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CNS Drugs
Dosing and Switching Strategies for Paliperidone Palmitate Based on Population Pharmacokinetic Modelling and Clinical Trial Data Mahesh N. Samtani, et al.
Supplemental Digital Content
This Supplemental Digital Content contains the tables and figures referred to in the
full version of this article, which can be found at http://adisonline.com/cnsdrugs
© 2011 Adis Data Information BV. All rights reserved.
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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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