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Monitoring of haloperidol serum levels and it's clinical significance
Prog. Neuro-Psychopharmacol & Biol. Psychiot. 1984, VoI. 8. pp. 51-62
0278-5846/84 $0.00 + .50
Printed in Great Britain. All rights reserved.
Copyright ~ 1984 Pergamon Press Ltd.
MONITORING OF HALOPERIDOL SERUM LEVELS AND IT'S CLINICAL SIGNIFICANCE
HITOSHI ITOH*, GOHEI YAGI*, MASATO TATEYAMA*, YASUO FUJII*, KENICHIRO IWAMURA** and KAZUO ICHIKAWA** * Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo ** Department of Internal Medicine, School of Medicine, Tokai University, Kanagawa, Japan
(Final form, March,
1983)
Abstract Itoh, Hitoshi, Gohei Yagi, Masato Tateyama, Yasuo Fujii, Kenichiro Iwamura and Kazuo Ichikawa: Mcnitoring of halc~eridol ser~n levels and it's clinical significance. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1984, 8(1): 51-62. i.
2. 3. 4. 5. 6.
Haloperidol serum levels were determined by the recently developed radioimmunoassay technique to elucidate the relationship between serum levels and clinical effects and that between serum levels and adverse effects. The serum levels of haloperidol in divided daily doses schedule reached to the steady state more rapidly (within 7 days) than in single dose schedule. The single daily dose schedule showed significantly wider diurnal variation than the divided daily doses schedule. No remarkable differences in serum concentration was noted between different types of oral haloperidol preparation (liquid, granule, tablet). No definite relationship was established between the serum concentration of haloperidol and incidence of tardive dyskinesia. No definite positive relationship between clinical effects and serum concentration of haloperidol could obtained.
Keywords: absorption of haloperidol preparation, clinical effect, haloperidol, immunoassay, serum concentration, steady state, tardive dyskinesia. Abbreviation: area under curve pyramidal symptoms (EPS).
(AUC);
brief psychiatry
rating scale
(BPRS);
radio-
extra-
Introduction Expeditious progress has been made to the present in drug therapy for psychotic disorders, yet, the present stage still does not permit to obtain sufficient data that will facilitate assessment of clinicopharmacologic effects of drugs on scientific bases. In recent years, increasing attention has become focused on the study of measurement of plasma levels of psychotropic drugs with a view to contributing toward elucidation of the pathophysiology of psychoses as well as to expediting advances in medicinal treatment of these diseases in more scientific ways (Burrows, 1971; Lader, 1976; Ziegler, 1978; Morselli et al., 1980). Gas chromatography with a high degree of assay sensitivity modified for measurement of drug concentrations and various other techniques such as radioimmunoassay, radioreceptorassay and enzyme-immunoassay have become applied to determination of concentrations of antiepileptics, antidepressants, anxiolytics, lithium and antipsychotics in blood specimens. As yet, there is no unified view as to clinical significance of data on plasma levels of antipsychotic drugs and this still remains a subject of much controversy. The metabolism
51
52
H. Itoh et al.
of phenothiazines in human body is extremely complicated. With chlorpromazine, for example, more than I00 metabolites were shown to form besides the parent compound following administration. This made it difficult to draw a sound conclusion as to interrelation between their plasma levels and clinical and adverse effects (Lader, 1976). Administration of haloperidol yields relatively few metabolites which are devoid of psychopharmacologic activity, thus rendering it practicable to assess the interrelationship of plasma drug concentration and clinical effects. There have been intensive pursuits of clinical study on plasma concentrations of haloperidol since late in the 1970's (Forsman et al., 1974a, 1974b, 1977a, 1977b; Cressman et al., 1974; Ericksen et al., 1978; Tune, 1980). The present authors conducted a series of studies by the recently developed radioimmunoassay technique to delineate characteristics of plasma concentration patterns of haloperidol following various oral dosage schemes as well as to clarify the interrelation between plasma drug concentrations and dosage, clinical effects and adverse reactions (Rubin et al., 1980). The results were presented in part before the llth and 12th C.I.N.P. Congress as follows (Itoh et al., 1980a, b). I) The blood haloperidol concentration reaches its peak 6 hours after administration and then declines gradually to half the peak level at 12 to 24 hours; 2) In the long-term medicated patients, there exists a significant positive correlation between the blood concentration and the daily dose per kg of body weight of haloperidol; 3) The daily variation in the blood concentration is significantly narrower when haloperidol is administered in divided doses than when it is given at a time; 4) Extrapyramidal symptoms (EPS) often develop at a basal blood haloperidol level of I0 ng/m£ or over and at a peak level of 20 ng/ml or over, unless haloperidol is given in combination with antiparkinsonian drugs; and 5) Antiparkinsonian medication generally does not interfere with the blood level of haloperidol. This paper represents a further attempt to obtain blood haloperidol concentration data useful for management of haloperidol therapy in daily clinical practice.
