title: A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-released formulation of risperidone.
abstract: RBP-7000 is a sustained-release (once-monthly injection for subcutaneous administration) formulation of risperidone using the ATRIGEL® Delivery System, developed for treatment of schizophrenia to address compliance issues associated with oral administration. The objective of this analysis was to report the results of a population pharmacokinetic analysis and to describe the relationship between risperidone and 9-hydroxyrisperidone levels with dopamine (DA) D2-receptor occupancy, prolactin levels, and adverse events using data collected in 45 clinically stable schizophrenic patients receiving RBP-7000 in single ascending doses (risperidone) of 60, 90, and 120 mg. The population PK model accounted for an initial peak, a delayed and slow delivery, the disposition of risperidone, and the conversion of risperidone to 9-hydroxyrisperidone. BMI was a covariate affecting absorption of risperidone and ultimately formation of 9-hydroxyrisperidone. A logistic analysis indicated a correlation between the increase in Active Moiety (risperidone + 9-OH-risperidone) exposure (Cmax ) and the probability of observing GI disorders. An Emax population PK/prolactin model best described the relationship between the circulating Active Moiety and the serum prolactin levels. Gender was a significant covariate associated with Emax . These data provided a comprehensive characterization of the relationship between circulating Active Moiety and the efficacy/safety profile of RBP-7000 in clinically stable schizophrenic patients.
authors.affiliation: Alleantis, Research Triangle Park, North Carolina.
authors.forename: R
authors.initials: R
authors.lastname: Gomeni
authors.forename: C
authors.initials: C
authors.lastname: Heidbreder
authors.forename: P J
authors.initials: PJ
authors.lastname: Fudala
authors.forename: A F
authors.initials: AF
authors.lastname: Nasser
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007555:Isoxazoles / Q000097:blood; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000068882:Paliperidone Palmitate; D011098:Polyglactin 910 / Q000737:chemistry; D011388:Prolactin / Q000097:blood; D011743:Pyrimidines / Q000097:blood; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018967:Risperidone / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C581293:DRD2 protein, human; D003692:Delayed-Action Preparations; D007555:Isoxazoles; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D011098:Polyglactin 910; D011388:Prolactin; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: D2 receptor occupancy; long-acting risperidone; prolactin levels