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 bythe vehicle

Effective brain half lives should also be considered, as inadequate adherence may occur during the switch

Target LAI DeliveryNeed for adjunctive oral

antipsychotic during crossover

FGAs

Fluphenazine Oil-based Moderate

Haloperidol Oil-based Moderate

Flupenthixol/zuclopenthixol

Oil-based Moderate

SGAs

Risperidone LAI Microspheres High

Olanzapine pamoate LAI Crystal Nil/minimal

Paliperidone palmitate LAI Crystal Nil/minimal

Lambert T. WPA 2008, Prague, Czech Republic (Abstract SaS-04)

FGAs = first-generation antipsychoticsSGAs = second-generation antipsychotics

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 theoily globule

FGAs = first-generation antipsychoticsLAIs = 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 non-reciprocal)

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

3. Dencker SJ, Axelsson R. CNS Drugs 1996;6:367814. Jann MW, et al. Clin Pharmacokinet 1985;10:31533

FGAs = first-generation antipsychoticsLAIs = long-acting injectables

FGA-LAI release kinetics

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

Source: Lundbeck Education Program on FGA-LAI Antipsychotics (CD-ROM),Addat International Pty Ltd, St Kilda, Victoria, Australia Tim Lambert 1999

Animation

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

Fluphenazine decanoate: kinetics

Note that there is an immediate peak in the plasma concentration of fluphenazine within 8 hours of administration

While this ensures a treatment effect from the outset, regular injections often lead to exacerbation of extrapyramidal symptoms (EPS) around the injection period

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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

All three formulations have similar plasma-concentration profiles

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FGA-LAI kinetics

Real-world and computer models concur that steady state occurs in about23 months

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

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Actual curve (R = 0.9%)Computer model (half life of 19.8 daysyields steady state in 70 days)



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Haloperidoldecanoate

Zuclo-penthixoldecanoate

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Fluphenazinedecanoate

Effective half-lives of FGA-LAIs

Because the absorption () phase is the rate-limiting step determining plasma levels, the effective or apparenthalf lives (t1/2) of FGA-LAIs are long

Haloperidol decanoateis commonly given monthly (the others at 2-weekly intervals)

but most patients can tolerate monthly injections of all FGA-LAIs


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

Dose equivalencies of FGA-LAIs

The psycho-pharmacological 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

FGA-LAI

Dose equivalent to ~300mg/day

chlorpromazine*

Fluphenazine decanoate

25mg 2-weekly

Flupenthixoldecanoate

40mg 2-weekly

Zuclopenthixoldecanoate

200mg 2-weekly

Haloperidol decanoate

110mg 4-weekly

*The rationale for equivalency can be found in the software tool Switcha


The issue of variable neuroleptic-induced extrapyramidal symptoms (NIEPS)

Acute dystonia superimposed on tardive dyskinesia Acute dystonia superimposed on tardive dyskinesia (young person)(young person)

Jaw dystonia and tardive dyskinesia (TD)Moderate dose, acute on long-term first-generation antipsychotic treatment

Source: Recognition and Management of EPS (CD-ROM). Published by Janssen Cilag Pty Ltd Addat International Pty Ltd, St Kilda, Victoria, Australia, 20012003

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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

1. Farde L, et al. Arch Gen Psychiatry 1992;49:538442. Kapur S, et al. Am J Psychiatry 2000;157:51420

3. Grunder G, et al. Arch Gen Psychiatry 2003;60:9747

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FGA-LAI = first-generation

antipsychotic long-acting injectable

EPS = extrapyramidal symptoms

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Low-dose FGA-LAIs

For haloperidol, flupenthixol and zuclopenthixol LAIs, there is a fairly immediate post-injection release of antipsychotic, with a mild peak (Cmax) at 782 days

If the dose is kept as low as possible then at steady state, most EPS can be avoided

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FGA-LAI = first-generation antipsychotic long-acting injectable EPS = extrapyramidal symptomsCmax = maximum plasma concentration

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Moderate-dose FGA-LAIs

At steady state, moderate doses of FGA-LAIs are likely to lead to a Cmax that exceeds the EPS threshold

In these cases, EPS are more likely to be reported 510 days after the injection

If patients are seen by their doctor at the time of the trough plasma concentrations, they may have dropped into the non-EPS zone

such doses are equivalent to the low FGA-LAI doses prescribed by many clinicians

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High-dose FGA-LAIs

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 it was erroneously thought that these agents could not provide protection against psychosis without causing EPS

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FGA-LAIs: benefits/pros versus oral drugs

Both the pros and cons of prescribing FGA-LAIs should be considered

Where relapse prevention is paramount, FGA-LAIs are an indispensable component of community psychiatry

