PHARMACQKINETICSJRERAPEBTICS
`
`Clin. Pharmacokinet. 25 (3): 217-236, 1993
`O312-5963/93/0009—02l7/$10.00/0
`© Adis International Limited. All rights reserved.
`CPK1 347
`
`Pharmacokinetic Optimisation of the Treatment
`of Psychosis
`
`A.E. Balanl-Gorgia,la3 L.P. Balantz’3 and A. Andre011'3
`1 Therapeutic Drug Monitoring Unit, Psychiatric University Institutions of Geneva, Switzerland
`2 Clinical Research Unit, Psychiatric University Institutions of Geneva, Switzerland
`3 First Psychiatric Clinic, Psychiatric University Institutions of Geneva, Switzerland
`
`Contents
`
`23?
`333
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`25‘
`339
`3513
`335‘
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`23‘:
`
`Summary
`1. Historical Background
`2. Definitions of Psychoses and Psychotic Symptoms
`2.1 Psychoses
`2.2 Symptoms and Rating Scales
`3. Drugs Used to Treat Psychoses
`3.1 Schizophrenia
`3.2 Brief Reactive Psychoses
`3.3 Manic Episodes
`3.4 Pharmacokinetic Profile of Antipsychotics
`4. Pharmacotherapy of Schizophrenia
`4.1 Choice of Antipsychotic Drugs
`4.2 Choice of a Dosage Regimen
`4.3 Choice of a Pharmaceutical Formulation
`4.4 Management of Unwanted Effects
`5. Pharrnacotherapy of Short-Lasting Psychotic Episodes
`5.1 Choice of Antipsychotic Drugs for the Treatment of Brief Reactive Psychoses or
`Manic Episodes
`6. Factors Modifying Plasma Concentrations of Neuroleptics
`6.1 Age
`6.2 Genetic and Interethnic Differences
`6.3 Drug-Drug Interaction
`7. General Principles of Antipsychotic Pharmacotherapy in the Context of
`Therapeutic Drug Monitoring
`7.1 Pharmacokinetic Principles Related to Therapeutic Drug Monitoring
`7.2 Role of Active Metabolites
`7.3 Concentration-Effect Relationships
`7.4 Choice of Antipsychotics and Therapeutic Drug Monitoring
`8. Conclusions
`
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`218
`
`Clin. Pharmacakinet. 25 (3) 1993
`
`Summary
`
`Psychosis is a generic term covering (for the purposes of the present article)) schizophrenia,
`brief reactive psychoses and manic episodes. Traditionally, research has focnsed on the effect of
`antipsychotic agents on positive or productive symptoms such as hallucinations or delusions.
`More recently, attention has been focused on negative symptoms such as emotional withdrawal
`or impairment of social participation. Typical antipsychotic medications such as phenothiazines
`have little effect on these clinical manifestations. This has raised interest in atypical antipsychotics
`such as clozapine.
`Acute psychotic episodes are less difficult to treat than long term schizophrenic manifestations.
`Current research indicates that antipsychotics are effective only if a threshold concentration is
`reached, but that above a certain level, dose escalation is of no benefit to the patient. This implies
`the existence of an optimal therapeutic concentration range. Due to interindividual variability
`caused by age, genetic and interethnic factors or drug-drug interactions, antipsychotic plasma
`concentrations show a wide range of values for the same dosage regimen. This is why clinical
`pharmacokinetic principles and therapeutic drug monitoring are essential tools for dosage indi-
`vidualisation.
`Clinical pharmacokinetics in therapeutics implies that the pharmacokinetic parameters of the
`medication under scrutiny are known. This is, however, not always the case with antipsychotics
`since, due to the difficulties encountered in conducting phase I studies in healthy volunteers with
`these substances, published data are not always complete.
`
`
`
`1. Historical Background
`
`In the early 19505, chlorpromazine was studied
`as an anti-autonomic substance to protect the body
`against its own excessive compensatory reactions
`during major surgery (Laborit 1952). It spread into
`psychiatry from the field of anaesthesia when De-
`lay and Deniker (1952) demonstrated the efficacy
`of this drug in the treatment of acute psychosis.
