PHARMACOKIN ETIC - PHARMACODYNAMIC RELATIONSHIPS

Clin. Pharmacokinel. 24 (2): 161-176. 1993

0312-5963/ 93/0002-0161 /$08.00/ 0
© Adis International Limited. All rights reserved.
CPK1265

Pharmacokinetics and Pharmacodynamics of Clozapine

Michael W. Jann, Sara R. Grimsley, Eric C. Gray and Wen-Ho Chang
Departments of Pharmacy Practice and Pharmaceutical Sciences, Mercer University, Southern School of
Pharmacy, Atlanta, Georgia, USA, and Taipei City Psychiatric Center, Taipei, Taiwan, Republic of China

Contents
161 Summary
162 I. Analytical Methods
164 2. Fundamental Pharmacokinetic Properties
164 2.1 Intravenous and Oral Administration
165 3. Metabolism
166 4. Drug Disposition
166 4.1 Patient-Related Variables
166 4.2 Dose
166 4.3 Drug Interactions
167 5. Pharmacodynamics
167 5. 1 Neuroreceptor Binding Affinity
168 5.2 Neuroendocrine Effects
169 6. Clozapine Blood Concentrations and Clinical Response
169 6.1 Short Term Studies
170 6.2 Treatment of Patients with Refractory Schizophrenia
171 7. Adverse Effects
J71 7.1 Haematological
172 7.2 Orthostatic Hypotension
172 7.3 Seizures
173 7.4 Overdosage
173 8. Conclusions

Summary The introduction of c10zapine has given clinicians a unique agent for treating patients with
schizophrenia that is refractory to other neuroleptics. Despite its efficacy, the drug continues to
be prescribed with trepidation due to the incidence of agranulocytosis. This article reviews the
pharmacokinetic and pharmacological properties of c10zapine and the clinical implications for
monitoring plasma concentrations.
Various assays have been developed for c10zapine that include gas-liquid chromatography,
radioimmunoassay and high performance liquid chromatography. Only a few studies have ex-
amined the pharmacokinetics of c10zapine in patients with schizophrenia. These studies have
revealed a wide interpatient variability in pharmacokinetic parameters that include: time to reach
peak plasma concentrations 1.1 to 3.6h; elimination half-life 9.1 to 17.4h; clearance 8.7 to 53.3
L/ h; and a volume of distribution of 1.6 to 7.3 L/kg. C10zapine is metabolised via the hepatic
microsomal enzyme system into 2 principle metabolites: demethyl-c1ozapine and c10zapine N-
oxide. Urine samples have reported the ratio of c1ozapine: demethyl : N-oxide to be I : I : 2. The
162 Clin. Pharmacokinet. 24 (2) 1993

clozapine N-oxide binding affinity with 3H-haloperidol was 4 times lower than clozapine and its
conversion back to clozapine is hypothesised. Although the exact pharmacological mechanism of
action of clozapine is not fully understood, the drug does possess significant binding affinity for
different dopamine receptors, with recent evidence supporting binding to the D4 receptor sub-
type.
Clozapine transiently increases serum prolactin levels with minimal changes in homovanillic
acid plasma levels. Limited studies investigating the relationship between clinical response and
plasma clozapine concentrations have investigated the range between 100 and 800 /J.gjL. In the
treatment of patients with refractory schizophrenia, a minimum concentration of 350 /J.g/L was
suggested as needed. The occurrence of agranulocytosis could have a genetic basis and patients
should be rigorously monitored during treatment. The incidence of tardive dyskinesia and ex-
trapyramidal side effects is minimal. Clozapine can lower the seizure threshold in a dose- and
time-dependent manner. Careful patient selection and monitoring are required when clozapine
therapy is used in patients with schizophrenia.

Clozapine is a unique neuroleptic agent. Unlike spite the relative number of methods available
other neuroleptics, it does not produce significant (table I), there are only a few published articles de-
extrapyramidal side effects in treated individuals. scribing each technique with the exception of high
Further, some patients with schizophrenia have performance liquid chromatography (HPLC). The
improved with clozapine treatment who were pre- column in table I denoting coefficient of variation
viously refractory to other neuroleptics. Although (CV) does not specify either intra-assay or inter-
clozapine was only recently approved for use in the assay CVs, as some of these studies only reported
United States, it has been available in other coun- 1 value. Early investigations with gas liquid chro-
tries for many years. The reason for this discrep- matography (GLC) reported a linear correlation
ancy is that during the clinical trials with clozapine between the daily dose of clozapine in mg/kg and
in the US in the mid 1970s, reports of agranulo- clozapine serum concentrations (r = 0.938) [Hei-
cytosis appeared in the European literature (Hip- pertz et al. 1977). Serum drug concentrations tested
pius 1989). This resulted in the withdrawal of clo- ranged from 250 to 750 /J.g/L, with the linear
zapine in the US and the limiting of its distribution
regression line extrapolated to 100 /J.g/L. Interassay
in other countries. Since the reintroduction of clo-
CV was <5%. A gas chromatographic (GC) method
zapine into the market in the late I 980s, infor-
using a fused silica wide bore capillary column was
mation regarding its pharmacokinetics and phar-
shown to improve the lower limit of sensitivity to
macodynamics has been expanded. However, the
1 to 2 /J.g/L with a linear calibration graph of r =
routine monitoring of plasma neuroleptic concen-
0.999 up to 300 /J.g/L (Richter 1988). The precision
trations by clinicians still remains to be estab-
lished. A major factor that limits the everyday ap- (CV) at 1.5 /J.g/L was 18.2%. The GC-mass spec-
plication of routine monitoring is the lack of trometry (MS) with single ion detection method can
information regarding the metabolic disposition of be used to assay clozapine and 1 of its metabolites
the drug. This article reviews the pharmacokinetic - demethyl- or norclozapine (Bondesson & Lind-
properties of clozapine, its pharmacodynamic ac- strom 1988). The precision of the assay for clo-
tions and the potential applications in plasma con- zapine and norclozapine at 5.0 /J.g/L was 6.3 and
centration monitoring. 8.2%, respectively. The major drawback with GC-
MS is its low capacity compared with other assay
1. Analytical Methods methods and its high expense.
Various analytical techniques have been used to A thin-layer chromatographic (TLC) method was
measure clozapine concentrations usually obtained developed to measure clozapine and its demethyl
from the plasma in clinical or research studies. De- and N-oxide metabolites (Breyer & Villumsen
Kinetics and Dynamics of Clozapine 163

