12 - Pharmacokinetics and Clinical Pharmacology

Clinical pharmacology and practical
management issues with long-acting

injectable antipsychotic drugs
TBC
TBC
Agenda
LAI pharmacology: FGA-LAIs
LAI pharmacology: SGA LAIs
risperidone LAI
paliperidone palmitate
olanzapine pamoate
Open discussion facilitated
by moderator
Keypad question;
discussion led by
moderator
Switching long-acting injection (LAI)

antipsychotics: filling the initial gap
Care is required to cover the initial gap in antipsychotic levels when
switching medication, as standard dose-release profiles are limited by
the vehicle
Effective brain half lives should also be considered, as inadequate
adherence may occur during the switch
Delivery
Need for adjunctive oral

antipsychotic during crossover
Fluphenazine
Oil-based
Moderate
Haloperidol
Oil-based
Moderate
Flupenthixol/
zuclopenthixol
Oil-based
Moderate
Microspheres
High
Olanzapine pamoate LAI
Crystal
Nil/minimal
Paliperidone palmitate LAI
Crystal
Nil/minimal
Target LAI
FGAs
SGAs
Risperidone LAI
FGAs = first-generation antipsychotics

SGAs = second-generation antipsychotics
Lambert T. WPA 2008, Prague, Czech Republic (Abstract SaS-04)
LAI pharmacology: first generation

antipsychotics (FGA-LAIs)
Keeping the
skin taut with
your left
hand, insert
the needle at
a 90 angle
with your
right hand
FGAs to FGA-LAIs: background

FGA-LAIs are esters composed of long-chain fatty-acids and common FGAs
decanoate (a 10-carbon, straight-chain fatty acid) esters are most common, but
enanthate (C7), undecylenate (C10, with single double bond) and palmitate
(C16) esters are available for some agents in some countries
Once esterified, the FGA becomes fat soluble and can be dissolved in oil (e.g.,
sesame or coconut oil, or the synthetic vegetable oil, Viscoleo)
The resulting solution is delivered by deep intramuscular (IM) injection
The ester is slowly released from the oil reservoir formed in the muscle tissue
The active hydrophilic drug component of the ester orients itself to the interstitial
fluid compartment; the hydrophobic fatty acid tails orient themselves to the
oily globule

LAIs = long-acting injectables
FGAs to FGA-LAIs: background (contd)

This mode of action ensures slow release of the ester from the
FGA-LAI reservoir, resulting in long apparent half lives
After leaving the oily globule, the esterified drug is rapidly
hydrolysed by plasma esterases, allowing the free drug to diffuse
to the brain13
The clinical pharmacokinetics of FGA-LAIs are relatively complex
when given as regular injections, FGA-LAIs take weeks or
months to reach steady-state levels, and have a
correspondingly slow elimination period1,2,4 (perhaps nonreciprocal)
Slow elimination may be a critical feature with regard to the clinical
aspects of relapse prevention
The pharmacokinetics and route of administration of FGA-LAIs
confer several additional benefits 1. Ereshefsky L, et al. J Clin Psychiatry 1984;45:509
LAIs = long-acting injectables
2. Barnes TR, Curson DA. Drug Saf 1994;10;46479

3. Dencker SJ, Axelsson R. CNS Drugs 1996;6:36781
4. Jann MW, et al. Clin Pharmacokinet 1985;10:31533
FGA-LAI release kinetics

Animation
Place
holder
for
videoclip
The fatty acid tail is lipophilic and the antipsychotic head is hydrophilic
Once the head is out of the oily FGA-LAI, it is hydrolysed to the free drug
FGA-LAI = first-generation antipsychotic long-acting injectable
Source: Lundbeck Education Program on FGA-LAI Antipsychotics (CD-ROM),
Addat International Pty Ltd, St Kilda, Victoria, Australia Tim Lambert 1999
Fluphenazine decanoate: kinetics
While this ensures a

treatment effect from
the outset, regular
injections often lead to
exacerbation of
extrapyramidal
symptoms (EPS)
around the injection
period
1.6
Plasma concentration (ng/mL)
Note that there is an

immediate peak in the
plasma concentration
of fluphenazine within
8 hours of
administration
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
0 10
50
100
150
Time (hours)

