A quantitative systems pharmacology study on optimal scenarios for switching to paliperidone palmitate once-monthly

Long-acting injectable (LAI) antipsychotic formulations are increasingly used for improving patient compliance and long-term outcomes. Transitioning to LAIs raises questions regarding how optimum efficacy can be rapidly achieved while minimizing potential efficacy and safety concerns related to overlapping plasma levels of prior treatments and the new LAI. Ideally, randomized clinical trials would provide guidance regarding transition algorithms, but the number of studies and sample size required to address relevant questions makes this approach unachievable. We have used quantitative systems pharmacology, a clinically calibrated, mechanism-based computer model for schizophrenia to identify optimal switching scenarios to injectable paliperidone palmitate once-monthly (PP1M) from oral antipsychotics. We show that starting PP1M 1day after the last oral medication dose or 4weeks after the last LAI injection provides optimal benefit-risk compared to a delayed PP1M start after 1week with either a 1- or 2-week overlap with oral paliperidone. Although a similar or better therapeutic effect can be achieved within 2weeks for oral medications and LAI haloperidol decanoate and 8weeks for LAI aripiprazole, we identified a potential transient undertreatment liability in all cases except for risperidone. Switching from oral olanzapine may lead to a small reduction of antipsychotic efficacy in some patients. Switching to PP1M decreases extrapyramidal symptom liability in most cases, but increased dopamine D₂ receptor inhibition (except for haloperidol) might potentially increase prolactin synthesis. Overall, these results suggest time-windows for which the treating clinician must be most vigilant for potential efficacy and safety signals when switching to PP1M.