1976). The recovery of clozapine and demethyl- other metabolites. Specificity for the parent com-
clozapine from human plasma was 98 and 93%, pound could rest upon the selection of the proper
respectively. A lower recovery rate of 76% was de- antiserum model. Antiserum from rabbits pro-
termined for the N-oxide metabolite. In actual duced a lower specificity for clozapine than that
patient samples (n = 20), only clozapine and de- from the goat.
methyl-clozapine results were reported and these Meier (1975) reported the first HPLC technique
showed wide interpatient variability when cloza- to assay clozapine and the N-oxide metabolite. Only
pine daily doses from 75 to 700 mg/day were ad- very preliminary data on the assay specifications
ministered. Plasma clozapine and de methyl- were reported as the experiment was conducted in
clozapine concentrations ranged between 76 to 789 2 beagle dogs. Of the other HPLC studies in table
Ilg/L and 50 to 474 Ilg/L, respectively. I, only one reported the ability to assay clozapine
A radioimmunoassay (RIA) for clozapine and and its 2 principle metabolites (Zeren et al. 1986).
its N-oxide and demethyl metabolites was devel- Serum concentrations from 10 patients receiving
oped by equilibrium dialysis using a goat anti- clozapine 100 to 400mg daily were strongly cor-
serum (Rosenthaler et al. 1977). Binding coeffi- related (r = 0.724, p < 0.05). Data for the metab-
cients, association and dissociation constants were olites were not reported. Lovdahl et al. (1991) re-
reported for all 3 compounds at pH 7.5 and 20°e. ported the ability to detect clozapine and demethyl-
The investigators did not report any pharmacoki- clozapine using a liquid-liquid extraction followed
netic data from their 3 patients receiving single by reverse phase liquid chromatography. The other
doses of clozapine 100mg. The advantage in using HPLC methods assayed only clozapine and each
RIA is that it can detect these compounds using technique differed in detection or extraction meth-
only a very small plasma sample. The disadvan- ods. The method described by Haring et al. (1988)
tage of RIA is the possibility of cross-reactivity with used a laborious extraction procedure that required

Table I. Summary of the assay techniques for measuring clozapine

Assay Amount of Metabolites Lower limit8 CV C Reference

sample (I'g/L) (%) (I'g/L)
(ml)

GLC 2 None 250 5 NR Heipertz et al. (1977)

GC None 1-2 7.9 5.0 Richter (1988)
GC-MS 1 Demethyl 1.0-5.0 6.3,8.2 5.0 Bondesson & Lindstrom (1988)
TLC 3-6 Demethyl 40,20,25 5 NR Breyer & Villumsen (1976)
N-oxide
RIA 0.1 Demethyl 1.5, NR, NR 3.5 NR Rosenthaler et al. (1977)
N-oxide
HPLC NR N-oxide 10,10 NR NR Meier (1975)
Demethyl 5.0,5.0, NR 3-7 1.0 Zeren et al. (1986)
N-oxide
2 None 5.0 14 NR Haring et al. (1988)
0.1 None 20 8.8 25 Humpel et al. (1989)
0.5 None 0.45 <10 50 Wilhelm & Kemper (1990)
2 Demethyl 15, 30 9.9 150 Lovdahl et al. (1991)

a Clozapine, demethyl-clozapine, N-oxide.

Abbreviations: C= plasma drug concentration; GLC = gas liquid chromatography; GC = gas chromatography; GC-MS = gas
chromatography-mass spectrometry; HPLC = high performance liquid chromatography; RIA = radioimmunoassay; TLC = thin-layer
chromatography; CV = intra- or interassay coefficient of variation; NR = not reported.
164 Clin. Pharmacokinet. 24 (2) 1993

a pre-extraction step plus 2 analytical extractions ance of clozapine from whole blood (CLb) and
before assay with ultraviolet (UV) detection at plasma (CLp) were similar [250 ± 167 mljmin and
254nm. Later, these investigators developed a more 217 ± 145 mljmin (15.0 ± 10.0 L/h and 13.0 ±
simple I-step extraction procedure using electro- 8.7 L/h), respectively]. Three patients also received
chemical detection to measure clozapine (Humpel phenytoin (I received both phenytoin and carba-
et al. 1989). Wilhelm and Kemper (1990) reported mazepine), a hepatic enzyme inducing agent. The
a solid phase extraction method and UV detection concurrent use of these anticonvulsants could alter
to assay clozapine. the clearance of clozapine (see section 4). In a
Chinese study of 8 patients, 4 men received clo-
2. Fundamental Pharmacokinetic zapine 100mg and 4 women received 75mg of the
Properties drug (Gu 1988). The mean volume of distribution
2.1 Intravenous and Oral Administration (7.3 ± 2.7 L/kg) was larger than observed in other
studies. Although the mean time to reach peak
There have only been a few studies examining concentration (t max ) was 3.6 ± 3.2h, the investi-
the pharmacokinetics of clozapine in patients with gators noted that in 4 patients (1 male, 3 female)
schizophrenia. By their very nature, clinical drug t max was less than 1.5h. In the other 4 patients,
studies in these patients are extremely difficult to t max values were 6h in the 3 men and 3h in the I
accomplish, and, coupled with the intense char- woman.
acter of a pharmacokinetic study, these investiga- Choc et al. (1987) administered clozapine in 3
tions become exceedingly difficult to complete suc- different dosages (75, 150 and 300 mg/day) to psy-
cessfully. The known pharmacokinetic profile of chiatric patients (Choc et al. 1987). The geometric
clozapine in patients with schizophrenia is pre- mean volumes of distribution and elimination half-
sented in table II. Each study noted a wide inter- lives were pooled from the different dosages (table
patient variability for each parameter. Cheng et al. II). Clearance and peak plasma concentration
(1988) found the relative bioavailability of oral clo- (C max ) values for the 3 dosages were similar. The
zapine 200mg versus intravenous cIozapine 25mg mean area under the plasma concentration-time
to be 0.27 ± 0.21; however, the intravenous data curve (AUC) for each group increased proportion-
were not reported. The mean hepatic extraction ra- ally to the dosage. The investigators concluded that
tio was calculated to be 0.17 ± 0.11. Rates of clear- at doses below 300 mg/day, Michaelis-Menten ki-