FGA-LAIs pros

Overcome adherence issues with oral medication

Bypass the pharmacokinetic hurdles of absorption and first-pass hepatic elimination

Deliver a fairly constant dose of antipsychotic throughout theinjection cycle

Last for long periods between IM injections (particularly fluphenazine and haloperidol decanoate)

Body of evidence demonstrating superior prevention of relapse due to non-adherence

FGA-LAIs = first-generation antipsychotic long-acting injectablesIM = intramuscular

FGA-LAIs: risks/cons

Some of the pros are also cons

There is a clinical art to FGA-LAI prescribing

The last point in the table is key: FGA-LAIs may enhance relapse prevention, but they are still pro-toxic with regard to TD, neuroleptic-induced deficit syndrome (NIDS), etc.

FGA-LAI cons

Understanding PK and dosing requires specialist knowledge

Last for long periods between IM injections

It takes many weeks or months to reach steady state; a correspondingly long period of elimination is needed should an adverse event occur (e.g. EPS)

Patients dislike being coerced with needles (culturally dependent)

There is a tendency for clinicians to use polypharmacy with other (oral) neuroleptics; this may have adverse consequences

All current FGA-LAIs are limited in that they are first-generation antipsychotics

FGA-LAIs = first-generation antipsychotic long-acting injectables; TD = tardive dyskinesia; NIDS = neuroleptic-induced deficit syndrome; PK = pharmacokinetics; IM = intramuscular; EPS = extrapyramidal symptoms

LAI pharmacology: second generation antipsychotics (SGA-LANAs)

Drug particle

Polymer matrix

d

Initial release Sustained release

Hydration Drug diffusion Polymer erosion

Drug particle

Polymer matrix

dd



LAI = long-acting injectableLANA = long-acting novel antipsychotic

SGA-LAIs: different vehicles

All FGA-LAIs are oil based

existing and forthcoming SGA-LAIs (LANAs) no longer rely onoil-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

Lambert T. WPA 2008, Prague, Czech Republic (Abstract SaS-04)

SGA-LAIs = second-generation antipsychotic long-acting injectable; LAI long-acting injectable antipsychotic; FGA-LAIs = first-generation antipsychotic long-acting injectables

Microspheres: release of risperidone long-acting injectable (RLAI)

This mode of action should be contrasted with that of the oil-based, depot FGA-LAIs

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RLAI: microsphere release

Unlike FGA-LAIs, RLAI breaks down into completely natural products (CO2 and H2O)

there is a somewhat invariant decay cycle

Drug particle

Polymer matrix

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The mechanism of release of RLAI (Risperdal CONSTA)

Plasma profile of RLAI

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RLAI = risperidone long-acting injectable

Understanding the clinical profile of RLAI: kinetics

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RLAI

Positive symptoms

Negative + cognitive symptoms

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RLAI plasma-dose levels (1)

Partial adherence is an important factor: up to ~70% of patients miss oral doses at various times

Thus, the curve should look as follows

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High peak-to-trough suggests side effects

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RLAI oral versus plasma concentrations (simulation)

Oral

Time (days)

Data on file

See builds on

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Positive symptom response at the top ofthe D-R curve

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Hypofrontalsymptom response at the bottomof the D-R curve

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Positive symptoms


Brass razoo

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3Oral

RLAI

Time (days)

Data on file

High peak-to-trough suggests side effects

1RLAI = risperidone long-acting injectable D-R = dose-response

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4 Reduced peak-to-trough (less side effects)

Mean plasma levels tend towards the lower side (hypofrontaltargeting)

Positive symptoms


Brass razoo

Translation: reduced EPS and other side effectsGood profile for recovery due to effect on the prefrontal cortex


RLAI = risperidone long-acting injectable D-R = dose-responseEPS =

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 andmanagement tool

The original Switching to Risperdal tool wasreleased 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 switchedfrom, 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 examinedseparately in a supplementaryslide set

Switcha: calculation of initial RLAI dose

The initial dose is calculated from published risperidone oral toLAI equivalencies

The calculated dose is then modified by factors known to influence the efficiency of risperidone, such as age, ethnicity and episode status

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

Risperidone oral to LANA equivalence

Dose of oral risperidone (mg/day)

Dose of RLAI deep IM injection (mg every 2 weeks)

Trough D2 occupancy

(%)

Initial dose* Maintenance dose

2 25 25 2548

24 2537.5 2537.5

4 50 50 5983

RLAI = risperidone long-acting injectable antipsychoticLAI = long-acting injectable antipsychoticLANA = long-acting novel antipsychoticIM = intramuscular

*Supplementing the current antipsychotic for thefirst 3 weeks

Oral versus LAI risperidone:D2 occupancy, by dose

Oral dose (mg)