Other FGA-LAIs (flupenthixol, zuclopenthixol and

haloperidol decanoates): kinetics
With flupenthixol,
zuclopenthixol and
haloperidol decanoates,
release of the free drug
increases relatively
slowly around 57 days
after the injection
9
8
7
6
5
4
All three formulations

have similar plasmaconcentration profiles
3
2
1
0
0 1 2
14
21
28
Time (days)
FGA-LAI kinetics
However, elimination is
NOT reciprocal
many patients develop
fibrotic lumps, and the
FGA-LAI may become
loculated
Effective half lives of up to
18 months have been
recorded
Fluphenazine plasma concentration (ng/mL)
Real-world and computer

models concur that steady
state occurs in about
23 months
Actual curve (R = 0.9%)

Computer model (half life of 19.8 days
yields steady state in 70 days)
2.5
2.0
1.5
1.0
0.5
0
0
14 21 28 35 42 49 56 63 70
FGA-LAI = first-generation antipsychotic long-acting injectable Time (days)
Effective half-lives of FGA-LAIs

Because the absorption
() phase is the ratelimiting step determining
plasma levels, the
effective or apparent
half lives (t1/2) of FGALAIs are long
20
Effective t1/2 (days)
15
10
Haloperidol decanoate
is commonly given
monthly (the others at 2weekly intervals)
Haloperidol
decanoate
ZucloFlupenthixol Fluphenazine
penthixol
decanoate decanoate
decanoate
but most patients

can tolerate
monthly injections
of all FGA-LAIs
FGA-LAIs = first-generation antipsychotic long-acting injectables

Dose equivalencies of FGA-LAIs
FGA-LAI
Dose equivalent to
~300mg/day
chlorpromazine*
Fluphenazine
decanoate
25mg 2-weekly
Flupenthixol
decanoate
40mg 2-weekly
Zuclopenthixol
decanoate
200mg 2-weekly
Haloperidol
decanoate
110mg 4-weekly
The psychopharmacological
background to
equivalency between
various FGA and SGA
agents are reviewed in
the supplementary
on-line module
Antipsychotic
Switching
Note that US
equivalencies are not
consistent with those
used in Europe and the
rest of the world

*The rationale for equivalency can be found in the software tool Switcha
The issue of variable neuroleptic-induced

extrapyramidal symptoms (NIEPS)
Jaw dystonia and tardive dyskinesia (TD)

Moderate dose, acute on long-term first-generation antipsychotic treatment
Place
holder
for
videoclip
Acute dystonia superimposed on tardive dyskinesia

(young person)
Source: Recognition and Management of EPS (CD-ROM). Published by Janssen
Cilag Pty Ltd Addat International Pty Ltd, St Kilda, Victoria, Australia, 20012003
FGA-LAI dose and EPS (1)
Studies12 suggest
that there is a
threshold for
developing EPS (red
zone), which
corresponds to 80%
of D2-like receptor
occupancy in the
caudate (assuming
that occupancy is by
an antagonist)3
EPS zone
8
7
6
5
4
3
2
1
0
0 1 2
14
Time (days)
21
28
FGA-LAI = first-generation
1. Farde L, et al. Arch Gen Psychiatry 1992;49:53844
2. Kapur S, et al. Am J Psychiatry 2000;157:51420
antipsychotic long-acting injectable
3. Grunder G, et al. Arch Gen Psychiatry 2003;60:9747
EPS = extrapyramidal symptoms
Low-dose FGA-LAIs
9
For haloperidol,
flupenthixol and
zuclopenthixol LAIs,
there is a fairly
immediate postinjection release of
antipsychotic, with a
mild peak (Cmax) at
782 days
EPS zone
8
7
6
5
4
3
2
1
0
0 1 2
14
Time (days)
21
28
If the dose is kept as