Table II. Summary of the mean (± SO) pharmacokinetic parameters for clozapine

Reference No. Dose F Vd/F CL tV2a tV2~ tmax

(mg) (L/kg) (L/h) (h) (h) (h)

Cheng et al. (1988) 10 200 0.27 ± 0.21 1.6 ± 1.1 217 ± 145a 0.10 ± 0.12 10.3 ± 2.9 3.0 ± 1.5
Gu (1988) 8 100 NR 7.3 ± 2.7 36.9 ± 10.4 0.22 ± 0.23 9.1 ± 3.7 3.6 ± 3.2
(n = 4)
75
(n = 4)
Choc et al. (1987) 13 150 NR 5.1 ± 2.3 53.3 ± 29.3 1.7 ± NR 17.4 ± 7.7 1.1 ± 0.5
Choc et al. (1990) 16 225 NR 587 b 29.6 ± 14.1 0.48 ± NR 14.1 ± NR
NR

a ml/min. To convert to L/h, mUltiply by 0.06.

b Litres only.
Abbreviation: NR = not reported, F = bioavailability; Vd = volume of distribution; CL = total body clearance; t.lz. = absorption half-
life; tV2~ = elimination half-life; t max = time to peak plasma concentration.
Kinetics and Dynamics of Clozapine 165

netics were not observed with c1ozapine. The clear-

Hydroxy +--- Clozapine N-Oxide
ance (CL) and volume of distribution (Vd/F) of metabolites
c10zapine from the Choc et al. (1987) study are
similar to those found by Cheng et al. (1988), who
assumed oral bioavailability of 0.27.
1
Demethyl-clozapine
In a single- and multiple-dose pharmacokinetic
study with c1ozapine, 3 different dosages were ad- Fig. 1. Proposed metabolic scheme for c\ozapine.
ministered in different phases of the trial (Choc et
al. 1990). After a drug-free period of 7 days, a single N-oxide concentration was approximately double
dose of c10zapine 3 x 75mg tablets was admini- those of the other compounds. Therefore, the ap-
stered. This was followed by I drug-free day and proximate ratio of c10zapine : de methyl : N-oxide
then by dosage escalation from 150 to 300 mg/day is relatively I : I : 2. The pharmacological activity
over 12 days. Only the morning dose was given on of these metabolites was reported to be much lower
day 13. A 5-day drug-free period followed and fi- than ciozapine (Rosenthal et al. 1977). On the basis
nally a repeat single dose was administered on the of 3H-haloperidol binding affinity in rat striatal
final day. AUC and Cmax did not significantly dif- membranes, ciozapine N-oxide binding was at least
fer between the 2 single doses. Comparison of 4 times lower than that of ciozapine (Schmutz
single- and multiple-dose parameters yielded in- 1980). Both metabolites have been detected in the
teresting results. The mean AUC values, when nor- plasma of patients treated with ciozapine (Acken-
malised to 75mg, significantly increased after mul- heil 1989). The demethyl and N-oxide metabolite
tiple dose administration (1040 ± 493 J.tg/L· h vs concentrations were lower than those of c10zapine
1420 ± 972 J.tg/L· h, a 36.5% difference, p = 0.04). and ranged from approximately 20 to 30% and 10
The volume of distribution increased from 342 to to 50% of ciozapine concentrations, respectively.
587L and the elimination half-life (t'l,) increased The N-oxide metabolite of ciozapine could in-
from 8.1 h to 14.1 h. These changes could be due to fluence the pharmacokinetics of the parent com-
additional pharmacokinetic compartments or larger pound. The N-oxide metabolite of chlorpromazine
distribution of c10zapine during multiple-dose was shown in animal and human models to be
administration. Concurrent ingestion of food did converted back to chlorpromazine (Hubbard et al.
not alter the pharmacokinetics of the drug. Ack- 1985; Lewis et al. 1983). In dogs, ciozapine N-oxide
enheil (1989) reported similar findings in 12 and c10zapine were administered via intravenous
patients with schizophrenia given a single dose of and oral routes (Meier 1975). The ratio of cioza-
c10zapine 100mg. The t max was achieved in 1.5h pine: c10zapine N-oxide oscillated during the first
and the mean elimination tlh was 6.0 ± 1.5h. 6h after administration and pharmacokinetic model
analysis was not accomplished. Oxidation of cio-
3. Metabolism zapine and reduction of the N-oxide metabolite oc-
curred very rapidly after oral or intravenous
In early studies, the metabolism of ciozapine was administration. However, the reduction process was
examined in mice, dogs and humans (Gauch & Mi- faster than oxidation. This pattern of reduction/
chaelis 1971). Using 2.6L of urine obtained from oxidation is similar to that of other drugs that
5 patients with schizophrenia treated with cioza- undergo a reversible metabolic process (Bickel
pine 150 to 250 mg/day, TLC analysis revealed that 1969). Therefore, the potential exists for ciozapine
the metabolites of ciozapine were demethyl-cioza- to share this property and this only be confirmed
pine and ciozapine N-oxide. The hepatic micro- when the N-oxide metabolite is administered to
somal enzyme system most likely accounts for their humans. The metabolic scheme for ciozapine is
formation. Clozapine and demethyl-ciozapine were presented in figure 1.
detected in approximately equal portions while the Other metabolites of ciozapine, such as the 2-
166 Clin. Pharmacokinet. 24 (2) 1993