`After the initial enthusiasm with these drugs, it be-
`came evident that their use was associated with a
`
`variety of adverse effects including the extrapyr-
`amidal disorders such as acute dystonia, Parkin-
`sonism, akathisia, tardive dyskinesia, tardive dys—
`tonia and tardive akathisia, This fostered numerous
`
`studies of the pharmacology, pharmacokinetics and
`clinical effects of antipsychotics and the enhance-
`ment of our understanding of the mechanisms of
`both clinical improvement and adverse reactions
`(Verghese et a1. 1991). This subject has recently
`been reviewed by Schwartz and Brotman (1992).
`Despite the enormous amount of work in the
`field of psychoses, very little is known about the
`basic mechanisms responsible for the appearance
`of the disease and its clinical manifestations and,
`
`as a consequence, about the mode of action of anti-
`psychotic medication. Despite this lack of know-
`ledge, the measurement of plasma concentrations
`of the active principles and the use of this infor-
`mation in the frame of dosage regimen design and
`individualisation can be considered as a major im-
`provement of pharmacotherapy in the field of psy-
`choses. As a result, clinicians are beginning to adopt
`more conservative dosage strategies, and there is
`increased interest in the concepts of concentration
`thresholds and therapeutic margins for these agents.
`However, therapeutic drug monitoring of antipsy-
`chotics has not yet gained the official acceptance
`received by such authorities as the American Psy-
`chiatric Association (APA Task Force 1985) for
`monitoring of tricyclic antidepressants.
`
`The present review concentrates on the clinical
`pharmacokinetic progress that led to the present
`situation. For more details on analytical methods
`and the clinical pharmacokinetics of antipsychot-
`ics, reviews are available (Balant-Gorgia & Balant
`1987a; Dahl 1986; Jorgensen 1986; Simpson & Ya-
`dalam 1985). Accordingly, the bibliography in the
`present article is restricted to a minimum.
`
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`Pharmacokinetic Optimisation of Psychosis Treatment
`
`219
`
`2. Definitions of Psychoses and
`Psychotic Symptoms
`2.1 Psychoses
`
`Psychosis is a generic term which has been used
`with a variety of meanings. Recently, more precise
`diagnostic criteria have been established and, thus,
`for the specific purpose of this review, only 3 types
`of disorders will be considered: (a) schizophrenia
`(strictly speaking); (b) brief reactive psychoses; and
`(c) manic episodes.
`According to DSM-III-R (American Psychiatric
`Association 1987), schizophrenia is defined by the
`presence of characteristic psychotic symptoms (e.g.
`delusions, hallucinations, inappropriate affects, etc.)
`during the active phase of the illness and social or
`familial functioning below the highest level pre-
`viously achieved. The duration of the disease
`should be at least 6 months, including character-
`istic prodromal or residual symptoms. Thus, 2 sit-
`uations must be distinguished: an active phase (or
`active phases), followed by a residual phase. This
`is an important distinction, since treatment strat-
`egies are not identical in the 2 phases.
`A brief reactive psychosis is defined as a sudden
`onset of psychotic symptoms of at least a few hours’
`duration, but no more than 1 month’s duration,
`with eventual full return to premorbid level of
`functioning.
`The essential feature of a manic episode is a
`distinct period during which the predominant mood
`is either elevated, expansive, or irritable, and there
`are associated symptoms of the manic syndrome
`(e.g.
`inflated self—esteem, flight of ideas, marked
`impairment of functioning and possibly a short pe-
`riod of delusions or hallucinations).
`It is, however, mandatory to remember that
`these classifications represent, by obligation, an
`overall simplification of the clinical pictures en-
`countered in psychiatric practice. Patients are in-
`dividuals and the clinical symptoms reflect these
`individualities. As a consequence, treatment strat-
`egies must imperatively be individualised even if,
`as presented in this article, some generalisations
`are necessary for the sake of simplicity and teach-
`ing. As experienced in the Psychiatric University
`
`Institutions of Geneva, among possible methods
`of treatment
`individualisation,
`therapeutic drug
`monitoring represents one of the more promising
`approaches.