low as possible then
at steady state, most
EPS can be avoided

Cmax = maximum plasma concentration
Moderate-dose FGA-LAIs
9
At steady state, moderate

doses of FGA-LAIs are likely
to lead to a Cmax that exceeds
the EPS threshold
EPS zone
8
7
In these cases, EPS are more

likely to be reported 510
days after the injection
6
5
4
If patients are seen by their

doctor at the time of the
trough plasma concentrations,
they may have dropped into
the non-EPS zone
3
2
1
0
0 1 2
14
Time (days)
21
28
such doses are equivalent

to the low FGA-LAI doses
prescribed by many
clinicians

High-dose FGA-LAIs
9
8
7
6
5
4
EPS zone
When high doses of

FGA-LAIs are
prescribed, both the
Cmax and trough levels
are likely to exceed the
threshold for EPS
Such doses were

common in the past as
2
it was erroneously
1
thought that these
0
0 1 2
7
14
21
28
agents could not
Time (days)
provide protection
against psychosis
without causing EPS
3

FGA-LAIs: benefits/pros versus oral drugs

FGA-LAIs pros
Both the pros and cons of

Overcome adherence issues with oral
prescribing FGA-LAIs
medication
should be considered
Where relapse prevention Bypass the pharmacokinetic hurdles of
is paramount, FGA-LAIs
absorption and first-pass hepatic
elimination
are an indispensable
component of community Deliver a fairly constant dose
psychiatry
of antipsychotic throughout the
injection cycle
Last for long periods between IM
injections (particularly fluphenazine and
haloperidol decanoate)
FGA-LAIs = first-generation
antipsychotic long-acting
injectables
IM = intramuscular
Body of evidence demonstrating

superior prevention of relapse due to
non-adherence
FGA-LAIs: risks/cons
FGA-LAI cons
Some of the pros are also

Understanding PK and dosing requires
cons
specialist knowledge
There is a clinical art to
FGA-LAI prescribing
Last for long periods between IM injections

It takes many weeks or months to reach
The last point in the table

steady state; a correspondingly long period of
is key: FGA-LAIs may
elimination is needed should an adverse
event occur (e.g. EPS)
enhance relapse
prevention, but they are
Patients dislike being coerced with needles
still pro-toxic with regard to (culturally dependent)
TD, neuroleptic-induced
There is a tendency for clinicians to use
deficit syndrome (NIDS),
polypharmacy with other (oral) neuroleptics;
etc.
this may have adverse consequences
FGA-LAIs = first-generation antipsychotic longacting injectables; TD = tardive dyskinesia;
NIDS = neuroleptic-induced deficit syndrome;
PK = pharmacokinetics; IM = intramuscular;
All current FGA-LAIs are limited in that

they are first-generation antipsychotics
LAI pharmacology: second generation

antipsychotics (SGA-LANAs)
d
Initial release
Hydration
Sustained release
Drug diffusion
Drug particle
Polymer matrix
LAI = long-acting injectable

LANA = long-acting novel antipsychotic
Polymer erosion
SGA-LAIs: different vehicles

All FGA-LAIs are oil based
existing and forthcoming SGA-LAIs (LANAs) no longer rely on
oil-based delivery
Risperidone LAI has an interim delivery formulation based on use of
microsphere technology; other new agents use crystal technology
Target LAI
Delivery
FGAs
Fluphenazine
Oil-based
Haloperidol
Oil-based
Flupenthixol/
zuclopenthixol
Oil-based
SGAs
Risperidone LAI
Microspheres
Olanzapine pamoate LAI
Crystal
Paliperidone palmitate LAI
Crystal
SGA-LAIs = second-generation antipsychotic long-acting injectable;

LAI long-acting injectable antipsychotic; FGA-LAIs = first-generation
antipsychotic long-acting injectables
Lambert T. WPA 2008, Prague, Czech