Materials and Methods i.
subjects 166 cases material used in these study consisted of chronic inpatients from ten mental hospitals.
2.
Drug administration 166 patients had been flexible medication for various period.
3.
Study design The contents of our present study consisted of four parts. Ist study ..... comparison of the blood concentration pattern between different administration schedules. 2nd study ..... influence of alteration in form of haloperidol preparation. 3rd study ..... steady state of serum haloperidol concentration, and relationship between serum level and incidence of EPS in longitudinal observation. 4th study ..... relationship between serum concentration of haloperidol and clinical response, and serum level after withdrawal of medication.
4.
Blood level determination Serums were separated and kept in frozen storage. The r a d i o i ~ u n o a s s a y technique employed for determination of the serum level of haloperidol was a modification of the method of Michiels (Janssen group). (Michiels et al., 1976).
Results and Discussion i.
Number of daily divided poses and ~attern of daily variation in blood d ru~ co.nceqtration The blood concentration pattern of haloperidol varied with the number of daily divided doses in three groups of patients undergoing long-term oral haloperidol therapy, as
Haloperidol
serum levels and it's clinical significance
53
shown in Figure i. There was a distinct tendency for the amplitude of within-day variation (difference between peak and lowest concentrations) in serum drug concentration to diminish with increasing number of daily divided doses. Analysis of blood haloperidol concentration data from 38 patients receiving chronic oral medication disclosed a significantly higher rate of elevation of serum drug concentration (= ~peak conc.-lowest conc.)/(lowest conc.)] x I00) in a group given the drug in single daily doses than other groups receiving two or more divided doses. A further assessment of the interrelationship in an increased number of 133 cases confirmed the finding; the mean range of within-day variation in serum haloperidol level was significantly greater in a group receiving single daily doses as compared to other groups given the drug in three to four divided doses daily (Fig. 2).
Drug Administration
Drug administration
ng/ml~
ng/mlI
,°I
40.
45
//,o
Y':::. 20-
\.~ o '":~'-. "-.
,o.
",.',..
"-..-..,,-
2o-~
I0-
~
2
V" '//,o0
25
31o 3.0 40
10
6 a) once a day
b) twice a day
Drug administration
ng/mi 201
0?'5
~ 0
6
12
18
24h
C) three time a day Fig. I.
1'2 1'8
Comparison of the blood concentration pattern between different administration schedules.
24 h
54
H. Itoh et al.
.45.0 rig/.,~
so.
0
20.
~
I0.
.i 4"
.E g
|
o
L,.
~ --I0 9.6+0.0 once/day N=9 ~NS
Fig. 2.
5.0±7,5 4.5::E5,1 2.9+4.2 two times/day three times/day four times/day N=56 N=62 'P- 0.025 P, 0.051
N= 6
Comparison of the range of variation in serum concentration of haloperidol between different administration schedules.
Inasmuch as the group receiving haloperidol in daily four divided doses in that assessment, a reassessment was carried out to compare the within-day variations in a group with single daily dosage and a group of increased number of cases with four divided daily doses. Samples of blood were collected before the dose or an initial dose of the day (basal serum drug level) and at periods when a peak serum level was estimated to be seen from the preceding studies, i.e. 6-7 hours after a single daily dose or 1-2 hours after a fourth divided dose, as in the foregoing assessment. The daily dosage of haloperidol tended to be inevitably greater in the cases receiving four divided daily doses than in the single daily dose group, with a significant inter-group difference (0.162 + 0.085 mg/kg vs. 0.079 + 0.045 mg/kg, p < 0.01), since the patients were selected from among those being-treated in daily clinical practice. Their serum drug concentrations were, therefore, corrected according to actual dosage to calculate the range of within-day variations. The results are shown in Figure 3. As can be noted, the group receiving haloperidol in four divided doses daily displayed apparently smaller within-day variations, thus confirming the findings in our previous observations. It would be seen that administration of the drug in daily divided doses is more advisable in routine practice from the viewpoint that untoward side-effects such as extrapyramidal symptoms which interfere with antipsychotic drug treatment tend to arise once its blood concentration has exceeded a certain level.
