Summary
`
`- - - - - -----------------------------------------------------------
`
`Clinical Pharmacokinetics 10: 315-333 (1985)
`0312-5963/85/0007-0315/$9.50/0
`© ADIS Press Limited
`All rights reserved
`
`Clinical Pharmacokinetics of the Depot
`Antipsychotics
`
`Michael W. Jann, Larry Ereshefsky and Stephen R. Saklad
`College of Pharmacy, The University of Texas at Austin; Clinical Pharmacy Program,
`and Departments of Pharmacology and Psychiatry, The University of Texas Health
`Science Center at San Antonio; San Antonio State School and San Antonio State
`Hospital
`
`The clinical pharmacokinetics of the 4 depot antipsychotics for which plasma level . . Ie
`studies are available (i.e. fJ.uphenazine ena!Jthate and decanoate. 'rlaloJJ£¥idol decanwe. L?
`\ clopel)tkt1OldecanoatfdnIfI upenthixol,(/(Canoate) rpJ..eviewed. The proper study of these
`agents has been handicappe, un I recen y y t e necessity of accurately measuring sub(cid:173)
`nanomolar concentrations in plasma. Their kinetic properties. the relationship of plasma
`concentrations to clinical effects. and conversion from oral to injectable therapy are dis(cid:173)
`cussed.
`The depot antipsychotics are synthesised by esterification of the active drug to a long
`chain fatty acid and the. resultant compound is then dissolved in a vegetable oil. The
`absorption rate constant is slower than the elimination rate constant and therefore. the
`depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function
`of the absorption rate. and the concentration at steady-state is afunction of the elimination
`rate.
`Fluphenazine is available as both an enanthate and decanoate ester (both dissolved in
`sesame oil). although the decanoate is more commonly used clinically. The enanthate
`produces peak plasma concentrations on days 2 to 3 and declines with an apparent elim(cid:173)
`ination half-life (i.e. the half-time of the apparent first-order decline of plasma concentra(cid:173)
`tions) of 3.5 to 4 days after a single injection. The decanoate produces an early high peak
`which occurs during the first day and then declines with an apparent half-life ranging /rom
`6.8 to 9.6 days following a single injection. After multiple injections of fluphenazine de(cid:173)
`canoate. however. the mean apparent half-life increases to 14.3 days. and the time to reach
`steady-state is 4 to 6 weeks. Withdrawal studies with fluphenazine decanoate suggest that
`relapsing patients have a more rapid plasma concentration decline than non-relapsing
`patients. and that the plasma concentrations do not decline smoothly but may exhibit
`'lumps' due to residual release /rom previous injection sites or multicompartment redis(cid:173)
`tribution. Cigarette smoking has been found to be associated with a 2.33-fold increase in
`the clearance of fluphenazine decanoate. In 3 different studies. fluphenazine has been
`proposed to have a therapeutic range from < 0.15 to 0.5 ng/ml with an upper therapeutic
`range of 4.0 ng/ml. Plasma concentrations following the decanoate injection are generally
`lower than. but clinically equivalent to. those attained with the oral form of the drug.
`Haloperidol decanoate plasma concentrations peak on the seventh day following in(cid:173)
`jection although. in some patients. this peak may occur on the first day. The apparent
`elimination half-life after multiple injections is approximately 3 weeks and the time to
`reach steady-state is approximately 3 months. The reduced metabolite of haloperidol is
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`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0001
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`Clinical Pharmacokinetics of the Depot Antipsychotics
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`316
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`present in significant quantities in humans following oral therapy; however, this has not
`been reported in pharmacokinetic studies with the depot preparation. The therapeutic range
`for haloperidol has been reported to be 3 to 40 ng/ml in several studies, but these studies
`did not measure the reduced metabolite. It has been suggested that the presence of high
`concentrations of the reduced metabolite may affect the response to haloperidol.
`Clopenthixol is only active as the cis (Z) isomer, which is the form of the drug present
`in the decanoate preparation. Peak plasma concentrations are usually reached between 4
`and 7 days after injection. Following mUltiple injections, the apparent elimination half(cid:173)
`life is 19 days. No correlation between plasma concentrations and clinical response has
`been reported, but concentrations have been observed to range from 10 to 100 ng/ml fol(cid:173)
`lowing a wide range of dosages and injection intervals.
