Switching Patients With Schizophrenia From Intramuscular Paliperidone Palmitate Once Monthly to TV-46000, a Long-Acting Subcutaneous Antipsychotic: An Exploration of Population Pharmacokinetic–Based Strategies

Abstract: Background This analysis used population pharmacokinetic (PopPK) modeling to characterize dosing conversions and switching strategies from intramuscular paliperidone palmitate once monthly (PP1m) to TV-46000, a long-acting subcutaneous antipsychotic formulation of risperidone, once monthly (q1m) or once every 2 months (q2m). Methods Total active moiety (risperidone + paliperidone) concentration–time profiles were simulated based on published PopPK models for PP1m and TV-46000 with virtual populations of 5000 patients. Percentage ranges (median Cmin divided by oral risperidone median Cmin minus 1, median Cmax divided by oral risperidone median Cmax) were evaluated. Results Simulations revealed the most comparable doses of TV-46000 to PP1m were 50mg-q1m/100mg-q2m TV-46000 to 78mg-PP1m (2mg/day oral comparable), 75mg-q1m/150mg-q2m TV-46000 to 117mg-PP1m (3 mg/day oral comparable), 100mg-q1m/200mg-q2m TV-46000 to 156mg-PP1m (4mg/day oral comparable), and 125mg-q1m/250mg-q2m TV-46000 to 234mg-PP1m (5 or 6mg/day oral comparable). Within each oral-comparable reference range (median Cmin to Cmax), TV-46000 ranges trended higher relative to PP1m, with a higher range estimated for TV-46000 q2m than q1m. Two potential switching scenarios were identified, both starting 4 weeks after the last PP1m injection: 1) a 1:1 comparable-dose switch, or if clinicians seek to reduce the initial post-switch Cmax peak, 2) transition to a lower q1m dose for 6 months (6 injections) or lower q2m dose for 2 months (1 injection) followed by 1:1 comparable dosing. Conclusion Switching to TV-46000 4 weeks after the last PP1m injection yielded generally comparable pharmacokinetic parameters upon steady-state. Clinician discretion will determine which switching strategy is appropriate for their context.Short Description: This analysis used population pharmacokinetic modeling to characterize dosing conversions and switching strategies from intramuscular paliperidone palmitate once monthly (PP1m) to TV-46000, a long-acting subcutaneous antipsychotic formulation of risperidone, once monthly or once every 2 months. TV-46000 steady-state total active moiety exposures were generally comparable with those of PP1m but tended to be higher within each oral risperidone range. Initiating TV-46000 4 weeks after the last dose of PP1m provided the most comparable pharmacokinetic parameters.Name of Sponsoring Organization(s): Teva Branded Pharmaceutical Products R&D, Inc.