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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
Author(s) -
Gomeni R.,
Heidbreder C.,
Fudala P.J.,
Nasser A.F.
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.141
Subject(s) - risperidone , pharmacokinetics , population , pharmacology , dopamine antagonist , medicine , covariate , schizophrenia (object oriented programming) , psychology , haloperidol , psychiatry , dopamine , mathematics , econometrics , environmental health
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 (C max ) and the probability of observing GI disorders. An E max 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 E max . 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.