`Flupenthixol is available as either the palmitate or decanoate ester, although most
`pharmacokinetic studies have used the decanoate formulation. Like clopenthixol, flupen(cid:173)
`thixol is only active as the cis (Z) isomer which is the form present in the decanoate
`preparation. Peak plasma concentrations occur on approximately the seventh day follow(cid:173)
`ing injection, and no pharmacokinetic differences have been observed between the 2% and
`10% concentrations of the drug. Following a single injection, an apparent elimination
`half-life of 8 days was reported, whereas after mUltiple injections, the apparent half-life
`was 17 days. Foliowing withdrawal, no statistically significant d(fJerences were noted be(cid:173)
`tween relapsing and non-relapsing patients, but there was a trend towards lower trough
`concentrations in the relapsing group. There was also a shorter apparent half-life in the
`relapSing group when compared with the non-relapsing patients. No correlations between
`plasma concentrations and clinical response were found.
`Most methods for converting oral preparations to depot injections have been empirically
`developed. One study that did examine plasma concentrations and clinical effects during
`conversion of oral fluphenazine to the decanoate found that 1.2 to 2.S times the oral dose
`(mg/day) given weekly resulted in a smooth transition between dosage forms. Fluphena(cid:173)
`zine plasma concentrations on the decanoate were lower during the first 3 weeks in com(cid:173)
`parison with oral fluphenazine therapy. It is recommended that the initially effective dose
`be reduced or the injection interval increased after 4 to 6 weeks to prevent possible ac(cid:173)
`cumulation of drugs as plasma concentrations approach steady-state. The recommended
`dose of haloperidol decanoate is 20 times that of the daily oral dose (mg/day) given monthly,
`but this should be reduced to a factor of IS in geriatric patients. Flupenthixol lOmg given
`orally daily is proposed to be equivalent to 2Smg of the decanoate given weekly. The use
`of the mean conversion ratios as a starting point for an individual patient's conversion is
`appropriate, but wide interindividual variations in pharmacokinetics require plasma level
`monitoring and careful clinical observation of the patient.
`Adverse effects from depot antipsychotics are relatively rare, except for extrapyramidal
`system reactions. The most serious (albeit very rare) problem that can occur with a long
`acting antipsychotic is the neuroleptic malignant syndrome. Due to their long apparent
`half-lives after injection, effective treatment of this syndrome following administration of
`depot antipsychotics can be difficult.
`
`The introduction of depot anti psychotics in the
`early 1960s represented a major advance in drug
`delivery systems as they facilitated drug adminis(cid:173)
`tration in psychiatric patients who are non-com(cid:173)
`pliant with oral therapy. One of their major ad(cid:173)
`vantages is that injections can be given on a weekly
`
`to a monthly basis, and dosages and administra(cid:173)
`tion intervals can be individually titrated. How(cid:173)
`ever, despite the worldwide use of the depot anti(cid:173)
`psychotics, very few reports have extensively
`investigated their pharmacokinetic properties. To
`properly study the pharmacokinetics of these agents,
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`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0002
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`Clinical Pharmacokinetics of the Depot Antipsychotics
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`317
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`the accurate quantitation of subnanomolar concen(cid:173)
`trations is required. The paucity of pharmacokin(cid:173)
`etic literature on depot antipsychotics stems from
`the inability of investigators to accurately measure
`low plasma concentrations of the drugs (below 1
`ng/mi).
`This article reviews the available literature on
`the pharmacokinetics of the depot antipsychotics.
`Only those drugs for which plasma level studies are
`available will be evaluated, i.e. fluphenazine en(cid:173)
`anthate and decanoate, haloperidol decanoate, clo(cid:173)
`penthixol decanoate, and flupenthixol decanoate.
`Each drug's pharmacokinetic properties, the rela(cid:173)
`tionship of their plasma concentrations to clinical
`response and adverse effects, and the conversion
`from oral to injectable treatment will be examined.
`At present, there is little pharmacokinetic infor(cid:173)
`mation available on other depot antipsychotics such
`as pipothiazine palmitate, fluspirilene and per(cid:173)
`phenazine enanthate, and these agents will not be
`discussed.
