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

Figures & data

Table 1 Scenarios analyzed in pharmacokinetic model-based simulations

Scenario 1	Complete treatment discontinuation without reinitiation of medication
Scenario 2	One week of treatment interruption, followed by treatment reinitiation at the following doses: Oral risperidone 3 mg once daily Risperidone LAI 37.5 mg every 2 weeks Oral paliperidone ER 6 mg once daily Paliperidone palmitate 117 mg (75 mg eq) every 4 weeks
Scenario 3	Four weeks of treatment interruption, followed by treatment reinitiation at the following doses: Oral risperidone 3 mg once daily Risperidone LAI 37.5 mg every 2 weeks AND oral risperidone 3 mg once daily supplementation administered from days 28 to 49 (ie, weeks 4–7 from time of interruption) Oral paliperidone ER 6 mg once daily Paliperidone palmitate 117 mg (75 mg eq) administered on days 28 and 35 (ie, weeks 4 and 5 from time of interruption) and every 4 weeks thereafter

Abbreviations: eq, equivalent; ER, extended-release; LAI, long-acting injection.

Figure 1 Active moiety concentrations following complete treatment discontinuation (week 0 denotes administration time of next scheduled dose, which was missed).

Notes: Within a few days of oral risperidone or oral paliperidone ER discontinuation, there was a substantial decrease in the concentration of the active moiety. Two weeks following the last injection of risperidone LAI, the concentration of the active moiety continued to approximate the steady-state concentration for approximately 3–4 weeks due to the delay in release (3-week lag time between last injection and last release phase). After this lag phase, there was a subsequent and rapid decline of the concentration of the active moiety, with near zero concentrations reached by week 5. As compared with the other formulations, discontinuation of paliperidone palmitate exhibited the slowest decline of the concentration of the active moiety with levels of approximately 7 ng/mL at week 8.
Abbreviations: ER, extended-release; LAI, long-acting injection.

Figure 2 Number of days until active moiety plasma concentrations approach 2 ng/mL, by agent.

Notes: Following treatment discontinuation, paliperidone palmitate long-acting injectable suspension required more than 4 months (136 days) for the plasma concentrations of the active moiety to approach 2 ng/mL, with attainment of this threshold met less than one week after discontinuation of oral paliperidone ER (3.5 days) and oral risperidone (5.4 days), respectively, and approximately one month after discontinuation of risperidone LAI (32.9 days).
Abbreviations: ER, extended-release; LAI, long-acting injection.

Figure 3 Active moiety concentrations following one week of treatment discontinuation (week 0 denotes administration time of next scheduled dose, which was missed).

Notes: One week of interruption of either oral risperidone or oral paliperidone ER resulted in concentrations of the active moiety that approached zero. Reinitiation of oral risperidone or oral paliperidone ER required a few days for reattainment of steady-state concentrations of the active moiety. Administration of risperidone LAI at week -2 followed by a one-week interruption in the next scheduled dose resulted in active moiety concentrations being lower between weeks 4 and 5 despite treatment reinitiation at week 1. A one-week interruption in paliperidone palmitate administration was associated with a slight decrease in active-moiety concentration, with one reinitiation dose producing a re-establishment of a near steady-state concentration.
Abbreviations: ER, extended-release; LAI, long-acting injection.

Figure 4 Lowest plasma concentration after one week of treatment discontinuation versus steady-state minimum concentration.

Notes: One week of interruption of either oral risperidone or oral paliperidone ER resulted in the concentrations of the active moiety decreasing to 2%–11% of the steady-state concentration. One week of interruption in risperidone LAI administration was associated with an active moiety concentration decrease to 35% of the steady-state minimum concentration. A one-week interruption in paliperidone palmitate treatment resulted in the plasma concentration being maintained at approximately 90% of the steady-state minimum concentration.
Abbreviations: ER, extended-release; LAI, long-acting injection.

Figure 5 Active moiety concentrations following a 4-week treatment interruption and reinitiation (week 0 denotes administration time of next scheduled dose, which was missed).

Notes: Four weeks of interruption of either oral antipsychotic agent, risperidone or paliperidone, was associated with a near zero active moiety concentration, with these near zero levels occurring within a few days of treatment interruption. Following reinitiation, steady-state concentrations of the active moiety were re-established in approximately one week. Four weeks of interruption in risperidone LAI administration (ie, 6 weeks following the last administered dose) resulted in the plasma concentration of the active moiety decreasing to approximately 7.2 ng/mL at week 4. Reinitiation of risperidone LAI 37.5 mg at weeks 4 and 6, with oral risperidone 3 mg once-daily supplementation during weeks 4–7 resulted in a re-establishment of concentrations of the active moiety within a few days. However, due to the delayed-release characteristics of risperidone LAI, the active moiety concentration exhibits another decline between weeks 7 and 8. Four weeks after the last administered dose of paliperidone palmitate, the concentrations of the active moiety continued a slow, steady decline. Reinitiation of paliperidone palmitate (117 mg [75 mg eq] on days 28 and 35), without oral supplementation, produced a rapid reattainment of active moiety plasma concentrations.
Abbreviations: ER, extended-release; LAI, long-acting injection.

Figure 6 Lowest plasma concentration after 4 weeks of treatment discontinuation versus steady-state minimum concentration (%).

Notes: Four weeks of interruption of either oral antipsychotic agent, risperidone or paliperidone, was associated with zero concentration of the active moiety. The plasma concentration of the active moiety in the risperidone LAI group decreased to approximately 33% of the steady-state minimum concentration following 4 weeks of treatment discontinuation. Four weeks after the last administered dose of paliperidone palmitate the minimum active moiety concentration decreased to 64% of the steady-state minimum concentration.
Abbreviations: ER, extended-release; LAI, long-acting injection.