`
`2.2 Symptoms and Rating Scales
`
`It is now customary to separate psychotic symp-
`toms, as observed in schizophrenia, into 2 major
`groups: positive or productive symptoms vs nega-
`tive symptoms. Broadly defined, positive symp-
`toms refer to abnormal productions of the patient,
`including hallucinations, delusions and some as-
`pects of thought disorder. Negative symptoms gen-
`erally identify deficits in the patient’s behaviour
`such as blunted affect (e.g. poverty of thought and
`speech content), emotional withdrawal and im-
`paired social participation. In the past several years,
`increasing interest has been raised in subtyping
`schizophrenic symptoms. Research has attempted
`to link these symptoms to such variables as cere-
`brospinal fluid (CSF) neurochemistry, brain neu-
`roanatomy, cognitive functioning or movement
`disorders such as tardive dyskinesia.
`Besides the potential effects of such investiga-
`tions in achieving a better understanding of schiz-
`ophrenia, they are also of great importance in the
`field of clinical psychopharmacology, particularly
`in light of the realisation that antipsychotics such
`as clozapine may have an effect on negative symp-
`toms. This is of potential importance since it is
`now well known that ‘typical’ antipsychotic agents
`are usually more efficacious in the reduction of
`positive than negative symptoms.
`Traditionally, the Brief Psychiatric Rating Scale
`or BPRS (Overall & Gorham 1962) is used to eval-
`uate psychotic symptoms. It is a widely studied and
`well validated instrument for positive symptoms,
`but it also assesses negative symptoms. In order to
`overcome its potential limitations in the latter area,
`specific scales have been developed; among them
`the Scale for the Assessment of Negative Symp-
`toms or SANS (Andreasen 1982; Andreasen & Ol-
`sen 1982).
`Note that positive symptoms are usually asso-
`ciated with acute exacerbations of schizophrenia,
`
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`220
`
`Clin. Pharmacokinet. 25 (3) 1993
`
`brief reactive psychoses and manic episodes. On
`the other hand, negative symptoms are a specific
`feature of the residual phases of schizophrenia,
`since, by definition, brief reactive psychoses imply
`a full return to premorbid level of functioning. Ma-
`nic episodes in mixed bipolar disorders, if followed
`by a morbid phase, turn into depressive states. The
`distinction between negative symptoms and de-
`pressive states is important, since depression in
`schizophrenic or bipolar disorders necessitates the
`intervention of antidepressive medication which is
`of no use in treating negative symptoms in schiz-
`ophrenic patients.
`Open issues in the area of treatment of schiz-
`ophrenia include the assessment of the overall rel-
`evance of quality of life and social adjustment.
`These problems are presently the subject of exten-
`sive clinical research and it is thus possible that,
`in the future, results of these investigations will
`modulate our approach to the pharmacological
`treatment of these diseases. Pharmacokinetic/phar-
`macodynamic issues such as minimum effective
`concentrations are, as stated below, of crucial im-
`portance in this context.
`
`3. Drugs Used to Treat Psychoses
`3.1 Schizophrenia
`
`Schizophrenic patients often receive different
`types of psychotropic drugs such as benzodiaze-
`pines and antidepressants in addition to their anti—
`psychotic medication. In some cases, drug-drug in—
`teractions may occur. In the following paragraphs
`only antipsychotics used in acute schizophrenic
`episodes or for long term treatment are presented.
`For the purpose of the present review, antipsy-
`chotics are classified in 3 categories:
`- ‘Typical’ low potency (i.e. on 3 mg/day basis)
`medications (e.g. chlorpromazine),
`' ‘Typical’ high potency medications (e.g. halo-
`peridol, fluphenazine),
`- ‘Atypical’ medications (e.g. clozapine).
`It is not clear if typical low potency and high
`potency antipsychotics
`show different overall
`clinical efficacy. However, there is 1 major differ-
`ence between these 2 types of compounds in that
`
`only drugs given at low doses (i.e. high potency
`antipsychotics) can be formulated as depot prep-
`arations to be administered once or twice per
`month.