hydroxy and 7-hydroxy compounds, have been de- average plasma clozapine concentration was found
tected (Rosenthaler et al. 1977). They are reported to be 20% lower in smokers than in nonsmokers
to be detected in plasma in concentrations twice (p < 0.01). Note that plasma clozapine concentra-
those of clozapine (I : 2 : 2). No other data were tions have not been reported in patients < 18 years
reported with the hydroxy metabolites. Fischer et old or >60 years old, although clozapine has been
al. (1992) reported that in human liver microsomal used in both populations (Birmaher et al. 1992;
preparations and in recombinant RT2D6 cells that Jann, personal communication).
the metabolism of clozapine was under the influ-
ence of the cytochrome P450IlD6 isozyme. How- 4.2 Dose
ever, the metabolites were unidentified and differ-
ent from the demethyl and N-oxide metabolites. The relationship between clozapine dose and
Further research is needed to determine the poly- plasma concentrations has been examined by vari-
morphic metabolism of clozapine and whether the ous investigators. Generally, each study reported
existence of extensive and poor metabolisers is wide interpatient variability between the dose and
clinically significant. plasma concentrations (Ackenheil 1989). The cor-
relation between the dose (in mg/kg) and plasma
4. Drug Disposition concentrations was r = 0.502, p < 0.001 in one
study (Haring et al. 1989a), but in other studies,
Factors influencing the disposition of clozapine when bodyweight was not factored into the analy-
are limited but include patient-related variables, the sis, higher correlations ofr = 0.74, p < 0.0001 and
dosage of the drug and drug interactions. They have r = 0.622, p < 0.001 were found (Bondesson &
been published as case reports and large multi- Lindstrom 1988; Haring et al. 1989b). Note that
centre clinical trials. when the data plots from both of these studies were
examined, the correlations between dose and
4.1 Patient-Related Variables plasma concentrations decreased as the daily dos-
age increased. The interpatient variability in plasma
Plasma clozapine concentrations were obtained concentrations at the lower doses <300 mg/day was
from 148 psychiatric patients treated with cloza- less than with doses >500 mg/day (Bondesson &
pine for at least 8 days (Haring et al. 1989a, 1990). Lindstrom 1988).
Demethyl-clozapine and clozapine N-oxide were
not measured. The study group consisted of 54 4.3 Drug Interactions
women and 94 men with a mean age of 30.6 ±
8.8 years (range 18 to 54 years). Age, gender, body- Plasma clozapine concentrations decreased in 2
weight and smoking were examined for their influ- patients upon the addition of phenytoin (Miller
ence on plasma clozapine concentrations. Patient 1991). Neither patient had a previous history of
data were analysed by regression analysis, Mann- seizure disorders before starting clozapine therapy.
Whitney U test and analysis of variance. The age The first patient received clozapine 400 mg/day and
distribution for the population was 18 to 26 years had a plasma concentration of 295.9 JLg/L 12h after
(n = 60); 27 to 35 years (n = 50); 36 to 44 years the last dose. The patient experienced a tonic-clonic
(n = 18) and 45 to 54 years (n = 15). Statistically seizure and phenytoin was added. The 12h plasma
higher plasma clozapine concentrations were de- clozapine concentration was reduced to 48.7 JLg/L.
termined in the patients <35 years old than in those The clozapine dose was increased to 500 mg/day
>45 years old (p < 0.01). Plasma clozapine con- with a resultant plasma concentration of 92.6 JLg/
centrations in men were only about 69.3% of those L. The second patient received clozapine 250 mg/
in women (p < 0.005). Bodyweight did not sig- day with a plasma concentration of940.5 JLg/L 12h
nificantly influence clozapine concentrations. The after the last dose. The patient had a tonic-clonic
Kinetics and Dynamics of Clozapine 167

seizure, was placed on phenytoin and a plasma clo- ever, since the 1980s, 5 dopamine receptor subtypes
zapine concentration obtained a week later meas- have been identified and their molecular structure
ured 334.7 JLg/L. Phenytoin and other anticonvul- cloned (Dearry et al. 1990; Meador-Woodruff &
sants are well known enzyme-inducing agents and Mansour 1991; Sokoloff et al. 1990; Sunahara et
coadministration with clozapine, thus, can result al. 1991; Van Tol et al. 1991; Zhou et al. 1990).
in decreased plasma clozapine concentrations. As The designations for these dopamine receptor sub-
noted in section 2.1, Cheng et al. (1988) included types are DI to Ds. Most of the investigations of
3 patients receiving anticonvulsants in a study of neuroleptic drugs such as clozapine have focused
the pharmacokinetics of clozapine. Clearance val- on their pharmacological actions at the DI and D2
ues in 2 of the 3 patients were higher [319 and 435 receptors. The molecular dynamics and 2 isoforms
ml/min (19.1 and 26.1 L/h)] than the mean value of the D2 receptor have been recently reported, as
of 217 ± 145 ml/min (13.0 ± 8.7 L/h) for the the binding of neuroleptic drugs occurs through
group. specific actions of protonated ligands and electro-
A case of cimetidine-induced clozapine toxicity static forces in the amino acid sequence of aspartic
has been documented (Szymanski et al. 1991). The acid 80 and asparagine 390 (Dahl et al. 1991; Giros
patient received clozapine 900 mg/day and aten- et al. 1989).
0101 50 mg/day. After a diagnosis of gastroesopha- The development of positron emission tomog-
geal reflux was confirmed, cimetidine 400mg 3 raphy (PET) and specific in vivo ligand binding
times daily was prescribed. Three days later, the methods over the past 10 years has led to further
patient complained of dizziness, vomiting, diapho- examinations of neuroleptic drug actions in the
resis, weakness and severe lightheadedness. Ci- central nervous system (CNS). So far, DI and D2
metidine was discontinued and the symptoms re- receptors in the human basal ganglia have been in-
solved. The clozapine dose was decreased to 200 vestigated for their relevance to mental disorders
mg/day and then gradually increased back to 900 (Sedvall 1990). The neuropharmacological mech-
mg/day. Ranitidine was added I week later with- anism of action of clozapine in relation to its ther-
out incident. Although plasma clozapine concen- apeutic efficacy in schizophrenia was originally
trations were not obtained before and after cimet- suggested to occur through its preference for DI
idine administration, various drug interactions with receptor vs D2 receptor binding affinity (Fitton &
cimetidine have been previously described and Heel 1990; J ann 1991 ). Using [II C]raclopride, the
clinicians should be aware of this potential prob- specific binding of neuroleptics agents including
lem. clozapine to the D2 receptor was investigated in
Benzodiazepines are often used as adjunctive psychiatric patients (Farde 1989; Farde et al. 1988).
medications or combined with clozapine in the The D2 receptor occupancy was lower with clo-
treatment of agitated patients and can potentially zapine (40%,300 mg/day) than with other standard
increase the sedation and other CNS-related prob- neuroleptics like haloperidol (86%, 12 mg/day) or
lems associated with clozapine therapy. chlorpromazine (80%, 200 mg/day). At a higher
dosage of clozapine 600 mg/day, the D2 receptor
5. Pharmacodynamics occupancy increased to only 65% (Farde et al.
5.1 Neuroreceptor Binding Affinity 1989).
In 25 patients with schizophrenia receiving a
5.1.1 Dopamine Receptors variety of neuroleptics, PET scans were conducted
In early receptor binding affinity studies that to assess both DI and D2 receptor occupancy (Farde
determined the relative potency of neuroleptic et al. 1992). The radioligands used were
drugs, clozapine was reported to be slightly less po- [11 Clraclopride for D2 receptors and [II ClSCH
tent than the standard comparative agent chlor- 23390 for D1 receptors. Five patients received clo-
promazine (0.79 versus 1.00) [Wyatt 1976]. How- zapine 300 to 600 mg/day, with plasma drug con-
168 Clin. Pharmacokinet. 24 (2) 1993

