Implementing gradual, hyperbolic tapering of long-acting injectable antipsychotics by prolonging the inter-dose interval: an in silico modelling study

Abstract

Gradual, hyperbolic tapering has been proposed as a method to reduce the risk of withdrawal effects and potential relapse of an underlying condition by minimising disruption of existing equilibria. We applied hyperbolic tapering principles in silico to long-acting aripiprazole to generate regimens for withdrawal in clinical practice. We derived thresholds for taper rates using existing studies and consensus. Using pharmacokinetic data for aripiprazole long-acting injectable antipsychotic (ALAI), we conducted in silico modelling to examine the impact of abrupt cessation of long-acting injectable antipsychotic (LAI) medication and the effect of prolonging inter-dose interval on plasma aripiprazole levels and consequent D₂ occupancy. We also modelled transitions from LAI medication to oral medication. Regimens were designed to afford a rate of reduction between 5 and 12.5 percentage points of D₂ occupancy per month. Abrupt discontinuation of ALAI was shown to lead to a maximal D₂ occupancy reduction of 16.8 percentage points per month; prolongation of the inter-dose interval of ALAI produced a slower reduction. Specifically, hyperbolic tapering was afforded by prolongation of a 400 mg ALAI inter-dose interval from 4 to 7 weeks, before reducing the dose to 300 mg ALAI. This could then be administered at up to 4-week (for 6% maximal D₂ occupancy change), 6-week (9% change) or 7-week (11% change) intervals. Switching to oral medication - 5, 2.5 and 1.25 mg for the three regimens, respectively - is required for ALAI to complete full cessation to prevent too rapid a reduction in D₂ occupancy. Oral medication should probably be maintained at a consistent dose for 3-6 months before further reductions to account for residual LAI being concurrently eliminated. Hyperbolic dose tapering is possible with ALAI through prolongation of the inter-dose interval and may reduce the risk of relapse compared to abrupt discontinuation of LAI medication.

Keywords: antipsychotic withdrawal; depot tapering; discontinuation; hyperbolic tapering; long-acting injectable antipsychotic; pharmacokinetic; stopping.

Figure 1.

Graphs demonstrating (a) the elimination of LAI medication from plasma peak levels (time = 0) following abrupt cessation, (b) the effect that increasing the plasma level of medication has in occupying D₂ receptors and (c) the combined effects of the phenomena illustrated in part labels a and b which demonstrates the decrease in D₂ occupancy as LAI medications are eliminated from plasma. LAI, long-acting injectable antipsychotic.

Figure 2.

Pictorial representation of how the rate of decreasing D₂ occupancy was assessed, in terms of both overall and terminal reductions.

Figure 3.

Effect of abrupt cessation of a 300 mg ALAI, in terms of both (a) plasma concentration levels and (b) occupancy of D₂ receptors. ALAI, aripiprazole long-acting injectable.

Figure 4.

Pictorial representation of how residual drug from previous ALAI administration affects the choice of dose for subsequent oral medications. This is reflected in both (a) plasma aripiprazole level and (b) the effect on changing D₂ occupancy. ALAI, aripiprazole long-acting injectable.

Figure 5.

Pictorial representations of how the proposed (a) ‘slow’, (b) ‘moderate’ and (c) ‘fast’ regimes would affect both (i) plasma aripiprazole level and (ii) D₂ receptor occupancy.