Haloperidol
serum levels and it's clinical
significance
55
[mean±S.D.~ pg/ml/dose 150-
[56.6_+30.0) N=24
[25.3+13.3) N=I4
| _o
100-
e
@
E e
._c
50-
II
e
I1 "6
$ e
once/day
four times/day
[__r:,. o.o1--1 Fig. 3.
2.
Comparison of the range of variation in serum concentration of haloperidol between once daily administration and four times daily administration.
Influence of alteration in form of ~reparation Haloperidol is currently available in many different forms of pharmaceutical preparation, such as tablets, powder, liquid, injectable solution and injectable depot preparation. Assessments were made to ascertain whether there might be any particular problem in alteration of the form of oral haloperidol preparation in patients undergoing treatment. Pharmaceutical manufacturers usually secure preclinical data on bioequivalence of a drug in animals and in human volunteers prior to introduction of different forms of preparation for clinical use. The following study was designed on the assumption that no such assessment of bioequivalence might have been done for haloperidol in psychiatric patients. In a series of twenty patients having been receiving a 10-fold dilution of a haloperidol liquid preparation over an extended period, the serum drug concentrations were determined following replacement of the regimen with equivalent doses of haloperidol tablets, fine granules and a higher concentration (1:5 dilution) and lower concentration (1:20 dilution) of the liquid preparation. As shown in Figure 4, there was generally no conspicuous change in blood level of the drug as assessed at 4 days after alteration in form of oral preparation. Figure 5 illustrates the patterns of serum drug level changes observed in a patient given haloperidol liquid and fine granules by cross-over design in doses of 6 mg. The peak time was slightly delayed with the liquid form but the AUC did not differ appreciably between the two forms of oral preparation. Despite our expectation that the liquid form might show a better absorption following administration , the data have indicated that both forms are absorbed at comparable rates as far as haloperidol is concerned. However, there are pharmaceutical preparations of haloperidol by several different manufactures in this country. Evaluation of such preparations to detect inter-brand differences would be necessary in view of the fact that tablet and powder forms of phenytoin and clofibrate vary in rate of absorption with some of the brands. The serum drug level that yields from administration of the depotpreparation may also become an important subject of investigation.
56
H. Itoh et al.
ng/ml
ng/,,,I
ng/ml
ng/ml 12mg/day
60-
60"
15mglday 8060
1 / 2mg/day 40 40
8mg/day
+............ +
40
60
]2rag/day
12mg/day
/ .12rag/day .---4
~.,~/day
12mg/day
~
+ ....... +
~
6 .r. . n. . . .~. . . 4. 20
20-
40
8mg/day 20
•/
(lOx)
~ Y Liquid ---*powder Liquid"--"High (10x) (10x) Liquid
15mg/day
12mg/day +..... + average Level
12rag/day
Li quid----~Tablet
Fig. 4.
~
day
Liquid (lOx)
• L;w
Liquid (20x)
(Sx)
4 days after the change of preparations•
Serum levels:
~- 50 years old body weight 50kg
ng/mE15.
--
-- Granule(G)
X. . . . "!,( Liquid (L) AUCG=108.35 55
o
2
~
.
A U C L = ]0 8
Peak time G=4 hour I L=6 hour , j G=7.2 t2 I L=7.8
,
",
5
•
,
6
,
12
,
18
i
24 hour
time after single oral administration Fig. 5.
S e r u m levels of h a l o p e r i d o l after single oral a d m i n i s t r a t i o n at a dose of 6 m g in the form of g r a n u l e and liquid.
