Population Pharmacokinetics and Prediction of Dopamine D2 Receptor Occupancy After Multiple Doses of RBP‐7000, a New Sustained‐Release Formulation of Risperidone, in Schizophrenia Patients on Stable Oral Risperidone Treatment

• Published in: Clinical pharmacokinetics 2014-06, Vol.53 (6), p.533-543
• Main Authors: Laffont, Celine M., Gomeni, Roberto, Zheng, Bo, Heidbreder, Christian, Fudala, Paul J., Nasser, Azmi F.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Adult and adolescent clinical studies; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - pharmacokinetics; Biological and medical sciences; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; General pharmacology; Humans; Injections, Subcutaneous; Internal Medicine; Isoxazoles - pharmacokinetics; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Original Research Article; Paliperidone Palmitate; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Pyrimidines - pharmacokinetics; Receptors, Dopamine D2 - metabolism; Risperidone - administration & dosage; Risperidone - pharmacokinetics; Schizophrenia; Schizophrenia - drug therapy; Young Adult
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-014-0132-7

Background and Objectives RBP-7000 is a long-acting formulation of risperidone administered once monthly via subcutaneous (SC) injections for the treatment of schizophrenia. The objectives of the present study were to characterize the pharmacokinetics of RBP-7000 after multiple doses in schizophrenic patients on stable oral risperidone therapy and to evaluate the switch between oral risperidone and SC injections of RBP-7000. Methods Data were collected in a phase IIa, open-label, multiple-ascending-dose study where 45 patients clinically stabilized on oral risperidone (2, 3 or 4 mg/day) were switched to receive 60, 90 or 120 mg/month SC injections of RBP-7000, respectively. Patients were thereafter switched back to oral risperidone. An integrated population pharmacokinetic model describing simultaneously risperidone and 9-hydroxyrisperidone after risperidone oral intake and RBP-7000 administration was developed in NONMEM using 5,232 quantifiable plasma concentrations. Predictions of dopamine D 2 receptor occupancy were derived using a previously published model. Results A two-compartment model with first-order absorption was selected for oral risperidone, while a three-compartment model with first-order absorption and a transit compartment absorption model was selected for RBP-7000. Body mass index was identified as a significant covariate affecting the initial absorption of risperidone following RBP-7000 injection. Steady state was reached after the second or third RBP-7000 injection but plasma concentrations close to steady-state values were obtained right after the first injection when switching from oral risperidone therapy. Predicted dopamine D 2 receptor occupancy after repeated doses of 90 and 120 mg showed less fluctuation than after oral risperidone with acceptable ranges for clinical efficacy and a potentially safer profile with respect to extrapyramidal side effects. Conclusion This analysis provided additional insight into the pharmacokinetics of RBP-7000 and for the comparison with oral risperidone treatment. The established model was used to support the design of a planned phase III study.