`
`The term ‘atypical’ antipsychotic broadly de-
`scribes antipsychotic medications that produce few
`or no extrapyramidal adverse effects. As an ex-
`ample, clozapine is relatively weak among anti-
`psychotics as a dopamine antagonist and shows
`similar binding affinities for both the D1 and D2
`receptors. This classification includes a heteroge—
`neous group of substances in terms of chemical
`structure, as well as pharmacological profile. Clas—
`sical or
`typical antipsychotics characteristically
`show greater D2 than 01 affinity. They also differ
`widely in chemical structures.
`As stated above, an important characteristic of
`a drug product is the potential existence of more
`than 1 pharmaceutical form (e.g. oral and depot).
`Table I indicates the most commonly used anti-
`psychotics, available formulations and average daily
`doses and suggested range of therapeutic concen-
`trations. All these drugs are used both in active and
`residual phases of the illness, although, as dis-
`cussed below, pharmaceutical formulations and
`dosages may be different. It is also important to
`remember that some patients will find one anti-
`psychotic agent more tolerable than others. Pres-
`ently there are no rules except careful clinical ob-
`servation to detect these particularities.
`
`3.2 Brief Reactive Psychoses
`
`As the definition of this illness implies (see sec-
`tion 2.1), a single acute episode needs pharmaco-
`therapy. The medications used are usually the same
`as those of the active phases of schizophrenia.
`During the acute phase, antipsychotic dosages
`are the same as are used during exacerbation states
`of schizophrenia. However, it seems that after 2 or
`3 days, patients usually benefit from lower dosages
`of typical antipsychotics than do relapsing schizo-
`phrenic patients (Balant—Gorgia, personal observ-
`ation). It can,
`thus, be speculated that careful
`clinical observation of the early response to anti-
`psychotic therapy might be used as a predictor of
`
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`Pharmacokinetic Optimisation of Psychosis Treatment
`
`
`221
`
`Table l. Available formulations, average daily doses and suggested therapeutic ranges for the most commonly used antipsychotic
`agents. This table is not exhaustive. it contains only some of the better known drugs
`
`Medication (proprietary name)
`
`Dosage torm
`IV
`
`IM
`
`PO
`
`“em
`
`Usual daily
`dose (mg)
`
`Suggested therapeutic
`concentration range
`(MG/L)
`
`Typical low potency antipsychotics
`Chlorpromazine
`Levomepromazine
`Thioridazine
`
`J
`
`Typical high potency antipsychotics
`Flupenthixol
`Fluphenazine
`Haloperidol
`Perphenazine
`Pimozide
`Zuclopenthixol
`
`Atypical antipsychotics
`Clozapine
`Sulpiride
`
`J
`
`J
`
`J
`
`J°
`
`‘/
`
`25-150
`150-250
`100—600
`
`3-15
`25-10
`5-20
`5-20
`2-6
`10-50
`
`200-600
`800-1600
`
`50-300
`
`2-5
`0.5-2.5
`5-15
`0.8—2.4
`
`6-308
`
`450-?f
`
`Ja
`
`Jb
`
`Jd
`
`\'\\\'\\
`
`\\
`
`a Usually 1 injection every 2 weeks.
`b Usually 1 injection every 4 weeks (rarely every 2 to 3 weeks).
`c An acetate ester, allowing injections every 3 days, is also available in some countries.
`d Usually 1 injection every 2 to 3 weeks.
`e Upper limit not determined.
`1‘ The upper limit has not been determined. but above 1000 ug/L, seizures have been observed.
`Abbreviations: IV = intravenous; N = intramuscular; P0 = oral.
`
`the course of the disease, particularly in patients
`suffering from a first psychotic episode. To test this
`hypothesis requires careful prospective and long
`term clinical trials in patients admitted for the first
`time in a psychiatric setting.
`
`3.3 Manic Episodes
`
`Manic episodes represent a particular moment
`of a mood disorder which can also comprise major
`depressive episodes or hypomanic phases. As a
`consequence, patients who suffer from this disease
`often receive preventive medication such as lith-
`ium or carbamazepine, antidepressant therapy dur-
`ing depressive episodes and antipsychotic medi-
`cation during manic episodes. In the present review,
`only the latter situation is discussed.
