title: Population pharmacokinetic modeling and simulation to guide dose selection for RBP-7000, a new sustained-release formulation of risperidone.
abstract: RBP-7000 is a long-acting formulation of risperidone designed for once-monthly subcutaneous injection for the treatment of schizophrenia. The objective was to estimate clinically effective doses of RBP-7000 based on model simulations and on the comparison with other long-acting injectable antipsychotics. A population pharmacokinetic model of RBP-7000 was developed in 90 clinically stable schizophrenic patients having received single/repeated doses of 60, 90, or 120 mg. Model simulations were conducted to compare active moiety plasma exposure after repeated RBP-7000 administrations to the published data of long-acting risperidone injection (Risperdal® Consta®) at 25 and 50 mg, and of paliperidone palmitate (Invega® Sustenna®) at 50 and 100 mg equivalent paliperidone. Predictions of dopamine D2 receptor occupancy were derived from the simulated active moiety concentrations. Simulations showed similar active moiety plasma exposure at steady-state for 90 mg of RBP-7000 and 25 mg of long-acting risperidone. In comparison to risperidone, RBP-7000 reached effective concentrations immediately after the first administration. RBP-7000 at the doses of 60 and 90 mg provided similar active moiety plasma concentrations at steady-state compared to 50 and 100 mg equivalent paliperidone, respectively. These findings provide guidance for dose selection in Phase III clinical trials and suggest potential benefits for RBP-7000 over competitors.
authors.affiliation: Pharmacometrica, La Fouillade, France.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Laffont
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomeni
authors.forename: Bo
authors.initials: B
authors.lastname: Zheng
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fudala
authors.forename: Azmi F
authors.initials: AF
authors.lastname: Nasser
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000068882:Paliperidone Palmitate; D010168:Palmitates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000097:blood; D018967:Risperidone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D007555:Isoxazoles; D010168:Palmitates; D011743:Pyrimidines; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: RBP-7000; dopamine D2 receptor occupancy; dose switching simulation; long-acting risperidone; paliperidone palmitate