Republic (Abstract SaS-04)
Microspheres: release of risperidone longacting injectable (RLAI)
Place
holder
for
videoclip
This mode of action should be contrasted with

that of the oil-based, depot FGA-LAIs
RLAI: microsphere release

Unlike FGA-LAIs, RLAI breaks down into completely natural
products (CO2 and H2O)
there is a somewhat invariant decay cycle
The mechanism of release of RLAI (Risperdal CONSTA)
Initial release
Hydration
Sustained release
Drug diffusion
Drug particle
Polymer matrix
Polymer erosion
Plasma profile of RLAI
50
Active moiety (ng/mL)
Place
holder
for
videoclip
40
30
20
Antipsychotic
cover
recommended
10
0
0
Time (weeks)
RLAI = risperidone long-acting injectable
10
Understanding the clinical profile of RLAI:

kinetics
Positive
symptoms
Active molety (ng/mL)
60
50
40
30
Negative +
cognitive
symptoms
20
Oral
10
RLAI
0
14 28 42 56 70 84 98 112
RLAI plasma-dose levels (1)

RLAI oral versus plasma concentrations
(simulation)
60
See
builds on
slide
Partial adherence is an
important factor: up to
~70% of patients miss oral
doses at various times
50
40
Thus, the curve should look

as follows
30
20
Oral
10
0
14 28 42 56 70 84 98 112
Time (days)
1 High peak-to-trough
suggests side effects
Data on file

(simulation)
60
Positive
symptoms
50
40
30
20
2 Positive
symptom
response at
the top of
the D-R curve
Negative +
cognitive
symptoms
3 Hypofrontal
symptom
Oral
10
response at
RLAI
the bottom
Brass razoo
0 14 28 42 56 70 84 98 112
of the D-R
Time (days)
curve
1 High peak-to-trough
RLAI = risperidone
suggests side effects
long-acting injectable
D-R = dose-response
Data on file

(simulation)
60
50
40
30
20
4 Reduced
peak-to-trough
Positive
(less side
symptoms
effects)
Mean plasma
levels tend
towards the
lower side
Negative +
(hypofrontal
cognitive
targeting)
symptoms
Oral
10
RLAI
Brass razoo
0
14 28 42 56 70 84 98 112
Time (days)
RLAI = risperidone
long-acting injectable
D-R = dose-response
EPS =
Translation: reduced EPS and other side effects

Good profile for recovery due to effect on the prefrontal cortex
Clinical use of risperidone long-acting

injectable (RLAI)
Switcha: brief overview
A full slide set is available from Concord CERP; each switch moderator is discussed individually
Switcha: a LAI switching and

management tool
The original Switching to
Risperdal tool was
released in 1999/2000
Although used in many
countries (including Japan),
Switcha has languished in
Australiauntil now
Version 6 incorporates
embedded educational/
training materials, switching
algorithms and outcome tools
LAI = long-acting injectable antipsychotic
Switcha: switching moderators
Switcha: switching moderators (contd)

In addition to the class and dose of antipsychotic being switched
from, parameters that should be assessed to ensure a smooth
switch include:
concurrent anticholinergic load
(intrinsic or extrinsic)
age
gender
ethnicity
episode status
recent adherence
Each of these parameters is examined
separately in a supplementary
slide set
Switcha: calculation of initial RLAI dose

The initial dose is calculated from published risperidone oral to
LAI equivalencies
The calculated dose is then modified by factors known to influence
the efficiency of risperidone, such as age, ethnicity and episode
status
Risperidone oral to LANA equivalence
Dose of oral
Trough D2
risperidone Dose of RLAI deep IM injection occupancy
(mg/day)
(mg every 2 weeks)
(%)
Initial dose*
Maintenance dose
25
25
2548
24
2537.5
2537.5
50
50
5983
*Supplementing the current antipsychotic for the

first 3 weeks
The selected dose has

confidence intervals based on
inter-patient variability (which
occurs even within similar
settings and cultural groups)
Higher (or lower!) doses
require an appropriate period
of stabilisation before switching
RLAI = risperidone long-acting injectable antipsychotic