`
`1. Fundamental Pharmacokinetic
`Properties
`
`The depot antipsychotics are synthesised by es(cid:173)
`terification of their hydroxyl group to a long chain
`fatty acid. The esters are then dissolved in either
`sesame seed oil, coconut oil, or Viscoleo® (a veg(cid:173)
`etable oil). Only fluspirilene is not esterified, but
`is formulated as an aqueous suspension (Simpson,
`1984). Once the drug is injected into muscle, it is
`then slowly released from the site. The diffusion
`and availability of free drug released from the oily
`depot site is most likely the initial rate-limiting ki(cid:173)
`netic step (Dreyfuss et aI., 1976a) since enzymatic
`hydrolysis from the ester occurs rapidly. Therefore,
`the apparent rate of elimination is controlled by
`the absorption (release) rate and not by the rate of
`hepatic metabolism (Ereshefsky et aI., 1984a;
`J0rgensen, 1980a). When the absorption rate con(cid:173)
`stant is less than the elimination rate constant, a
`'flip-flop' model results (Gibaldi and Perrier, 1982).
`The time necessary to achieve steady-state plasma
`concentrations is dependent on the absorption rate
`of the depot antipsychotic and may take up to 3
`
`months, yet plasma concentrations are still pro(cid:173)
`portional to clearance.
`Injectable depot administration bypasses oral
`absorption variability, gut wall metabolism, and
`first-pass extraction by the liver. Active drug be(cid:173)
`comes available as plasma esterases hydrolyse the
`esterified compound (see fig. 1). The sesame oil ve(cid:173)
`hicle may retard this hydrolysis resulting in a pro(cid:173)
`longed duration of action (Dreyfuss et aI., 1976a;
`J0rgensen, 1972). The free drug is then available
`to distribute (Ereshefsky et aI., 1984a) across the
`blood brain-barrier to the site of action, be metab(cid:173)
`olised to active or inactive metabolites, or bind to
`other tissues. Once sufficiently polar metabolites
`are formed, they are eliminated by biliary or renal
`excretion.
`
`1.1 Fluphenazine Enanthate and
`Decanoate
`
`Fluphenazine enanthate and decanoate are both
`formulated in sesame oil; however, their phar(cid:173)
`macokinetic profiles are quite different.
`
`1.1.1 Disposition Studies
`Studies determining fluphenazine enanthate and
`decanoate kinetics originally used radioactively-la(cid:173)
`belled compound or a radioimmunoassay (RIA)
`method (Curry et al., 1979a; Midha et al., 1980;
`Wiles et al., 1980). However, the RIA methods
`weakly crossreact with metabolites and the radio(cid:173)
`labelled detection method was unable to distin(cid:173)
`guish between parent drug and metabolites. Re(cid:173)
`cently, high-performance liquid chromatography
`(HPLC) [Harris et al., 1982] and high-performance
`thin-layer chromatography (HPTLC) [ Davis and
`Fenimore, 1983] have been developed which have
`lower limits of sensitivity of approximately 0.2 ng/
`ml.
`
`Plasma Concentration Profiles
`Fluphenazine enanthate apparently produces a
`slowly rising concentration that peaks at 2 to 3 days,
`whereas the decanoate has an earlier peak concen(cid:173)
`tration which occurs within 1 to 2 days (see fig. 2).
`Like other phenothiazines, fluphenazine has a large
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`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0003
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`Clinical Pharmacokinetics of the Depot Antipsychotics
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`318
`
`Injection
`
`Esterified
`drug in oil
`
`Released
`
`Metabolism to
`active or inactive
`metabolites
`
`Esterases
`
`Esterified drug
`in plasma
`
`Multicompartment
`tissue binding
`
`Renal and
`biliary
`elimination
`
`Fig. 1. Disposition of depot antipsychotics.