centrations ranging between 600 and 2500 nmol/ 5.1.2 Other Neuroreceptor Binding Affinities
L. DI receptor occupancy ranged from 36 to 52% Like other neuroleptic agents, clozapine pos-
and the D2 receptor occupancy was from 38 to 63%. sesses the properties to bind to various receptors.
Other neuroleptics administered included pheno- Clozapine was shown to have high binding affin-
thiazines, butyrophenones and thiothixenes. D I re- ities for muscarinic acetylcholine, histamine (H J},
ceptor occupancy was observed in only 5 patients and adrenergic a 1- and a2-receptors (Richelson
while every patient had a D2 receptor occupancy 1984). It was suggested that the adverse effect pro-
of at least 70%. II of these patients experienced file of clozapine could be partially related to these
receptor binding affinities.
extrapyramidal side effects (EPS), in contrast to
Before the discovery of the D4 receptor, cloza-
clozapine-treated patients who had no EPS. The
pine was shown to display potent binding affinity
investigators suggested that D2 receptor occupancy
for serotonin (5-HT) receptors. Like dopamine re-
without or with minimal DI receptor occupancy
ceptors, serotonin receptors exist in different sub-
could contribute towards the EPS effects of neu-
types and are designated as 5-HT 1,2 and 3. Within
roleptic drugs. the 5-HTI subtype, it can be further divided into
Binding to DI receptors was investigated using A, B, C, D and E types (Glennon 1990). Neuro-
[IIC]SCH 23390, as clozapine 300 mg/day and 500 leptic agents and the specific D I antagonists like
mg/day exhibited the highest DI occupancy rates SCH 23390 showed equal binding affinity for 5-
of 42 and 40%, respectively. Binding of other HT 2 as for DI receptors (Bischoff et al. 1986). Clo-
neuroleptic agents, such as thioridazine 200 mg/ zapine was reported to possess high binding affin-
day and perphenazine 16 mg/day, was reported to ities for 5-HT Ie and 5-HT2 receptors and moderate
be 29 and 0%, respectively (Wiesel et al. 1990). The affinity for 5-HT I receptors (Canton et al. 1990;
interactions between DI and D2 receptors are com- Wander et al. 1987).
plex and not fully elucidated, but on the basis of It is beyond the scope of this article to fully de-
animal models, most investigators agree that these scribe the complex interactions between the vari-
2 receptors interact in an oppositional and/or syn- ous neuroreceptors and other parameters including
ergistic manner in various biochemical measure- electrophysiological and behavioural studies that
ments or behavioural paradigms (Clark & White form the current model for the mechanism of ac-
1987). tion of clozapine. Other articles have reviewed these
Within the past 2 years, clozapine has been areas (Fitton & Heel 1990; Jann 1991; Meltzer
shown to bind with D3, D4 and Ds dopamine re- 1991). However, the suggested pharmacological ac-
ceptors (Sokoloff et al. 1990; Sunahara et al. 1991; tions of clozapine can be portrayed as a complex
Val Tol et al. 1991). Van Tol (1991) suggested that interaction between dopamine and serotonin
neuroreceptor systems which differs from other
the main actions of clozapine might occur through
neuroleptics.
the D4 receptor. The pharmacological character-
istics of the D4 receptor resemble those of the D2
5.2 Neuroendocrine Effects
and D3 receptors but the binding affinity of clo-
zapine for D4 receptors is I order of magnitude
5.2.1 Prolactin
higher. The dissociation constant of 9 nmol/L is It is well known that neuroleptic agents produce
suggested to be analogous to the plasma concen- a characteristic increase in prolactin release in hu-
trations of clozapine under therapeutic conditions. mans (Langer et al. 1977). Clozapine was reported
This linkage between a higher binding affinity and to increase serum prolactin levels in patients with
dissociation constant advocates that the main schizophrenia but the increase was significantly less
activity of clozapine could occur via the D4 re- than that produced by chlorpromazine (49.3 ± 23.3
ceptor. ILg/L vs 85 ± 35 ILg/L) [Meltzer et al. 1979]. Plasma
Kinetics and Dynamics of Clozapine 169