LAI = long-acting injectable antipsychotic
LANA = long-acting novel antipsychotic
IM = intramuscular
Oral versus LAI risperidone:

D2 occupancy, by dose
Oral dose
(mg)
D2
occupancy
(%)1
5971 (66)
25
2548
5355 (54)
6778 (73)
50
5983
6368 (65)
7483 (79)
75
6272
7179 (75)
D2
D2
LAI dose occupancy occupancy
(mg)
(%)2
(%)3
D2 occupancy data are given as ranges and means
1. Kapur S, et al. Life Sci 1995;57:1037

2. Gefvert O, et al. Int J Neuropsychopharmacol 2005;8:2736
3. Remington G, et al. Am J Psychiatry 2006;163:396401
Risperidone: pharmacokinetic equivalence

of oral and LAI formulations
Dose (oral, mg/day;
LAI IM, mg every 2 weeks)
Need to re-do build

if required
PK parameter
2/25
4/50
6/75
Oral
5,996
12,027
18,056
Depot
5,303
11,571
16,886
88
96
94
8197
89104
85102
Oral
17.8
35.8
53.7
Depot
15.8
34.4
50.3
AUC14 days, ng.h/mL
IM/oral ratio, %
90% CI
Cav, ng/mL
LAI = long-acting injectable; IM = intramuscular; PK =

pharmacokinetic; AUC = area under plasma
concentration-time curve; Cav = average steady-state
concentrations; CI = confidence interval
Eerdekens M, et al. Schizophr Res 2004;70:91100
Keypad question 1
Which of the following statements are possible explanations
for early RLAI failure?
A. Equivalent doses are ignored and shifts in D2 occupancy occur
when patients are switched to and maintained on a RLAI dose
that is too low (e.g. 25mg)
B. Patients are poorly selected an injection adherence strategy
is not planned
C. Clinicians become confused with the number of needles
D. A and B above
Second-generation long-acting injectable

antipsychotics (SGA-LAIs): paliperidone
palmitate
Modeled and in-vivo paliperidone

plasma levels
100/100mg eq. Day 1/Day 8
deltoid injections
50.0
50.0
Concentration (ng/ml)
Concentration (ng/mL)
150/100mg eq. Day 1/Day 8

deltoid injections
5.0
1.0
0.5
5.0
1.0
0.5
Median
Median
90% prediction interval
0.1
1
eq. = equivalent
15
22
Time (days)
29
36
90% prediction interval
0.1
1
15
22
Time (days)
29
36
Samtani M, et al. CPNP 2009, Jacksonville, FL, USA
Paliperidone palmitate: proportion meeting

minimal plasma levels
A dose of 7.5ng/mL provides 60% D2 receptor occupancy on PET scan
this would be a minimum effective dose for some patients
optimal receptor occupancy for SGA drugs is believed to be 7278%,
which equates to a dose range of 7.550ng/mL
therefore, when the 150/100mg eq. starting regimen is used, a
minimum plasma level is achieved in 84% of patients within 1 week
Patients achieving minimum
plasma level (%)
Regimen (mg eq. Day 1 and
Day 8, deltoid muscle)
Day 8
Day 36
75/85
64
68
100/100
73
76
150/100
84
84
PET = positron emission tomography

SGA = second-generation antipsychotic
Paliperidone palmitate: needles for deltoid

