Drug Design, Development and Therapy (Oct 2021)
The Steady-State Comparative Bioavailability of Intramuscular Risperidone ISM and Oral Risperidone: An Open-Label, One-Sequence Study
Abstract
David P Walling,1 Howard A Hassman,2 Lourdes Anta,3 Lourdes Ochoa,4 Ignacio Ayani,3 Javier Martínez,3 Ibon Gutierro4 1Collaborative Neuroscience Network, LLC Garden Grove, Garden Grove, CA, USA; 2Hassman Research Institute, Berlin, NJ, USA; 3Medical Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, Spain; 4R&D Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, SpainCorrespondence: Javier MartínezLaboratorios Farmacéuticos ROVI, S.A., Calle Alfonso Gómez, 45A, Madrid, 28037, SpainTel + 34 91 375 63 36Fax + 34 91 304 78 81Email [email protected]: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment.Methods: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized.Results: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40– 65% and 38– 52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80– 1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16– 1.34], 1.17 [1.08– 1.27], and 1.25 [1.16– 1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone.Conclusion: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.Keywords: bioequivalence, comparative bioavailability, long-acting injectables, LAIs, pharmacokinetic, risperidone, schizophrenia