`Essentially, these drugs are the same as those
`listed in table I, but therapy is usually limited in
`
`duration. If a patient is receiving lithium therapy,
`it does not need to be interrupted during antipsy—
`chotic administration. It has also been advocated,
`in the case of a clearcut diagnosis, to start lithium
`during the manic episode in parallel to the anti-
`psychotic agent. However, this approach has the
`disadvantage of combining 2 drugs which are al-
`ready difficult to handle when administered alone,
`and which when combined have no clear advan-
`
`tage in the majority of patients.
`
`3.4 Pharmacokinetic Profile of
`
`Antipsychotics
`
`Human pharmacokinetics of the antipsychotics
`under review have been studied only partially for
`some drugs and in more detail for others. It is thus
`often difficult to obtain more than minimal infor-
`
`mation from the published results.
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`222
`
`Clin. Pharmacokinet. 25 {3) I993
`
`Gastrointestinal absorption: With the exception
`of sulpiride, all the presented antipsychotics share
`some pharmacokinetic properties as they are all
`highly lipophilic compounds. They are well
`ab—
`sorbed from the gastrointestinal tract, but their sys-
`temic availability is low because they undergo ex-
`tensive first-pass hepatic metabolism. In addition,
`their systemic clearance is high because of a high
`hepatic extraction ratio. Renal elimination of the
`unchanged drug is negligible.
`Clearance values are usually not calculated by
`investigators because intravenous administration
`in healthy volunteers has rarely been performed and
`intramuscular data may not necessarily lead to ac-
`curate results. In any case, with the notable excep-
`tion of sulpiride, antipsychotics are substances with
`high hepatic extraction ratios (Balant-Gorgia &
`Balant 1987a).
`Metabolism: Because the antipsychotic drugs
`under review belong to different chemical groups,
`no general rule concerning their metabolism can be
`given, due to the wide variety of pathways in—
`volved. In addition, although most of these drugs
`have been available for many years, their metab-
`olism in humans has usually not been satisfactorily,
`elucidated. It appears, as discussed below, that in
`humans none of the typical high potency sub-
`stances produces metabolites with relevant anti-
`psychotic effects at concentrations which would
`necessitate their measurement for routine clinical
`
`monitoring. In contrast, typical low potency anti—
`psychotics usually have many active metabolites
`which make drug monitoring strategies difficult to
`implement in clinical practice.
`Distribution of a drug in the body is in part a
`function of its binding to plasma proteins and tis-
`sue components. Accordingly, if a drug is highly
`bound to plasma proteins, as is the case with anti-
`psychotic drugs, its apparent volume of distribu—
`tion can be considerable if tissue distribution and
`
`binding are high. In this respect, sulpiride (section
`3.4.1 1) displays a behaviour different from the other
`drugs discussed in this review. Most antipsychotics
`are lipophilic drugs, a condition probably import-
`ant for their crossing the blood-brain barrier. They
`bind to many tissue components and dissolve in
`
`adipose tissue. These ‘silent receptors’ are import-
`ant for the pharmacokinetic behaviour of antipsy-
`chotics.
`
`The hepatic extraction coefficient of antipsy-
`chotic drugs is high, as is their systemic clearance
`(about 30 to 60 L/h). Elimination half-life values
`around 24 hours are obtained only because the ap—
`parent volumes of distribution are about 100L. This
`is important if peak and trough concentrations at
`steady-state are to remain within reasonable limits.
`The specific binding of the drug to its receptor sites
`must also be considered. It is not known at present
`if fluctuating plasma concentrations of antipsy-
`chotic drugs are better than constant concentra-
`tions at steady-state as far as the interaction be-
`tween the active principle and the receptors is
`concerned. However, the distribution of the anti-
`psychotics and their binding to the silent receptors
`plays an important role in the modulation of their
`plasma profiles and in establishing dosage regi-
`mens. The large volume of distribution also im-
`plies that the concentrations of antipsychotics in
`blood after a single dose are low and often difficult
`to determine. This may explain, in part, why data
`in healthy volunteers are generally much less read-
`ily available than for other classes of drugs, at least
`if we consider the high potency antipsychotics.
