Management of antipsychotic treatment discontinuation and interruptions using model-based simulations

Abstract

Mahesh N Samtani,1 John J Sheehan,2 Dong-Jing Fu,2 Bart Remmerie,3 Jennifer Kern Sliwa,2 Larry Alphs21Janssen Research and Development, Raritan, NJ, USA; 2Janssen Scientific Affairs, Titusville, NJ, USA; 3Janssen Research and Development, Division of Janssen Pharmaceutica, Beerse, BelgiumBackground: Medication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation.Methods: Starting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents)/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies.Results: Following complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week.Conclusion: Due to the long half-life of paliperidone palmitate (25–49 days), putative therapeutic plasma concentrations persisted longest in simulated cases of complete discontinuation or treatment interruption. These simulations may help clinicians better conceptualize the impact of antipsychotic nonadherence on plasma concentrations, and the impact of medication-specific reinitiation strategies after intermittent nonadherence.Keywords: paliperidone palmitate, risperidone, long-acting injection, pharmacokinetics, nonadherence, plasma concentrations