prolactin samples were obtained Ilh after the through to day 21. Plasma HVA decreased during
evening dose. In the second phase of that study, 4 clozapine therapy and early investigations suggest
patients had an indwelling catheter through which that a correlation exists between improvement in
prolactin levels were measured up to 4h after clo- clinical response and plasma HVA levels (Green et
zapine administration. Plasma prolactin levels rose al. 1991).
during the first 2h, dropped for the third hour and
increased again during the fourth hour. Maximum
6. Clozapine Blood Concentrations and
prolactin levels were about 60 ILg/L.
Plasma prolactin levels and clozapine concen-
Clinical Response
6.1 Short Term Studies
trations were reported in 2 case reports during clo-
zapine treatment (Kane et al. 1981). In I patient
blood samples were obtained for up to 70 days while Only a few studies have examined the relation-
they were collected in the other patient for 105 days. ship between clozapine plasma concentrations and
Blood samples were obtained 12h after the evening clinical response in patients with schizophrenia.
dose, before the morning dose. In the first patient, Table III summarises the clinical trials investigat-
clozapine doses were increased to the 60th day with ing clozapine plasma concentrations in psychiatric
subsequent increasing plasma prolactin levels. Pro- patients. Only I study used a fixed daily dose with
lactin levels remained stable, although 2 elevations clinical evaluations obtained at baseline and days
occurred at days 10 and 40. The second patient 5, 10, 20 and 30 (Ackenheil et al. 1974). Patients
displayed a similar profile with elevated prolactin were evaluated with the AMP scale [similar to the
levels at days 20 to 40, 60 and 90. The investiga- Brief Psychiatric Rating Scale (BPRS) developed in
tors noted that the effects of clozapine on serum the early 1970s]. Plasma clozapine concentrations
prolactin levels differ from those of other neuro- reached a plateau by day 10. Overall clinical im-
leptics. The elevations produced by clozapine ap- provement was observed; however, no detailed an-
pear to occur transiently within the first several alysis of plasma clozapine concentrations and the
hours after drug administration and exhibit peri- change in AMP scores was provided. The inves-
odic elevations during long term therapy. tigators stated that in 4 patients, no correlations
between plasma concentrations and clinical re-
5.2.2 Homovanillic Acid sponse were seen.
Homovanillic acid (HVA) is a dopamine me- In a subsequent study with a larger number of
tabolite which also increases during neuroleptic patients and a variable daily dosage schedule, Ack-
treatment. HV A levels have been measured in enheil et al. (1976) reported a lack of correlation
plasma, CSF and urine in psychiatric patients. between plasma concentration and clinical re-
Transient increases in brain and plasma HV A lev- sponse. AMP evaluations were obtained at base-
els up to 3h after drug administration have been line, days 3, 6, 10, 15, 20 and 30. This analysis
reported in rats and humans (Ackenheil 1989; included the degree of change in AMP scores vs
Chang et al. 1987). In 9 patients with schizophre- plasma concentrations. Specific items in the AMP
nia, urine and CSF HVA levels were measured scale such as paranoid-hallucinatory syndrome, de-
during 20 days of clozapine treatment (Ackenheil pressive and manic syndromes were also evaluated
et al. 1976). No changes in urine HVA occurred and no correlations were found. Finally, in the last
before and after clozapine. On the other hand, CSF phase of that study which included 6 additional
HVA levels increased by 114% and no correlation patients, Brau et al. (1978) reported similar find-
was found between urine and CSF levels. In con- ings except for a positive linear correlation (p <
trast, clozapine was reported to decrease CSF HV A 0.05) between paranoid-hallucinatory scores and
levels by 34% (p < 0.05) after 4 days of treatment. plasma clozapine concentrations on day 3. Other
The decline (23%, p = not significant) continued correlations between clinical response for the re-
170 Clin. Pharmacokinet. 24 (2) 1993

Table III. Relationship between blood concentrations of clozapine and clinical efficacy in patients with schizophrenia

Reference No. Length of Dosage Cp Comments

of pts study (mg/day) (llg/L)
(days)

Ackenheil et al. (1974) 4 30 300a 200-600 Two patients did not respond, improvement
noted to occur by day 10
Ackenheil et al. (1976) 26 30 100-600 100-800 No significant relationship found between
clinical response or side effects
Bruau et al. (1978) 32 30 100-600 100-800 Continuation study of Ackenheil et al.
(1976) with similar results
Perry et al. (1991) 29 28 384 ± 42b >350 A minimum threshold was reported in
refractory schizophrenics

a Fixed daily dose.

b Mean ± SO.
Abbreviation: Cp = plasma concentration.

maining periods and plasma concentrations were ing, those who had not responded to haloperidol
not found. were assigned either clozapine up to 900 mg/day
Ackenheil (1989) reported the evaluation of a or chlorpromazine up to 1800 mg/day (Kane et al.
V-shaped relationship between clozapine and 1988). Patients were then assigned to prospective
clinical response. The plasma concentrations were haloperidol treatment, with dosages up to 60 mg/
stratified into 3 groups: <30, 30 to 100 and> 100 day. Clozapine was shown to be effective in 30%
JLg/L. In all 3 groups, a significant improvement of these refractory patients compared with only 5%
was found in the psychopathological syndromes. of chlorpromazine-treated patients. To mask the
This finding is not surprising, as the strata for the potential extrapyramidal side effects of chlorprom-
3 groups were below the minimum plasma con- azine, each patient received benztropine 2mg 3
centrations noted in the previous studies. The mean times a day. No other routine medications were
value for the > 100 JLg/L group was not reported allowed.
and may have been less than 600 JLg/L. In conclu- Perry et al. (1991) measured clozapine and de-
sion, the studies conducted in psychiatric patients methyl-clozapine plasma concentrations in patients
examining the potential relationship between with refractory schizophrenia. Patients were eval-
plasma clozapine concentrations and clinical re- uated at baseline and at weeks 1, 2, 3 and 4 by the
sponse have not provided consistent results. BPRS. Blood samples were obtained at the same
times. 11 patients were clozapine responders (de-
6.2 Treatment of Patients with fined as 20% or greater decrease in BPRS score) as
Refractory Schizophrenia their mean BPRS scores decreased from baseline
(46.0 ± 8.9) to week 4 (29.8 ± 2.6). Corresponding
Clozapine is clearly an effective neuroleptic agent plasma clozapine and demethyl-clozapine concen-
for the treatment of schizophrenia (Fitton & Heel trations for the responding patients were 404 ±
1990; Jann 1991). In patients with refractory 199 and 123 ± 70 JLg/L, respectively. In the non-
schizophrenia, defined as over the preceding 5 responding patients (n = 18), BPRS scores at base-
years, at least 3 periods of treatment with other line were 57.4 ± 8.6 and at week 4, were 44.9 ±
neuroleptic agents from 2 different chemical classes 7.7. Mean plasma clozapine and demethyl-cloza-
at dosages greater than 1000 mg/day of chlorprom- pine concentrations in the nonresponders were 356
azine equivalents and no period of good function- ± 255 and 112 ± 63 JLg/L, respectively. The in-
Kinetics and Dynamics of Clozapine 171