`
`number of metabolites; however, only the sul(cid:173)
`phoxide and 7-hydroxyfluphenazine metabolites
`have been studied (Whelpton and Curry, 1976). The
`apparent elimination half-lives (i.e. half-times of
`the apparent first-order decline of plasma concen(cid:173)
`trations) of fluphenazine enanthate (Curry et aI.,
`1979a) and decanoate (Ereshefsky et aI., 1984a)
`range between 3.5 and 4 days and 6.8 and 9.6 days,
`respectively, after single injections of 25mg. How(cid:173)
`ever, when fluphenazine decanoate plasma con(cid:173)
`centrations were measured in 4 patients main(cid:173)
`tained for over 5 weeks on weekly injections, their
`mean apparent half-life was calculated to be 14.3
`± 2.2 days. This increase in apparent half-life from
`single to multiple injection is perhaps due to re(cid:173)
`distribution from tissue storage sites or residual
`drug absorption from multiple depot injection sites
`(see fig. I). There was no measurable evidence of
`the esterified compound in plasma, urine or faeces;
`however, conjugated forms of fluphenazine, flu-
`
`phenazine sulfoxide and 7-hydroxyfluphcnazine
`were found in the urine. Fluphenazine and 7-hy(cid:173)
`droxyfluphenazine were found in faeces, but not
`their conjugates. 7-Hydroxyfluphenazine glucoron(cid:173)
`ide has been reported to be excreted in the bile of
`dogs and subsequently hydrolysed in the gastroin(cid:173)
`testinal tract (Whelpton and Curry, 1976).
`Cerebrospinal fluid fluphenazine concentra(cid:173)
`tions measured in 6 schizophrenics were 38% of
`the plasma concentrations (Wiles and Gelder,
`1980).
`
`Interindividual Variability
`Wide interpatient variation in plasma concen(cid:173)
`trations following a standard dose has been observed
`with many antipsychotic agents (Cooper, 1978).
`Similarly, wide interpatient variation in fluphen(cid:173)
`azine decanoate plasma concentrations was ob(cid:173)
`served in 9 patients following a single 50mg intra(cid:173)
`muscular dose (Nasrallah et al., 1979). Peak plasma
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`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0004
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`Clinical Pharmacokinetics of the Depot Antipsychotics
`
`319
`
`concentrations were achieved from 1 to 6 hours
`after the dose and ranged between 3 and 13 ng/ml,
`with 6 of9 patients having subsequent rises in their
`plasma concentrations over the 2-week study. Er(cid:173)
`eshefsky et ai. (l984c) reported that in 42 plasma
`samples drawn at steady-state, a wide variability
`existed following doses of 25mg (mean level 0.73
`± 0.71 ng/ml, range < 0.10 to 2.22 ng/ml) and
`SOmg (mean level 1.45 ± 1.44 ng/ml, range 0.20
`to 2.49 ng/ml).
`
`Plasma Concentration-Dose Correlation
`Linear least squares regression correlation ana(cid:173)
`lysis in 39 patients on decanoate therapy, after 4
`or more weekly injections at a constant dose,
`yielded a high correlation between standard dos(cid:173)
`ages and mean plasma concentrations (r = 0.96,
`p < 0.01) at each dose [Ereshefsky et ai., 1984a).
`The intramuscular route bypasses the variability
`associated with oral absorption and first-pass me(cid:173)
`tabolism. Thus lower correlations were observed
`with oral absorption (r = 0.71, p < 0.001) [Eresh(cid:173)
`efsky et ai., I 984a).
`
`Possible Explanations for the Early Peak with
`the Decanoate Formulation
`Animal studies have confirmed the hypothesis
`that the rate of release of fluphenazine from the
`injection site controls the plasma concentration
`(Dreyfuss et ai., 1971). This does not, however, ac(cid:173)
`count for the presence of an initial peak with the
`decanoate. It has been suggested by Altamura et ai.
`(1979) that the early peak seen with the decanoate
`could reflect the presence of unesterified fluphen(cid:173)
`azine in the decanoate preparation (3% free flu(cid:173)
`phenazine) as compared with the enanthate (1 % free
`fluphenazine). However, Curry et ai. (l979a) noted
`that these peak plasma concentrations may be too
`large to be ascribed to just the presence of unes(cid:173)
`terified fluphenazine (e.g. a SOmg injection yielded
`only l.Smg of unesterified drug).
`The conversion from the esterified compound
`to the active drug in vivo is due to enzymatic hy(cid:173)
`drolysis (Dreyfuss et aI., 1976a,b). It appears that
`hydrolysis at the injection site is not as important
`as the hydrolytic activity in the plasma. However,
`
`others believe that hydrolysis at the site of injec(cid:173)
`tion is important (Altamura et aI., 1979). If hydro(cid:173)
`lysis in plasma were the only factor, the early peak
`seen with the decanoate should also be observed
`with the enanthate, but the enanthate data does not
`demonstrate an early peak in the early 14C-Iabelled
`recovery studies (Curry et aI., 1976).