administration
Clinical trial data and population pharmacokinetic simulations
suggest that the impact of body mass index (BMI) on paliperidone
plasma concentrations can be mitigated by administering the
day 1 and day 8 i.m. deltoid injections using varying needle
lengths
Body weight (kg)
Needle length
(inches)
<90*
1.0
90*
1.5
*The 90kg cut off is for the population averaged equivalence of a BMI of 30. For patients
at the extremes of the height distribution, BMI, as indicator of body fat, might be a better
metric than weight
IM = intramuscular
Paliperidone palmitate:
deltoid versus gluteal route
Plasma concentrations after the first injection are slightly higher
with the deltoid compared with the gluteal route
probably due to the relative amounts of of adipose and muscle
tissue at each site, the former being relatively hypovascularised
the 150mg eq. deltoid starting dose appears to well tolerated
A dose of 150mg eq. on day 1 and 100mg eq. on day 8 (and once
monthly thereafter) achieves target plasma levels within the
first week
During a switch, the slow elimination of the previous drug should
not result in a switch-level deficit
eq. = equivalent
Paliperidone palmitate:
kinetics of gluteal versus deltoid injection
The Cmax of paliperidone after a single injection of paliperidone
palmitate was generally higher after the deltoid injection compared
with the gluteal injection
the difference was less pronounced for AUC
Median tmax ranged from 1317 days across all doses and
both injection sites
Median t1/2 increased with dose for both injection sites
Paliperidone palmitate (25150mg eq.) was well tolerated after a
single injection into the deltoid or gluteal muscle
AUC = area under the plasma concentrationtime curve
tmax = time to Cmax
t1/2 = half-life
Cleton A, et al. ASCPT 2008, Orlando, FL, USA (Abstract PI-74)
eq. = equivalent
Equivalence of paliperidone ER and LAI
Concentration (ng/mL)
The plasma concentration profile of the paliperidone palmitate initiation

(150/100mg eq. on days 1 and 8, respectively) and maintenance (75mg
eq. once monthly) dosing regimen shows considerable overlap with the
projected profile for once-daily paliperidone ER 6mg
100
50
40
20
7.5
3.5
1
0.3
Paliperidone ER 6mg once daily
= median
Paliperidone palmitate
= 90% prediction
interval
0.1
0
ER = extended release
13 17 21 25 29 33 37 41 45 49 53
Time (weeks)
Paliperidone ER and LAI equivalence table

This table is a first estimate of equivalence
An initiation/maintenance strategy is necessary to ensure
adequate plasma levels in first 3 months
Dose of paliperidone
Dose of paliperidone
ER once daily (mg)
palmitate 28d IM (mg)
23
25
75
12
150
The kinetics are such that post-injection Cmax may be higher in

the deltoid sites, but AUC should be equivalent
The larger the dose, the longer the apparent t1/2
ER = extended release; LAI = long-acting injectable; IM = intramuscular; AUC = area under concentration-time curve
Cmax = maximum plasma concentration; t1/2 = half-life
Second-generation long-acting injectable

antipsychotics (SGA-LAIs): olanzapine pamoate
Lambert T. WPA 2008, Prague, Czech Republic

Lambert T. WPA 2009, Florence, Italy.
Olanzapine pamoate: time to steady state

Mean SD olanzapine plasma concentrations
Oral olanzapine
405mg/q4w in LOBE patients
100
120
Olanzapine average
steady-state concentration
(ng/mL)
Olanzapine oncentration (ng/mL)
Link does
not work.
Need to
check the
build if
required
80
60
40
20
100
80
60
40
20
0
12
Time after first injection (weeks)
16
20mg
Study HGAJ
Daily dose, 16 weeks

(n=474 in 333
20
24 patients)
FDA website. Available at:

http://www.fda.gov/OHRMS/DOCKETS/ac/08/slides/2008-4338s-Lilly-Core-Backup.ppt.
Accessed 16 November 2008
SD = standard deviation
Approximate dose correspondence between

olanzapine pamoate and oral olanzapine
Dose of oral
olanzapine
(mg/day)
Dose of olanzapine Dose of olanzapine