`Clearly, it would be useful to have detailed in-
`formation about the relationship between plasma
`concentrations and the presence of the active prin-
`ciple in the central nervous system, i.e. where the
`active receptors are located. Understandably, this
`type of data is scarce in humans. Numerous studies
`have been published on steady-state concentra-
`tions of antipsychotic drugs. In general they have
`been performed to establish a relationship between
`plasma concentrations and clinical efficacy or to
`monitor the appearance of adverse effects. Phar-
`macokinetically, these studies can be summarised
`by saying that, under normal conditions, the anti-
`psychotics under review (with the possible excep-
`tion of perphenazine) seem to show linear phar-
`macokinetics and that steady-state concentrations
`show important interindividual variations. These
`2 facts are important for an adequate implemen-
`tation of plasma
`antipsychotic
`concentration
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`Pharmacokinetic Optimisation of Psychosis Treatment
`
`
`223
`
`monitoring strategies. The large variability in
`steady-state concentrations is a good reason for ad-
`justing the posology based on measured concen-
`tration. Linear pharmacokinetics enable the dosage
`to be easily adjusted when steady-state plasma con-
`centrations have been measured previously.
`Depot preparation: The main pharmacokinetic
`characteristics of depot preparations may be sum-
`marised as follows. Once the drug (administered as
`an ester dissolved in oil) is injected into the muscle,
`it is slowly released from the depot site. The dif—
`fusion of the drug from this site is probably the
`rate-limiting pharmacokinetic step,
`since enzy-
`matic hydrolysis of the esters occurs
`rapidly.
`Therefore, the apparent rate of elimination is con-
`trolled by the release rate and not by the rate of
`hepatic metabolism. When the release rate con-
`stant is less than the elimination rate constant, a
`‘flip-flop’ model results. The time necessary to
`achieve steady-state plasma concentrations may
`thus be as long as 3 months, although plasma con-
`centrations measured 1 week following the first in-
`jection are usually close enough to the steady—state
`values to be used for monitoring purposes.
`The time to reach peak plasma concentrations
`is very different from one preparation to another.
`At present it is, however, difficult to understand
`which are the main factors governing the phar-
`macokinetics of these depot preparations. For drug
`concentration monitoring, it is probably useful to
`measure plasma concentrations immediately be-
`fore injection and 7 days postdose. This should al-
`low an approximation of the overall plasma profile
`in most patients.
`Long elimination half-lives have been measured
`for depot preparations. This protracted elimination
`may provide a progressive (and potentially bene-
`ficial) decrease in plasma concentrations if a patient
`decides to stop therapy by avoiding visits to the
`psychiatrist. On the other hand, adverse effects that
`persist for several months after discontinuation of
`the depot drug therapy may also be explained (at
`least partially) by the ‘flip-flop’ pharmacokinetics.
`The ‘flip-flop’ pharmacokinetics of the depot prep-
`aration will also influence the elimination of the
`
`drug after long term therapy is terminated.
`
`The nature of the fatty acid determines to some
`extent the rate of release from the depot and thus
`the apparent elimination half-life. It is therefore
`possible to modulate the pharmacokinetics of these
`drugs by the choice of the esterifying agent. Clo-
`penthixol has also been esterified with acetic acid.
`With this injectable preparation, maximum plasma
`concentrations are observed after 24 to 48 hours,
`followed by an elimination phase reaching a plasma
`concentration of about one-third of the maximum
`after 72 hours.
`
`From a practical point of view, if a depot in-
`jection is made into adipose tissue of an obese
`patient instead of into muscle (e.g. using a short
`needle), the pharmacokinetics of these drug prep-
`arations will likely be altered. Thus, very low con-
`centrations of the active principle may result, at
`least before steady-state is reached, because the
`lipophilic drug remains locally concentrated at the
`site of injection in the adipose tissue. Conversely,
`in very lean or elderly patients high concentrations
`may be reached immediately after the injection.