vestigators suggest that a minimum of at least 350 7. Adverse Effects

JLg/L of clozapine or a combined total (clozapine
plus demethyl-clozapine) of 450 JLg/L was needed There are numerous adverse side effects that oc-
to achieve a therapeutic threshold concentration. cur with clozapine therapy. Only the adverse ef-
An upper therapeutic limit was not proposed; how- fects that have been associated with clozapine
ever, several patients with plasma clozapine con- plasma concentrations are discussed in this sec-
centrations >600 JLg/L appeared not to benefit from tion. For a complete presentation of the adverse
clozapine treatment. One patient had a plasma clo- effects of ciozapine, the reader is referred to the
zapine concentration of 1088 JLg/L and de methyl- reviews of Fitton & Heel (1990) and Jann (1991).
ciozapine concentration of 272 JLg/L and the BPRS
scores slightly increased from 51 at baseline to 55 7.1 Haematological
at week 4.
In another study of patients with refractory The main problem with clozapine which re-
schizophrenia, ciozapine was evaluated in a similar sulted in its earlier withdrawal from the US market
fashion, but with significant differences compared has been the occurrence of blood dyscrasias that
with the Kane (1988) study (Pickar et al. 1992). inciude granulocytopenia and agranulocytosis (Saf-
After 'long term' use of neuroleptics, 21 patients ferman et al. 1991). Systematic haematological
received mean dosages of fluphenazine 28.9 ± 21.2 monitoring programmes were established in vari-
mg/day for an average of 45.8 ± 15.8 days. Patients ous countries in order to minimise this problem
then received placebo for 17 to 55 days (mean 37.1 (Grohmann et al. 1989; Hummer et al. 1991; Krupp
& Barnes 1989; Peacock & Gerlach 1991). The de-
± 11.3 days). Subsequently, patients were started
on moderate dosages of ciozapine (mean 373.8 ± tection of agranulocytosis was generally quite low
«1.0%) with weekly or monthly monitoring. The
110.8 mg/day) for 50 days, after which each
mechanism for clozapine-induced agranulocytosis
patient's dosage was increased to the optimal (mean
remains to be elucidated but appears to involve the
S42.9 ± 207.4 days) for an additional SO days.
immune system and differs from the mechanism
Plasma clozapine concentrations obtained 1 week
of chlorpromazine-induced agranulocytosis (Claas
after the optimal dosage ranged from 119.0 to 2167
1989; Lieberman et al. 1988). This haematological
JLg/L (mean 439.1 ± 430.7 JLg/L). Eight patients
abnormality could have a genetic basis as the oc-
benefited from ciozapine therapy, with reduced
currence of agranulocytosis w~s reported to occur
mean BPRS scores from baseline (placebo) after among Jewish and Scandinavian populations (Jann
the optimal dosage (7S.6 ± 20.2 vs 48.3 ± 10.2). 1991; Lieberman et al. 1988). A preliminary study
No significant correlations between clinical re- with human leucocyte antigen (HLA) typing sug-
sponse (responders vs nonresponders) and cloza- gests that a certain combination of alleles B38, DR4
pine dosage could be determined. Monoamine me- and Dqw3 in Jewish persons could predispose them
tabolite plasma levels were also measured, including to developing agranulocytosis (Lieberman et al.
HV A, prolactin and cortisol. CSF levels of HVA, 1990). Clozapine is the second most popular neu-
the serotonin metabolite S-hydroxyindole acetic roleptic agent in the People's Republic of China
acid (S-HIAA) and 3-methoxy-4-hydroxyphenyl- (PRC). No cases of agranulocytosis were reported
glycol (MHPG) were obtained in II patients. No among 290 clozapine-treated Chinese patients
significant differences were measured between pla- (Potter et al. 1989). Thorp and Fog (1977) reported
cebo and clozapine periods regarding plasma pro- no relationship between plasma clozapine concen-
lactin. Plasma HVA and serum cortisol levels were trations and blood coagulation factors in 11 patients
lower (p < O.OS) during ciozapine than placebo with schizophrenia. Treatment for clozapine-
treatment. Superior clozapine response occurred induced agranulocytosis is mainly supportive;
when CSF HVA/S-HIAA ratios were low (p < O.OS). however, I case report documented the use of
172 Clin. Pharmacokinet. 24 (2) 1993

granulocyte and monocyte colony stimulating fac- Table IV. Plasma and urine concentrations of clozapine and its
tor (GM-CSF) in successfully elevating blood counts metabolites in an overdose patient receiving clozapine 10g (after
Pall et al. 1976)
from 63/mm 3 to over ISOO/mm 3 within S days
without adverse drug effects (Barnas et al. 1991). Days after Cp Ae
ingestion (I'g/L) (mg/vol)
7.2 Orthostatic Hypotension
1 2190 106.61
2 2170 41.70
Two studies report a positive correlation be- 3 620 20.30
tween orthostatic hypotension and plasma c1oza- 4 630 11.60
pine concentrations (p < O.OS) [Ackenheil 1989; 5 170 12.20
6 90 16.20
Klein et al. 1980]. In 12 patients with schizophre-
7 320 2.40
nia, this correlation occurred at day 6 (r = 0.83, p
< 0.05) and day 10 (r = 0.72, p < O.OS) of treat- = plasma concentration; Ae
Abbreviations: Cp = amount excreted
unchanged in the urine.
ment (Ackenheil 1989). Unfortunately, the actual
data were not presented; therefore, interpatient
variability could not be observed. Norris and Is-
raelstam (197S) reported 3 cases where severe the patient had a grand mal seizure. An hour after
orthostatic hypotension occurred and resulted in the seizure, plasma c10zapine concentration meas-
fainting. One of the 3 patients received only c10- ured 1313 J.Lg/L. A pill count showed that the patient
zapine 2Smg 3 times a day. ingested approximately 2000mg in excess of the
prescribed amount. The second patient was pre-
7.3 Seizures scribed c10zapine 350mg twice daily and acciden-
tally ingested 700mg within I h. Within 2h, the
Neuroleptics drugs are well known to lower the patient had a seizure and the plasma c10zapine
seizure threshold (Cold et al. 1990). The incidence concentration measured 2194 J.Lg/L. The investi-
of seizures with cIozapine in 1418 patients was re- gators suggested that high cIozapine plasma con-
ported to be 2.8% (Devinsky et al. 1991). Life-table centrations could lead to seizure activity. In con-
analysis predicted a cumulative risk of seizures of trast to those reports, Haring et al. (1991) described
10% after 3.8 years. Clozapine-related seizures also the effects of plasma c10zapine concentrations upon
appear to be dose related as the prevalence was EEGs in 29 patients. CIozapine dosages ranged from
reported to be 1% at dosages <300 mg/day, 2.7% 2S to 600 mg/day. All patients had normal EEGs
at dosages of 300 to 600 mg/day and 4.4% at dos- before c1ozapine. During treatment, the patients
ages of >600 mg/day (Devinsky et al. 1991; Saf- were divided into 2 groups: (a) pathological changes
ferman et al. 1991). Tiihonen et al. (1991) reported (n = IS) and (b) no changes (n = 14). Discriminant
that in IS patients with schizophrenia all had dis- analysis showed that EEG changes were dependent
turbed electroencephalographic (EEG) background on plasma c10zapine concentrations (p = 0.0009).
activity during c10zapine treatment. Before c1oza- However, mean plasma c10zapine concentrations
pine, EEGs were normal. Ten patients had epilep- were lower in the patients with pathological changes
tiform discharges with a mean c10zapine dose of than in those with no change (81.6 ± 64.6 vs 23S.7
S30 mg/day and 2 patients experienced seizures. ± 169 J.Lg/L).
Simpson and Cooper (1978) reported 2 case re- If a patient experiences a seizure during c1oza-
ports of c1ozapine-induced seizures and associated pine treatment, anticonvulsant medications such
plasma c10zapine concentrations. The first patient as phenytoin have been recommended (Haller &
received 800 mg/day and had plasma concentra- Binder 1990). However, clinicians should be aware
tions of ",,600 J.Lg/L. Due to a panic attack, the dose of the potential for drug interaction between these
was increased to 900 mg/day, and within 1 day, 2 agents (see section 4.3).
Kinetics and Dynamics of Clozapine 173