LAI every 2 weeks LAI every 4 weeks
(mg)*
(mg)*
10
150
300
15
210
405
20
300
*After 2 months of treatment
For full dosing information, please refer to the olanzapine

pamoate Summary of Product Characteristics
Olanzapine pamoate starting regimen

Although olanzapine pamoate can be started without oral
supplementation, initiation and maintenance phases are
recommended (as for paliperidone palmitate)
For the typical olanzapine-treated patient (Caucasian, large build),
commence with a dose of 300mg every 2 weeks for three
injections and then move on to a monthly dose of (say) 405mg
adjustments to the received dose can be made by adjusting
both the frequency of injections and dose per injection
Clinical management and subsequent

antipsychotic treatment
Management of a post-injection syndrome event
treat symptomatically
continue with close medical supervision and monitor the patient
until symptoms have resolved
Following a post-injection syndrome event
if treatment with olanzapine pamoate is continued
the next injection may occur as previously scheduled (or
earlier if clinically indicated for exacerbation of symptoms)
temporary oral supplementation may be considered
if olanzapine pamoate is discontinued
the effects of olanzapine pamoate will continue for some time
after discontinuation
treatment with alternative medication may be started when
clinically indicated
Safety precautions
With each olanzapine pamoate injection
Before the injection
determine that the patient will not travel alone to their
post-injection destination
After the injection
patients should be observed in a healthcare facility for at least
3 hours by appropriately qualified personnel
the patient should be located where he can be seen
and/or heard
at least hourly checks are recommended to detect signs of a
post-injection syndrome event
Safety precautions (contd)

With each olanzapine pamoate injection
Before leaving the healthcare facility
confirm that the patient is alert, oriented and without signs or
symptoms of a post-injection syndrome event
advise patients to be vigilant for symptoms of a post-injection
syndrome event for the remainder of the day; patients should
know how to obtain assistance if needed
After leaving the healthcare facility
patients should not drive or operate machinery for the remainder
of day

12 - Pharmacokinetics and Clinical Pharmacology

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12 - Pharmacokinetics and Clinical Pharmacology

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Clinical pharmacology and practical

management issues with long-acting

Switching long-acting injection (LAI)

Need for adjunctive oral

Olanzapine pamoate LAI

Paliperidone palmitate LAI

FGAs = first-generation antipsychotics

LAI pharmacology: first generation

FGAs to FGA-LAIs: background

FGAs = first-generation antipsychotics

FGAs to FGA-LAIs: background (contd)

2. Barnes TR, Curson DA. Drug Saf 1994;10;46479

FGA-LAI release kinetics

Fluphenazine decanoate: kinetics

While this ensures a

Note that there is an

Source: Lundbeck Education Program on FGA-LAI Antipsychotics (CD-ROM),

Other FGA-LAIs (flupenthixol, zuclopenthixol and

All three formulations

Fluphenazine plasma concentration (ng/mL)

Real-world and computer

Actual curve (R = 0.9%)

Effective half-lives of FGA-LAIs

Effective t1/2 (days)

but most patients

FGA-LAIs = first-generation antipsychotic long-acting injectables

Dose equivalencies of FGA-LAIs

FGA-LAIs = first-generation antipsychotic long-acting injectables

The issue of variable neuroleptic-induced

Jaw dystonia and tardive dyskinesia (TD)

Acute dystonia superimposed on tardive dyskinesia

Plasma concentration (ng/mL)

FGA-LAI dose and EPS (1)

FGA-LAI dose and EPS (2)

Plasma concentration (ng/mL)

If the dose is kept as

FGA-LAI = first-generation antipsychotic long-acting injectable

FGA-LAI dose and EPS (3)

Plasma concentration (ng/mL)

At steady state, moderate

In these cases, EPS are more

If patients are seen by their

such doses are equivalent

FGA-LAI = first-generation antipsychotic long-acting injectable

FGA-LAI dose and EPS (4)

Plasma concentration (ng/mL)

When high doses of

Such doses were

EPS = extrapyramidal symptoms

FGA-LAIs: benefits/pros versus oral drugs

Both the pros and cons of

Body of evidence demonstrating

Some of the pros are also

Last for long periods between IM injections

The last point in the table

All current FGA-LAIs are limited in that

LAI pharmacology: second generation

LAI = long-acting injectable

SGA-LAIs: different vehicles

Olanzapine pamoate LAI

Paliperidone palmitate LAI

SGA-LAIs = second-generation antipsychotic long-acting injectable;

Lambert T. WPA 2008, Prague, Czech