`The decanoate, unlike the enanthate, may bind
`differently to the muscle favouring exposure to
`plasma esterases and resulting in the early peak
`concentrations. Partition studies (Altamura et aI.,
`1979) have demonstrated that the decanoate ester
`does bind to the soluble fraction of the muscle tis(cid:173)
`sue. However, the decanoate, in contrast to the en(cid:173)
`anthate, fails to bind to the insoluble fraction of
`the muscle tissue. This increases the decanoate's
`accessibility to plasma and muscle esterases in the
`initial stages following an injection (Altamura et
`aI., 1979).
`Further investigation of both the in vitro sta(cid:173)
`bility and in vivo esterase and absorption mech(cid:173)
`anisms are required to explain how the observed
`initial peak concentrations are achieved with the
`decanoate formulation.
`
`1.6
`
`'E
`'C;1.4
`.s
`5 1.2
`~
`~ 1.0
`8
`tIS 0.8
`~
`Ci 0.6
`Q) c
`
`'N ! 0.4
`
`~ 0.2
`
`50
`10
`Time (hours)
`
`100
`
`150
`
`Fig. 2. Plasma concentrations of fluprenazine enanthate
`(0-0) and decanoate (e-e) after single injections of
`25mg (after Curry et al.. 1978 and Ereshefsky et al.. 1984a).
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0005
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`

`
`Clinical Pharmacokinetics of the Depot Antipsychotics
`
`320
`
`Pharmacokinetic Model
`In a study in 7 patients, multiple plasma con(cid:173)
`centrations were obtained following administra(cid:173)
`tion of fluphenazine decanoate (Ereshefsky et al.,
`1984a; Young et al., 1984). Three patients had an
`apparent terminal elimination phase half-life of 8.6
`± 0.2 days following a single dose injection. One
`of these 3 patients who had 11 samples taken fol(cid:173)
`lowing a 2Smg intramuscular injection (see fig. 2)
`had a peak plasma concentration at 20 hours; this
`is consistent with previous investigations by Curry
`et a1. (1976, 1979a). The remaining 4 patients are
`described below.
`Ereshefsky et a1. (1983) proposed a 'flip-flop'
`model to explain the 8-day apparent elimination
`half-life (t'l211) observed in patients receiving flu(cid:173)
`phenazine decanoate therapy. In this model, the
`terminal elimination phase represents the absorp(cid:173)
`tion (release) rate and not hepatic elimination.
`Based upon data from these patients, computer
`simulations using the Advanced Computer Simu(cid:173)
`lation Language were performed (Mitchell and
`Gauthier, 1975; Young et aI., 1984). The rate con(cid:173)
`stants used were t,/,,, = 16 hours, and t'/'II = 8 days.
`Additionally, 4 other patients who were main(cid:173)
`tained on medication for more than 5 weeks had
`apparent terminal elimination half-lives (t'/,r) equal
`to 14.3 ± 2.2 days (Ereshefsky et aI., 1984a; Young
`et aI., 1984). Moreover, patients treated with flu(cid:173)
`phenazine decanoate for a mean of 23 months
`demonstrated an apparent elimination half-life of
`2.5 to 16 weeks following discontinuation (Wistedt
`et aI., 1981). The t,/,,, might represent a combina(cid:173)
`tion of redistribution and absorption from unes(cid:173)
`terified fluphenazine; the t'/,II phase probably rep(cid:173)
`resents the rate of absorption; and the t'l2,), phase
`might represent residual release from previous in(cid:173)
`jection sites and redistribution of drug from tissue
`storage sites. These computer simulations were
`performed with and without the 14-day terminal
`phase. The results showed that the percentage of
`the steady-state level reached after 35 days of flu(cid:173)
`phenazine decanoate was not significantly affected
`by the presence or absence of the terminal phase
`(9S.2% versus 91.2%). This simulation supported
`our earlier model, in that the time to reach steady-
`
`state was approximately 4 to 6 weeks for fluphen(cid:173)
`azine decanoate.
`Ereshefsky et a1. (1984a) reported that the mean
`plasma concentrations of 39 patients receiving
`weekly injections of fluphenazine decanoate nor(cid:173)
`malised for a 50mg dose, were at week 1: 0.58 ng/
`ml; at weeks 2 and 3: 1.09 ng/ml; at weeks 4 and
`S: 1.73 ng/ml, and at week 6: 1.99 ng/ml. The ac(cid:173)
`cumulation (see fig. 3) of plasma levels indicates
`that the approximate time to reach steady-state is
`4 to 6 weeks. However, the longer time a patient
`is on fluphenazine decanoate, the longer the ap(cid:173)
`parent elimination half-life.
