Using in silico methods to determine optimal tapering regimens for decanoate-based long-acting injectable psychosis drugs

Abstract

Background: Reducing the dose of psychosis drugs in a gradual hyperbolic manner may minimise withdrawal effects and risk of relapse. There is presently limited guidance on tapering decanoate-based long-acting injectable dopamine antagonists (LIDAs). Objectives: We aimed to apply hyperbolic principles of tapering to the decanoate-based LIDAs flupentixol, zuclopenthixol and haloperidol to develop withdrawal regimens. Design: We used in silico methodology to predict plasma drug levels and D2 occupancy for different LIDA regimens. Methods: Existing pharmacokinetic and receptor occupancy data from nuclear neuroimaging studies were used to power modelling. Abrupt discontinuation was examined as a potential strategy, and dose reduction was modelled with pre-defined constraints used in similar work of 10 (fast regimens), 5 (moderate) and 2.5 (slow) percentage points of D2 occupancy change per month. Results: Abrupt discontinuation of decanoate-based LIDAs leads to excessive change in D2 occupancy which violated our pre-defined constraints, potentially resulting in withdrawal symptoms and increased risk of relapse. Reduction of LIDA dose allowed hyperbolic reduction in plasma level consistent with imposed constraints on receptor occupancy reduction rate. For equivalent per-weekly LIDA dosing, more frequent administration allowed a more gradual reduction of D2 occupancy. However, switching to oral forms is required to continue hyperbolic tapering to full discontinuation; reduction to zero using only LIDA produces too large a reduction in D2 occupancy. Guidance for reduction and cessation of LIDAs according to slow, moderate and fast criteria is provided. Conclusion: Abrupt cessation of decanoate LIDAs is not consistent with gradual hyperbolic tapering, despite their longer half-lives compared with oral formulations. Reduction to the point of full discontinuation can only be achieved by switching to oral therapy to complete the taper. These results are limited by the in silico and theoretical nature of the study, and there is a need to confirm these findings through real-world observational and interventional studies.