Switching Patients With Schizophrenia to TV-46000, a Long-Acting Subcutaneous Antipsychotic, From Risperidone Microspheres (R064766): An Exploration of Population Pharmacokinetic-Based Strategies

Abstract: Background: This analysis used pharmacokinetic (PopPK) modeling to characterize dosing conversions and switching strategies from R064766 (a once-every-2-weeks [q2w] intramuscular long-acting injectable antipsychotic formulation of risperidone microspheres) to TV-46000 (a once-monthly [q1m] or once-every-2-months [q2m] long-acting subcutaneous antipsychotic formulation of risperidone). Methods: Total active moiety (TAM; risperidone + 9-OH risperidone) concentration-time profiles were simulated based on published PopPK models with virtual populations of 5000 patients. Simulations were performed to predict TAM exposures when switching to TV-46000 q1m and q2m 2–6 weeks after the last steady-state R064766 injection. Results: TV-46000 50 mg q1m/100 mg q2m (comparable to 2 mg/day oral risperidone), 75 mg q1m/150 mg q2m (3 mg/day), and 100 mg q1m/200 mg q2m (4 mg/day) were found to correspond most closely with R064766 25 mg, 37.5 mg, and 50 mg q2w, respectively. Initiating TV-46000 4–6 weeks after the last dose of R064766 resulted in similar trends for maximal (Cmax) and minimal (Cmin) plasma concentration ratios after the first injection for all TV-46000 doses, durations (q1m, q2m), and sites of administration (abdomen, upper arm), compared with R064766 at steady state. For all washout durations (q1m), Cmax and Cmin ratios began to approach 1.0 with subsequent injections. Conclusion: These PopPK simulations revealed switching to TV-46000 at 4–6 weeks after the last dose of R064766 provided generally comparable PK exposures by the second dose of TV-46000. Clinician discretion will determine which switching strategy is best in context based on factors such as patient preference, scheduling convenience, and concerns about tolerability.Short Description: Population pharmacokinetic modeling characterized dosing conversions and switching strategies from R064766 (a once-every-2-weeks intramuscular formulation of risperidone microspheres) to TV-46000 (a once-monthly or once-every-2-months long-acting subcutaneous antipsychotic formulation of risperidone). Initiating TV-46000 4–6 weeks after the last dose of R064766 led to comparable trends in maximal and minimal plasma concentration ratios after the first injection for all TV-46000 doses, durations, and sites of administration, compared with R064766 at steady state.Name of Sponsoring Organization(s): Teva Branded Pharmaceutical Products R&D, Inc.