflected a clinical dose range of 5–30 mg.ConclusionsPharmacokinetics of RP5063 behaved predictably and consistently. Pharmacodynamics were characterized using an Emax model, reflecting total PANSS score as a function of cumulative AUC, that showed high predictability and low variability when correlated with actual observations.Electronic supplementary materialThe online version of this article (10.1007/s13318-018-0472-z) contains supplementary material, which is available to authorized users.

Brilaroxazine (RP5063) Clinical Experience in Schizophrenia: "A New Option to Address Unmet Needs"

“…The parameters predicted from the population analysis were similar to those obtained from previous brilaroxazine Phase 1 studies in normal healthy volunteers and patients with stable schizophrenia using a traditional pharmacokinetic approach 34 . The results from these studies offer valuable insights into the direction of dosing regimen design in future stages of clinical investigation.…”

“…Analysis of Phase 2 trial data involving patients with schizophrenia and schizoaffective disorder was undertaken to define: (1) the pharmacokinetics of brilaroxazine; and (2) the pharmacokinetic/ pharmacodynamic relationships of brilaroxazine utilizing the improvement in the primary endpoint (Total PANSS) 34 . This analysis was performed to complement the pharmacokinetic profile and to provide useful data to guide dose planning in patients with acute exacerbations of schizophrenia or schizoaffective disorder for the Phase 3 trial.…”

“…The population pharmacokinetic analysis involved the development of 1-and 2-compartment models and the evaluation of the impact of co-variates utilizing bootstrap techniques. The population pharmacodynamic analysis included the development of an Emax model for total PANSS from the Phase 2 trial as the response factor against cumulative AUC 34 .…”

“…These agents are also limited by their side effects 13,40 . Furthermore, atypical agents have been linked with weight gain and type 2 diabetes mellitus, leading to a US Food and Drug Administration warning in the package inserts of agents in this class [31][32][33][34][35][36][37][38][39][40][41][42][43] . Dibenzodiazepine-derived atypical agents (e.g., clozapine, olanzapine, and quetiapine) have also produced elevated serum triglyceride levels, with clozapine and olanzapine showing increased cholesterol levels after 8 weeks of treatment 44,45 .…”

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod‐induced mouse model

“…[25][26][27][28][29] Brilaroxazine has an established efficacy, safety, and pharmacokinetic profile from previous phase 1 and 2 studies in healthy volunteers and schizophrenia patients. [25][26][27][28][29] Also, preclinical work indicates that this agent inhibits the release of multiple proinflammatory cytokines.…”