`More information relating to such perturbing fac-
`tors would help to clarify these points which may
`prove to be clinically relevant.
`Pharmacokinetic and metabolic features of sel-
`
`ected antipsychotics are presented to highlight the
`fact that each drug must be considered individ-
`ually, and that substance-specific rules must be ap-
`plied in clinical situations. As a consequence, it can
`be stated that
`the basic principle of pharmaco-
`therapy with antipsychotics is the individualisation
`of the drug to match the clinical situation, the in-
`dividualisation of dosage regimen to match the
`patient’s situation and, finally, the individualisa-
`tion of drug use to match the specific pharmaco-
`kinetic profile of each substance.
`The pharmacokinetic parameters given in table
`II are derived from combination of studies. These
`
`are selected from a highly variable range of pub-
`lished values to show those that seem most com-
`
`patible with the known behaviour of the drugs un-
`der consideration in healthy volunteers or patients
`with normal renal and hepatic function. However,
`effective treatment of acute or long lasting psy-
`chotic episodes requires that steady-state concen-
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`224
`
`Clin. Pharmacokinet. 25 (3) 1993
`
`Table ll. Pharmacoktnetic parameters of orally administered antipsychotic agents
`
`Drug
`
`Chlorpromazine
`Clopenthixol
`Clozapine
`Flupenthixol
`Fluphenazine
`Haloperidol
`Levomepromazine
`Perphenazine
`Pimozide
`Sulpiride
`Thioridazine
`
`tmax
`0‘)
`
`2-4
`3-5
`1-6
`3-8
`2-5
`3-6
`1-4
`3—5
`4-8
`2-6
`2-4
`
`F
`PM
`
`25-65
`40-60
`40-60
`30-70
`17-50
`40-80
`30-70
`60-80
`15-25
`15-65
`10-60
`
`ty,
`(hi
`
`12-36
`15-25
`12-36
`24-36
`8-32
`15-30
`15-30
`10-20
`30-150
`6-15
`10-30
`
`Vd
`(L/kg)
`
`10-35
`
`4-8
`10—20
`5?-60?
`15-20
`20-45
`10-36
`20-40
`3
`10
`
`tu
`
`0.05-0.01
`0.01
`0.05
`0.01
`<0.1
`0.08
`
`0.8-0.9
`0.03
`
`0.03
`
`Ae
`(% of
`dose)
`
`<6
`
`<3
`
`<1
`30-50
`10-20
`
`Abbreviations: tmax = time to reach peak plasma concentration; F = bioavailability; h,2 = elimination half-life; Vd = volume of distribution;
`fu = unbound fraction of the drug; A9 = amount of the drug excreted unchanged in the urine.
`
`trations of the drug are reached. Thus, in clinical
`practice, the most important parameter is the elim-
`ination half-life, which indicates the time to reach
`steady-state after the start of therapy or following
`changes in dosage regimen. Of equal importance is
`the magnitude of first—pass metabolism for those
`antipsychotics which can be administered both
`orally and parenterally. This knowledge is very im-
`portant if therapeutic drug monitoring is used to
`help guide the clinician’s choice of drug, route of
`administration and daily or weekly dose.
`
`3.4.1 Chlorpromazine
`Many pharmacokinetic studies have focused on
`chlorpromazine. Studies with substances such as
`fluphenazine or haloperidol are more difficult to
`perform in healthy volunteers because of the fre—
`quent occurrence of neurological adverse effects.
`The fact that the dosages are high (i.e. about 10
`times higher than for high potency antipsychotics)
`increases the possibility of measuring a variety of
`metabolites in biological fluids (Jorgensen 1986).
`The pharmacokinetics of chlorpromazine dis-
`play high interindividual variability, even in ho-
`mogeneous groups of healthy volunteers (Midha et
`a1. 1989). 30-fold interindividual variability in area
`under the curve has been observed under such con-
`
`ditions. Chlorpromazine is extensively metabol-
`ised during its first pass through the liver and sys-
`temic availability has been reported as less than
`10% relative to single intravenous doses (Loo et al.
