CNS Drugs

Dosing and Switching Strategies for Paliperidone Palmitate Based on Population Pharmacokinetic Modelling and Clinical Trial Data Mahesh N. Samtani, et al.

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Table 1. Terminal half-life of first- and second-generation oral antipsychotics

First-generation oral antipsychotic Terminal half-life

Chlorpromazine 8–35 hoursa

Flupenthixol 22–36 hoursa

Fluphenazine 14–24 hoursa

Haloperidol 12–36 hoursa

Loxapine 4 hoursb

Perphenazine 8–21 hoursa

Thioridazine 9–30 hoursa

Second-generation oral antipsychotic Terminal half-life

Amisulpride 12 hoursc

Aripiprazole 47–68 hoursc

Clozapine 9–17 hoursc

Olanzapine 33 hoursc

Paliperidone (9-hydroxy-risperidone) 25 hoursd

Quetiapine 6 hoursc

Risperidone active moietye 22 hoursc

Sertindole 70 hoursc

Ziprasidone 8–10 hoursc

a Ereshefsky,[30] 1996. b Wikipedia,[33] 2010. c Mauri et al.,[31] 2007. d Vermeir et al.,[32] 2008. e Active moiety is the sum of parent drug plus its active metabolite 9-hydroxy-

risperidone.

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Table 2. Commonly used long-acting intramuscular injectable antipsychotic agents

Drug Administration interval t1⁄2 e

Perphenazine enanthatea 2 weeks 4–6 days

Haloperidol decanoatea 4 weeks 21 days

Zuclopenthixol decanoatea 2–4 weeks 19 days

Flupenthixol decanoateb 2–4 weeks 17 days

Fluphenazine decanoateb 2–5 weeks 14 days

Fluphenazine enanthatec 1 week 4 days

Risperidone microspheresd 2 weeks 4–6 days a Altamura et al.,[34] 2003. b Kane et al.,[36] 1998. c Levron and Ropert,[35] 1987. d Gefvert et al.,[37] 2005.

e t1⁄2 = apparent terminal half-life after multiple dosing.

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Figure 1 Population PK simulations for maintenance regimens using 75 mg eq.

paliperidone palmitate and paliperidone ER 6 mg, compared with observed clinical

PK data. Lines and shaded/hatched areas represent the medians and 90% prediction

intervals, respectively. Strength expressed as 75 mg eq. paliperidone equates to 117

mg paliperidone palmitate. [A] Observed steady-state exposure after 1 week of

dosing with once-daily paliperidone ER 6 mg is similar to the simulated model-based

projection. [B] Observed exposure after 6 months of dosing with 75 mg eq. once-

monthly paliperidone palmitate is similar to the simulated model-based projection.

[C] Comparison of the simulated projections in [A] and [B] suggests the equivalence

of 75 mg eq. paliperidone palmitate with paliperidone ER 6 mg.

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P aliperidone ER 6 mg once daily P a liperidone palmitate 75 mg eq. injections every 28 days

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Figure 2 Population PK simulations for maintenance regimens using 150 mg eq.

paliperidone palmitate and paliperidone ER 12 mg, compared with observed clinical

PK data. Lines and shaded/hatched areas represent the medians and 90% prediction

intervals, respectively. Strength expressed as 150 mg eq. paliperidone equates to

234 mg paliperidone palmitate. [A] Observed steady-state exposure after 1 week of

dosing with once-daily paliperidone ER 12 mg is similar to the simulated model-

based projection. [B] Observed exposure after 3 months of dosing with 150 mg eq.

once-monthly paliperidone palmitate is similar to the simulated model-based

projection. [C] Comparison of the simulated projections in [A] and [B] suggests the

equivalence of 150 mg eq. paliperidone palmitate with paliperidone ER 12 mg.

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P aliperidone ER 12 mg once daily P a liperidone palmitate 150 mg eq. injections every 28 days

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Figure 3 Simulations assessing a ±2-day window for the second (Day 8) paliperidone

palmitate initiation dose showing that the median Cmax varies by ±2 ng/mL. Day 1/Day

8 initiation was compared with (A) Day 1/Day 6 and (B) Day 1/Day 10 scenarios at

the 150/100 mg eq. dosage strength, administered in the deltoid muscle. Lines and

shaded/hatched areas represent medians and 90% prediction intervals, respectively.

Strengths expressed as 100 and 150 mg eq. paliperidone equate to 156 and 234 mg

paliperidone palmitate, respectively. Cmax= maximum plasma concentration.