7.4 Overdosage immunological and neurophysiological dysfunc-

tions (Ad Hoc Committee 1987). Like other neu-
Case reports of clozapine overdose have de- roleptic agents, clozapine possesses significant
scribed symptoms of drowsiness, agitation, dis- binding affinity for dopamine receptors. It was
orientation, hypersalivation, delirium, tachycardia, originally thought that the novel therapeutic ac-
coma and respiratory depression. Physostigmine tions of clozapine occurred via its slightly higher
2mg intravenously has been reported to reverse the specificity for the DI receptor, but recent investi-
central anticholinergic toxicity of clozapine (Schus- gations have cloned 5 dopamine receptor subtypes.
ter et al. 1977). Clozapine overdosages < 1000mg Clozapine has been reported to display significant
could have a highly variable effect as the patient binding affinity for the D4 and 5-HT2 receptors at
may have mild symptoms of stupor (Levinson therapeutic plasma concentrations. The interaction
1975) or experience seizures (see section 7.3). Pall between the various dopamine and serotonin re-
et al. (1976) described a case report in which a ceptors most probably accounts for the pharma-
patient ingesting clozapine 109 was unconscious and cological activity of clozapine or other neuroleptics
required ventilatory support. In addition to these in the regulation of dopaminergic function (Grace
symptoms, the patient experienced pulmonary 1991). However, clozapine differs from other neu-
oedema in both lungs, for which furosemide (fru- roleptics in that a causative relationship to tardive
semide) therapy was ineffective. Intravenous dyskinesia has not yet been established and the oc-
methylprednisolone 500mg was administered and currence of acute extrapyramidal syndromes is in-
within 24h the respiratory problems resolved. Three frequent (Casey 1989). In fact, some reports have
days later, the patient was removed from the re- suggested that clozapine treatment has reduced the
spirator and discharged from the ward. Concentra- dyskinetic movements of tardive dyskinesia in-
tions of clozapine and its demethyl and N-oxide duced by other neuroleptic agents (Lieberman et
metabolites were monitored in the plasma and urine al. 1989; Small et al. 1987).
during the clinical course. Concentrations reported Clozapine is an effective agent for the treatment
in total amounts and not delineated between par- of acute and chronic schizophrenia (Fitton & Heel
ent drug and metabolites are shown in table IV. 1990; Jann 1991). The continued therapeutic bene-
The total plasma drug concentration 24h after fit of the drug and tolerability to its adverse effects
ingestion was 2130 ,."g/L and by day 7 measured in psychiatric patients are well documented (Juul
320 ,."g/L. It is interesting that plasma drug con- Povlsen et al. 1985; Leon 1979; Lindstrom 1987).
centrations were lower on days 5 and 6 than on Clozapine is effective in treating refractory schiz-
day 7. The urinary excretion data were similar to ophrenia (Kane et al. 1989). Therefore, the drug
the plasma concentration results except for an in- can be used in selected patients who have experi-
crease in the urinary amounts on day 6, with lower enced severe extrapyramidal side effects that in-
concentrations measured during the 2 previous terfere with their daily functions while taking other
days. These results suggest the possibility of neuroleptic drugs or in patients who have not re-
enterohepatic recycling when oscillating drug con- sponded to other neuroleptics (Marder & Van Pat-
centrations are observed during withdrawal. ten 1988).
The pharmacokinetic parameters of clozapine
8. Conclusions have been characterised in adult populations. Fu-
ture investigations should include children, ado-
The reintroduction of clozapine to the US has lescents and the elderly. Clozapine is only available
generated renewed interest in the development of in an oral preparation. A therapeutic plasma con-
innovative neuroleptic agents for the treatment of centration range has not been established for the
schizophrenia. Schizophrenia is a complex disease drug, but a minimum therapeutic threshold ap-
with a heterogeneous biology that includes genetic, pears to be ,., 100 ,."g/L and an upper limit has not
174 Clin. Pharmacokinet. 24 (2) 1993

Breyer U. Villumsen K. Measurement of plasma concentrations

been established. Preliminary evidence suggests that of tricyclic psychoactive drugs and their metabolites by UV
in patients with refractory schizophrenia, at least reflectance photometry of thin layer chromatography. Euro-
pean Journal of Clinical Pharmacology 9: 457-465. 1976
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Pharmacology 191: 93-96.1990
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kinesia. Psychopharmacology 99: S47-S53. 1989
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concentrations has not been established but this is vanillic acid in caudate and prefrontal cortex following acute
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