`1980) or a mean of about 30% compared with single
`intramuscular doses (Dahl & Strandjord 1977). The
`effect of first-pass metabolism on therapy is diffi-
`cult to evaluate since an important number of me-
`tabolites are formed in humans, some of them pos-
`sessing pharmacological activity.
`Studies of repeated administration (Loga et a1.
`1975; Sakalis et a1. 1972) showed decreasing plasma
`concentrations of chlorpromazine despite a con-
`stant dosage, and Dahl and Strandjord (1977) found
`on average about 40% lower areas under the plasma
`drug concentration curves after multiple-dose
`administration than was estimated from the first
`
`single oral dose. Metabolic patterns were also dif-
`ferent in the 2 situations.
`
`Chlorpromazine and its metabolites can cross
`the placenta to the fetus (O’Donoghue 1974).
`Breastmilk from mothers administered chlorprom-
`azine contains both the parent compound and some
`of its metabolites. The concentration of chlor-
`
`promazine in breastmilk is in the same order of
`magnitude as that in plasma. Similar, essentially
`anecdotal, reports are available for other antipsy-
`
`InnoPharma Exhibit 1097.0008
`
`

`

`Pharmacokinetic Optimisation of Psychosis Treatment
`
`225
`
`chotics. This is not surprising in view of the high
`lipophilicity of these substances.
`In some cases
`pharmacological effects have been observed in
`neonates.
`
`3.4.2 Thioridazine
`
`As observed with other phenothiazines, thiori-
`dazine undergoes extensive first-pass metabolism.
`Plasma concentrations of the parent drug and me-
`tabolites are influenced by the debrisoquine/spar-
`teine oxidation phenotype (von Bahr et al. 1991).
`It has recently been shown that slow hydroxylators
`of debrisoquine obtain higher serum concentra—
`tions of the parent compound, with a 2.4-fold higher
`peak plasma concentration (Cmax) and a 4.5-fold
`larger area under the curve, associated with a 2-
`fold longer half-life compared with that of rapid
`hydroxylators (von Bahr et al. 1991). This indi-
`cates that first-pass metabolism is different in slow
`and rapid hydroxylators of debrisoquine.
`Overall,
`the pharmacokinetics of thioridazine
`are complex for a number of reasons: there is a
`trend towards nonlinear pharmacokinetics (Chak-
`raborty et al. 1989) and,
`in addition, the parent
`compound and its metabolites are racemic mix—
`tures. It has also been noted that phenothiazines
`may remain in the body for long periods of time
`due to storage in a deep compartment (Curry &
`Hu 1990).
`
`3.4.3 Levomepromazine
`Recent information on the pharmacokinetics of
`levomepromazine is difficult to obtain. It is, how-
`ever, probable that the overall pharmacokinetic be-
`haviour of this phenothiazine is essentially similar
`to chlorpromazine and thioridazine. A number of
`metabolites are formed and detected in biological
`fluids, and interindividual pharmacokinetic vari-
`ability is important.
`A pharmacokinetic study comparing single and
`multiple intramuscular and oral doses of levome-
`promazine to patients leads to the calculation of
`pharmacokinetic parameters, as indicated in table
`II (Dahl 1976). The sulphoxide metabolite is found
`in concentrations greater than those of the parent
`
`compound after oral administration, but is not de-
`tectable after intramuscular injection. This indi-
`cates that the sulphoxide is to a large extent formed
`in the gut wall and/or during the first passage of
`the drug through the liver.
`
`3.4.4 Perphenazine
`The pharmacokinetics of perphenazine after
`single-dose administration are difficult to investi-
`gate. This is probably due to the low concentra-
`tions measured at doses given to healthy volun-
`teers and the resulting difficulty in developing
`sufficiently sensitive analytical methods. As an ex-
`ample, following a single intravenous injection of
`5 to 6mg to healthy volunteers, multicompartmen-
`tal pharmacokinetics can be observed (Eggert Han-
`sen et al. 1976), but after an identical oral dose, no
`perphenazine could be measured by gas chroma-
`tography. However, continuous administration of
`double doses to patients at 8-hour intervals re-
`sulted in measura