`
`1.1.2 Correlation Between Plasma
`Concentrations and Prolactin Levels
`Few studies have investigated the relationship
`between long-acting fluphenazine plasma concen(cid:173)
`trations and prolactin levels. Nasrallah et aI. (1979)
`reported a 2- to 16-fold increase in prolactin levels
`in 9 patients given fluphenazine decanoate SOmg
`every 2 weeks. Although the prolactin level fluc(cid:173)
`tuated, it remained elevated in all patients, despite
`fluphenazine concentrations being undetectable in
`
`E
`Ci
`oS
`c
`
`0
`r..l
`
`~
`C
`lS c
`'" E
`(/) '" C.
`C1l c
`'N
`'" c
`C1l .c
`0.
`::J u::
`
`2.5
`
`2.3
`
`2.0
`
`1.8
`
`1.5
`
`1.3
`
`1.0
`
`0.8
`
`0.5
`
`0
`
`0
`
`7
`14
`Time (days)
`
`tv, = 19.8 days
`r = 0.97
`
`21
`
`28
`
`35
`
`42
`
`Fig. 3. Pattern of fluphenazine decanoate accumulation after
`weekly doses of 50mg to 39 subjects (after Ereshefsky et aI.,
`1984a).
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0006
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`Clinical Pharmacokinetics of the Depot Antipsychotics
`
`321
`
`Some cases. Consequently no correlations were
`found between the plasma concentrations of flu(cid:173)
`phenazine and prolactin.
`Elevated prolactin levels have also been ob(cid:173)
`served with fluphenazine enanthate given at both
`low and high dosages to 9 patients (Wiles et aI.,
`1980). Patients who received the high dosages (250
`mg/week) had higher prolactin levels than those
`who received the low dosages (12.5 mg/week).
`Again, no correlations were observed between pro(cid:173)
`lactin
`levels and fluphenazine concentrations.
`Plasma prolactin levels remained above normal
`levels (600 MIU/L) in 2 patients for 4 to 6 months
`after decanoate was discontinued (Wistedt et aI.,
`1981 ).
`
`1.1.3 Pharmacokinetic Studies Following
`Fluphenazine Withdrawal
`The long apparent half-life of fluphenazine de(cid:173)
`canoate suggests that the drug's effects should per(cid:173)
`sist for a long period after medication is discon(cid:173)
`tinued. Adverse effects have been reported to persist
`for months after drug discontinuation, further sup(cid:173)
`porting a long half-life secondary to a deep-com(cid:173)
`partment kinetic model. Plasma fluphenazine con(cid:173)
`centrations have been measured following drug
`discontinuation in schizophrenics who had re(cid:173)
`ceived the decanoate preparation 25mg intramus(cid:173)
`cularly every 3 weeks (Wistedt, 1981). In 5 of 7
`patients, plasma concentrations ranged between 0.3
`and 1.0 ng/ml at 12 weeks after drug discontinua(cid:173)
`tion, with detectable concentrations still being
`measurable at 24 weeks in some patients. In an(cid:173)
`other withdrawal study in 4 patients (Wistedt et aI.,
`1982), mean plasma concentrations at week 0 (drug
`discontinuation) were l.08 ng/ml and at 24 weeks
`were 0.23 ng/ml. Interestingly, relapsing patients
`had a more rapid decline in their plasma fluphen(cid:173)
`azine concentrations than non-relapsing patients.
`This phenomenon was also observed in 11 patients
`studied over 20 months by Pelckmans (1980). Upon
`withdrawal, the plasma concentrations declined but
`not in a simple linear fashion (Wistedt et aI., 1981,
`1982).
`The mechanism for the observed slow drug con(cid:173)
`centration decline following withdrawal could be
`
`related to the drug absorption rate or to multicom(cid:173)
`partment tissue binding. It has also been suggested
`that the injection technique may contribute to the
`long absorption times (Amdisen and Thomsen,
`1981). Repeated injection at the same site may im(cid:173)
`pair local vascularisation and hence delay absorp(cid:173)
`tion; therefore, clinicians should rotate injection
`sites. Consequently, further investigations are re(cid:173)
`quired to better understand the mechanisms which
`account for these very slowly declining plasma
`concentrations.