D2occupancy

(%)1

2 5971 (66)

4 6778 (73)

6 7483 (79)

LAI dose (mg)

D2 occupancy

(%)2

D2 occupancy

(%)3

25 2548 5355 (54)

50 5983 6368 (65)

75 6272 7179 (75)

1. Kapur S, et al. Life Sci 1995;57:10372. Gefvert O, et al. Int J Neuropsychopharmacol 2005;8:2736

3. Remington G, et al. Am J Psychiatry 2006;163:396401

D2 occupancy data are given as ranges and means

LAI = long-acting injectable

Risperidone: pharmacokinetic equivalence of oral and LAI formulations

Dose (oral, mg/day;LAI IM, mg every 2 weeks)

PK parameter 2/25 4/50 6/75

AUC14 days, ng.h/mL

Oral 5,996 12,027 18,056

Depot 5,303 11,571 16,886

IM/oral ratio, % 88 96 94

90% CI 8197 89104 85102

Cav, ng/mL

Oral 17.8 35.8 53.7

Depot 15.8 34.4 50.3

Eerdekens M, et al. Schizophr Res 2004;70:91100

LAI = long-acting injectable; IM = intramuscular; PK = pharmacokinetic; AUC = area under plasma concentration-time curve; Cav = average steady-state concentrations; CI = confidence interval

Need to re-do build if required

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 strategyis 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 paliperidoneplasma levels

Samtani M, et al. CPNP 2009, Jacksonville, FL, USA

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100/100mg eq. Day 1/Day 8deltoid injections

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90% prediction interval

Median

90% prediction interval

eq. = equivalent

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 andDay 8, deltoid muscle) Day 8 Day 36

75/85 64 68

100/100 73 76

150/100 84 84

PET = positron emission tomographySGA = second-generation antipsychotic

Samtani M, et al. CPNP 2009, Jacksonville, FL, USA

Paliperidone palmitate: needles for deltoid administration

Clinical trial data and population pharmacokinetic simulations suggest that the impact of body mass index (BMI) on paliperidoneplasma concentrations can be mitigated by administering theday 1 and day 8 i.m. deltoid injections using varying needle lengths

Body weight (kg)Needle length

(inches)

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 thefirst week

During a switch, the slow elimination of the previous drug should not result in a switch-level deficit

Samtani M, et al. CPNP 2009, Jacksonville, FL, USAeq. = 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 andboth 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

Cleton A, et al. ASCPT 2008, Orlando, FL, USA (Abstract PI-74)

Cmax = maximum plasma concentrationAUC = area under the plasma concentrationtime curvetmax = time to Cmaxt1/2 = half-lifeeq. = equivalent

Equivalence of paliperidone ER and LAI

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 6mgC

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Paliperidone palmitate

= median

= 90% prediction interval

Samtani M, et al. CPNP 2009, Jacksonville, FL, USAER = extended releaseLAI = long-acting injectable

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

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

Dose of paliperidone ER once daily (mg)

Dose of paliperidone palmitate 28d IM (mg)

23 25

6 75

12 150

ER = extended release; LAI = long-acting injectable; IM = intramuscular; AUC = area under concentration-time curveCmax = maximum plasma concentration; t1/2 = half-life

Second-generation long-acting injectable antipsychotics (SGA-LAIs): olanzapine pamoate

Lambert T. WPA 2008, Prague, Czech RepublicLambert T. WPA 2009, Florence, Italy.

Olanzapine pamoate: time to steady state

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Oral olanzapine20mg

Study HGAJ

Mean SD olanzapine plasma concentrations405mg/q4w in LOBE patients

Time after first injection (weeks)

Link does not work. Need to

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SD = standard deviation

FDA website. Available at:http://www.fda.gov/OHRMS/DOCKETS/ac/08/slides/2008-4338s-Lilly-Core-Backup.ppt.

Accessed 16 November 2008

Approximate dose correspondence between olanzapine pamoate and oral olanzapine

*After 2 months of treatment

For full dosing information, please refer to the olanzapine pamoate Summary of Product Characteristics

Dose of oral olanzapine(mg/day)

Dose of olanzapine LAI every 2 weeks

(mg)*

Dose of olanzapine LAI every 4 weeks

(mg)*

10 150 300

15 210 405

20 300

LAI = long-acting injectable

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 patientuntil 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 theirpost-injection destination

After the injection

patients should be observed in a healthcare facility for at least3 hours by appropriately qualified personnel

the patient should be located where he can be seenand/or heard

at least hourly checks are recommended to detect signs of apost-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 orsymptoms 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 remainderof day

12_Pharmacokinetics and Clinical Pharmacology

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