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Figure 4 Simulations assessing the re-initiation regimen after a missed injection on

Day 8 where less than 4 weeks have elapsed since the first dose. Panel A depicts

the recommended Day 1/Day 8 initiation regimen followed by monthly 75 mg eq.

maintenance dose and the recommended 6 mg paliperidone ER exposure,

(references for scenarios involving missed doses on Day 8 in the remaining 3

panels). Panels B, C, and D compare Day 1/Day 15, Day 1/Day 22, Day 1/Day 29

versus 6 mg paliperidone ER. The first two doses in all four panels for paliperidone

palmitate are 150 and 100 mg eq. The third and subsequent doses for paliperidone

palmitate are 75 mg eq. The third dose for paliperidone palmitate is administered on

Day 36 in all four panels, which is followed by monthly maintenance dose. Lines and

shaded/hatched areas represent medians and 90% prediction intervals, respectively.

Paliperidone ER 6 mg once daily

Paliperidone palmitate

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Figure 5 Simulation assessing where more than 4 weeks have elapsed since the first

paliperidone palmitate injection. These involve two deltoid injections of 100 mg eq. on

Weeks 5 and 6 followed by the normal monthly cycle of 75 mg eq. in the gluteal

muscle. Paliperidone exposure from this missed dose scenario is compared with 6

mg paliperidone ER temporal profile. Lines and shaded/hatched areas represent

medians and 90% prediction intervals, respectively.

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Figure 6 Simulation assessing where 7 weeks have elapsed since the first

paliperidone palmitate injection. These involve two deltoid injections of 150/100 mg

eq. on Weeks 7 and 8 followed by the normal monthly cycle of 75 mg eq. in the

gluteal muscle. Paliperidone exposure from this missed dose scenario is compared

with 6 mg paliperidone ER temporal profile. Lines and shaded/hatched areas

represent medians and 90% prediction intervals, respectively.

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Figure 7 Simulations assessing flexibility in dosing window around normally

scheduled monthly injections for [A] –1 week and [B] +1 week excursions at the 150

mg eq. dose. Median Cmax decreases by 8% (from 52 to 48 ng/mL) at +7 days and

increases by 4% (from 52 to 54 ng/mL) at –7 days either side of the scheduled

monthly injection, indicating that a ±7 day dosing window is acceptable. Lines and

shaded areas represent medians and 90% prediction intervals, respectively. Strength

expressed as 150 mg eq. paliperidone equates to 234 mg paliperidone palmitate.

Cmax= maximum plasma concentration.

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Figure 8 Simulations of scenarios where the Week 4 dose is missed and treatment is

re-initiated with a single injection of the previously stabilized dose on (A) Week 5, (B)

Week 6, (C) Week 7 and (D) Week 8. Strengths expressed as 25, 50, 100 and 150

mg eq. paliperidone equate to 39, 78, 156 and 234 mg paliperidone palmitate,

respectively.

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Figure 9 Simulations of scenarios where the Week 4 dose is missed and treatment is

re-initiated with two injections of the previously stabilized, administered 1 week apart,

on (A) Week 5 and 6, (B) Week 6 and 7, (C) Week 7 and 8 and (D) Week 8 and 9.

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Figure 10 Simulations of paliperidone plasma concentrations after stopping

paliperidone palmitate therapy administered at 25, 50, 100 and 150 mg eq. Lines and

shaded areas represent medians and 90% prediction intervals, respectively. The

arrows represent days of injection with paliperidone palmitate.

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Figure 11 Simulations to assess the influence of age on paliperidone

pharmacokinetics. (A) and (B) show similar simulations, except that in (B) the CrCL

for patients aged >60 years was fixed at 112 mL/min, to correct for the influence of

poor renal function in the older population. Lines and shaded areas represent

medians and 90% prediction intervals, respectively. CSSmax= maximum steady state

plasma concentration; CrCL = creatinine clearance.

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Figure 12 Distribution of CrCL in the population pharmacokinetic database for the

two subgroups in SDC11A. Horizontal lines represent the medians (also presented)

for the two age groups. The choice of fixing CrCL to 122 mL/min in the older

population in SDC11B was based on the median CrCL for the group aged ≤ 60

years. CrCL = creatinine clearance.

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Figure 13 Simulation to assess the influence of gender on paliperidone

pharmacokinetics. Lines and shaded areas represent medians and 90% prediction

intervals, respectively. CSSmax = maximum steady-state plasma concentration.

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