`
`1.2 Haloperidol Decanoate
`
`This long acting injectable form of haloperidol
`is now marketed in some countries. Haloperidol
`decanoate is the product of the synthesis of halo(cid:173)
`peridol and decanoyl chloride; it is dissolved in se(cid:173)
`same seed oil.
`
`1.2.1 Disposition Studies
`The available pharmacokinetic data on halo(cid:173)
`peridol are consistent with the long apparent half(cid:173)
`life and time to steady-state reported with flu(cid:173)
`phenazine decanoate. In an early study in dogs,
`Heykants et al. (1981) found that peak plasma con(cid:173)
`centrations of haloperidol after administration of
`the decanoate occurred at 4 to 11 days. In humans,
`Meco et al. (1983) observed peak plasma concen(cid:173)
`trations on the seventh day following single injec(cid:173)
`tions of 120mg (see fig. 4). Interestingly, after the
`first injection, a small rise in plasma concentra(cid:173)
`tions has been observed in some patients during
`the first few days and remaining stable thereafter
`(Deberdt et aI., 1980).
`Viukari et ai. (1982) noted peak plasma con(cid:173)
`centrations on the first day in geriatric patients. In
`other studies, steady-state plasma concentrations
`were found to be reached in approximately 3
`months (Parent et aI., 1981; Reyntijens et at, 1982).
`Based on monthly injections, Richards et al. (1982)
`and Reyntijens et al. (1982) measured the decline
`of haloperidol plasma concentrations between 2 in(cid:173)
`jections. From their data an apparent elimination
`half-life of approximately 3 weeks was determined.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0007
`
`

`
`Clinical Pharmacokinetics of the Depot Antipsychotics
`
`322
`
`Plasma Concentration-Dose Correlation
`A strong linear correlation (r = 0.86) between
`haloperidol decanoate dose and plasma concentra(cid:173)
`tions was calculated on day 28 after the third
`monthly injection at a constant dose (Reyntijens
`et a!., 1982). The linear regression equation was:
`plasma concentration (ng/ml) = 0.0291 X dose (mg!
`month). Parent et a!. (1981) also reported a linear
`correlation between dose and plasma concentra(cid:173)
`tion of r = 0.996, p = 0.004 in 8 schizophrenic
`patients.
`
`Metabolism
`The metabolism of haloperidol in man usually
`involves the initial cleavage at the C-N bond to
`form fluorophenyl-carbonic acid and piperidine
`metabolites which are inactive (see fig. 5) [Fors(cid:173)
`man et a!., 1977]. Haloperidol's reduced metabo(cid:173)
`lite (hydroxyhaloperidol), which is formed by the
`reduction of the benzylic ketone to an hydroxy
`group, was identified later (Forsman and Larsson,
`1978) and was subsequently measured in a post-
`
`mortem patient (Pape, 1981). More recently, halo(cid:173)
`peridol and reduced haloperidol plasma concentra(cid:173)
`tions have been measured in schizophrenic patients
`by various investigators (Ereshefsky et aI., 1984b;
`Jann et a!., 1984; Korpi et a!., 1983; Larsson et aI.,
`1983). Very high reduced haloperidol plasma con(cid:173)
`centrations (> 100 ng/ml) have been reported in
`several patients (Ereshefsky et a!., 1984b; Larsson
`et at, 1983).
`In a rat model, the conversion of haloperidol to
`reduced haloperidol has been observed to occur by
`gastrointestinal enzymatic mechanisms (Browning
`et a!., 1982); however, reduced haloperidol is re(cid:173)
`ported to be both produced and converted back to
`the parent drug in the liver (Korpi and Wyatt,
`1984). Reduced haloperidol was found to be ap(cid:173)
`proximately 1/400 as potent as haloperidol in in(cid:173)
`hibiting 3H-spiperone binding in striatal mem(cid:173)
`branes. However, in the apomorphine-induced
`stereotype assay in rats, reduced haloperidol was
`about 25% as active as haloperidol (Browning et
`a!., 1982). Further research is needed to elucidate
`
`10
`
`9
`
`8
`
`7
`
`~ 6
`.s 5
`(/)
`c::
`0 ;
`~ c::
`2l c::
`'"
`E
`.!!1
`0-
`
`0
`0
`
`(/)
`
`4
`
`3
`
`2
`
`1 2
`Time (days)
`
`7
`
`14
`
`21
`
`28
`
`Fig. 4. Plasma concentrations of haloperidol decanoate (0-0), clopenthixol decanoate (0-0) and flupenthixol decanoate
`(A_A) after single injections of 120mg. 100mg and 100mg, respectively (after Meco et al .• 1983 and J"rgensen and Overo, 1980].