Haloperidol
3.
serum levels and it's clinical significance
Steady state of serum ha loperidolconcentration in longitudinal observation Serum basal levels of haloperidol were followed serially (days O, 3, 7, 14 and 28) after initiation of oral medication with tablets in single daily doses or in three divided daily doses in 23 patients. The dosage was 6 mg per day as a rule but might be individualized according to the patient's conditions, although kept fixed at least for the first one-month period in every case. No restriction was posed on concomitant use of other neuroleptios while the use of antiparkinsonian drugs was withheld until development of extrapyramidal symptoms. The observation revealed that the basal serum level of haloperidol attained a plateau 7 days after start of oral medication (Figure 6). In Figure 7, the data from the cases stratified according to the number of divided daily doses are illustrated. With single oral doses, the blood level appeared to have not necessarily reached a steady state by Day 7 of medication but to be slightly delayed, whereas with three divided doses, it can be said that a steady state was accomplished by this period. Thus, administration in divided daily doses affords a faster attainment of a steady state of basal serum drug concentration.
ng/ml
~ mean_+S. E. N=23
I o
-}
io
doses a day (mean_+S. D) 1
I
0.101_+0.043mg/kg J
0
days of drug treatment Fig. 6.
4.
57
day.
Time required to reach steady state serum level of haloperidol after successive oral administration.
Interrelation between serum level and incidence of extrapyramidal symptoms Twenty of these patients excluding 3 who had extrapyramidal symptoms already at initiation of the oral haloperidol therapy were classified into two groups, i.e. those who developed any of such symptoms as akathisia, parkinsonism and acute dystonic reaction following the treatment and those who did not, and their patterns of changes in serum basal level compared. The latter group exhibited a mean basal level of about
58
H. Itoh et al.
three tiros daily administration ng/mt
N=15
20
÷ Fig. 7.
•.,e... once daily administration N=7
Comparison of the time required to reach steady-state serm. level of haloperidol between different administration schedules.
mean-i-S. E.
I.
T
o
.c
10-
"6 I I I I I I • I I I I
S Doses a day (mean-t-S D )
I
l
three times daily administration : 0 112-10.043mg/kg once daily administration : 0. 088 + 0 033mg/kg
0|
o
ng/ml
~
~
,'4 days of drug treatment
2,
20-
2'e day
Fig. 8. + Serum levels of haloperidol in patients after successive oral administration in relation to the incidence of EPS.
o
EPS (--) cases
"5 10'
E
/
I !
0 0
mean-f S E.
~
1'4
2',
~8 N.S.
t-test days of drug treatment
Haloperidol serum levels and it's clinical significance
59
I0 ng/m£ during the observation period of 28 days, compared to a mean level in the region of 20 ng/m£ in the former group (Figure 8). The mean serum drug concentration of the patients during manifestation of extrapyramidal symptoms was calculated to be 20.0 + 4.0 ng/mZ. In contrast, the mean of highest serum basal levels was 11.7 + 2.4 ng/m£ in the patients who did not develop such reactions and their serum levels at Day 28 averaged at 10.4 + 2.6 ng/m£. The data seem to show that monitoring of blood haloperidol concentration provides adequate information for prediction of development of extrapyramidal symptom. 5.
Relation between serum haloperidol level and incidence of tardive dyskinesia Tardive dyskinesia was found p r e s e n t in 14 patients and suspected in 7 patients among those who were undergoing long-term treatment with haloperidol. We assessed their basal serum levels of haloperidol in comparison with those of patients without such complication. As shown in Figure 9, no definite relationship is established between the serum concentration of haloperidol and the incidence of tardive dyskinesia. The mean of haloperidol serum level in the tardive dyskinesia-positiv e group is 26.7 + 18.4 ng/m£, in the tardive dyskinesia-suspected group 17.9 + 9.7 ng/m£, and in the tardive dyskinesia-negative group 39.4 + 36.9 ng/m£. And, the mean daily doses of haloperidol in these groups were 174 ~ 94 ~g/kg and, 116 ~ 63 ~g/kg and 217 + 197 ~g/kg, respectively. A variety of factors may probably be involved in the development of side-effects that are associated with long-term therapy; hence unpredictable merely from serum drug concentration data.
6.