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0008
`
`

`
`Clinical Pharmacokinetics of the Depot Antipsychotics
`
`323
`
`00 !C I
`OH
`~/,
`~I
`F ~ C - CH2 - CH2 - CH2-N
`OH ---~ Metabolites?
`
`Reduced Haloperidol ~
`1
`F-{}8-CH2 - CH2 -CH2-N~
`/
`
`o
`
`Haloperidol
`
`Conversion back
`to parent drug?
`
`_ CI
`
`OH
`
`o0J CI
`
`OH
`
`4-Fluorobenzoylpropionic
`acid
`
`Piperidine metabolite
`
`Fig. 5. Proposed pathways of metabolism of haloperidol.
`
`the influence of reduced haloperidol on the thera(cid:173)
`peutic response.
`
`1.2.2 Correlation Between Plasma
`Concentrations and Prolactin Levels
`In a study in schizophrenic patients, plasma
`prolactin levels paralleled plasma haloperidol con(cid:173)
`centrations (Meco et aI., 1983), peaking at the sev(cid:173)
`enth day. By day 28, prolactin levels had declined
`to only slightly above than the predrug baseline
`concentrations.
`
`1.3 Clopenthixol
`
`Clopenthixol decanoate is dissolved in a low
`viscosity vegetable oil (Viscoleo®) at a concentra(cid:173)
`tion of 200 mg/m!. Structurally, clopenthixol is a
`thioxanthine that exists in 2 isomeric forms, the
`cis-(Z) isomer and the trans-(E) isomer. It has been
`demonstrated (Aaes-Jergensen, 1980) that only the
`cis-(Z) isomer possesses antipsychotic activity. The
`marketed clopenthixol decanoate preparation con(cid:173)
`tains only the cis-(Z) isomer.
`
`1.3.1 Disposition Studies
`Early studies investigating clopenthixol metab(cid:173)
`olism used tritium radioactive labelling. This
`method provides a flawed but sensitive estimate of
`drug kinetics, but also measures metabolites and
`water that has been produced by catabolism. Later,
`a fluorimetric detection method (Fredricson(cid:173)
`Overo, 1980) and a specific HPLC assay (Aaes(cid:173)
`J0rgensen, 1980) were developed to measure the
`parent drug and its N-desalkyl metabolite. HPLC
`can also separate and quantify the cis and trans
`isomers with a lower limit of sensitivity of 0.5
`ng/ml for clopenthixol and 2.5 ng/ml for the N(cid:173)
`desalkyl metabolite.
`Peak plasma concentrations from the decanoate
`injection are usually reached between 4 and 7 days
`(fig. 4) [Jergensen and Overo, 1980; Aaes-J0rgen(cid:173)
`sen et aI., 1983]. Based upon the amount of drug
`remaining at the injection site in dogs (Aaes(cid:173)
`Jergensen et aI., 1977), the rate of drug release ap(cid:173)
`pears to be monoexponential with a half-life of 4
`to 5 days. The hydrolytic rates for man and dog
`were found to be similar (Aaes-J0rgensen et aI.,
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2016 - 0009
`
`

`
`Clinical Pharmacokinetics of the Depot Antipsvchotics
`
`324
`
`1977) and appeared linear. Plasma samples taken
`4 hours post-injection contained some unhydro(cid:173)
`lysed decanoate, approximately 35% remaining in
`humans and 15% in dogs. Once the drug is hydro(cid:173)
`lysed from the decanoate, the metabolic pathway
`is identical to oral clopenthixol. Metabolites are
`formed by dealkylation of the side chain, by S-ox(cid:173)
`idation and N-oxidation (Aaes-J0rgensen et aI.,
`1977). Clopenthixol is also excreted as a glucuron(cid:173)
`ide (Sieberns and Spechtmeyer, 1983).
`Based on a multiple-dose injection study in hu(cid:173)
`mans (J0rgensen and Overo,