Clinical response and serum haloperidol level Some of the studies reported in the literature purport to demonstrate correlation of the clinical effect and serum levels of haloperidol while others present data which defy such interrelationship; there has been no unified conclusion in this respect. Investigations on this subject are also in progress at the author's department. The results heretofore obtained have failed to show any definite interrelationship between the BPRS total score and the serum basal level of haloperidol in a series of 20 cases under treatment. That is, the patients with lower BPRS total scores did not necessarily show higher serum levels of the drug, nor did those with higher scores display lower serum concentrations (Fig. i0). A previous clinical observation of 9 patients undergoing haloperidol therapy with oral dosage of 3-9 mg q.d. over periods of several months revealed that the psychotic condition was markedly improved in 1 case, moderately improved in i, unimproved in 4 and worsened in 4 by overall assessments of the therapeutic response. And, there was no significant interrelation between the clinical response to haloperidol therapy and the serum level of the drug. These findings seem to stress importance of further pursuit of study in full detail on the relationship of blood levels and serial changes in BPRS and other parametric scoring on various psychiatric and behavioral rating scales in order to attain a more precise conclusion as to interrelation of serum concentrations and clinical effects of the drug.
7.
Serum level after withdrawal of medication Another problem of profound interest to the clinician would be the question of how long the drug administered remains in the circulating serum after the medication is discontinued. Figure Ii shows pertinent data from 4 patients followed in our clinic by periodic measurements of serum levels. As can be noted, it took 2-4 days after withdrawal for the serum haloperidol level to decline to half the basal level during 2- to 4-week medication, and it was not until more than i0 days had elapsed after withdrawal that the drug became scarcely demonstrable in the circulation.
60
H. Itoh et al.
ng/m~ 150"
o. o --~ 1"
100Tardlve Dyskmesla • Negat,ve N=24 ,~. Suspected N----7 O Positwe N~I4
o
u') ~'
5og
•
o
o
o
÷ Fig. 9. R e l a t i o n b e t w e e n serum conc e n t r a t i o n of h a l o p e r i d o l and i n c i d e n c e of tardive dyskinesia.
•
|
,60
26o
360
4oo
5/)0
6i)o
7/)0
800ng/kg
daily dose of Haloperidol/body weight ng/ml
ng/ml 40.
•
stop medication stop medication / 3.0m~!day
•
I0-
6.0mg/ly
~ / d a y i ~ ~
30" -6 o
2
,0
"5 20-
~o
~5
day
"lFig. 11.
00
E
2o
ee
N=20 ~/=--0.011
10"
Serum levels of h a l o p e r i d o l a f t e r w i t h drawal o f haloperidol.
Fig. I0.
e
e •
0 ~0
io
•
~o
R e l a t i o n s h i p b e t w e e n B P R S total score and serum level of haloperidol.
~o
9
/o
~o
BPRS total score
Haloperidol
serum levels and it's clinical
significance
61
Summary and Conclusion The results of the present study have demonstrated
the following:
i) From the practical advantage of haloperidol showing modest within-day variations in serum concentration and a fast attainment of a steady state of serum level, it is more advisable to administer the compound in divided daily doses rather than in single daily doses. This may effect prevention of evoking such undesirable reactions as extrapyramidal symptoms. 2) Absorption of the compound by oral administration does not vary noticeably whichever the form of pharmaceutical preparations, i.e. liquid, granules or tablets. 3) A steady state of serum basal concentration of the drug is usually reached about one week after initiation of medication in divided daily oral doses. It is delayed slightly with single oral daily dosage. 4) The lowest serum haloperidol level at which, practically, extrapyramidal symptoms may develop is estimated to be in the region of i0 ng/m£. 5) No significant correlation has been noted to exist between the incidence of tardive dyskinesia and the serum level of haloperidol. 6) Analysis of the data failed to reveal any appreciable correlationship between clinical effects and serum levels of the drug, but this remains to be further investigated in full detail.
Acknow!edgements This work was supported in part by Grant-in-Aid for Scientific Research No. 448248 from the Japanese Ministry of Education. The analytical-reagents for radioimmunoassay were kindly supplied by Dai-Nippon Pharmaceutical Co., Ltd. We are grateful to H. Suzuki, M. Iwasaki, Y. Sekine, M. Hashimoto, A. Kagemoto and Y. Utsui for their excellent technical assistance.
References BURROWS, G., SCOGGINS, B.A., TURECEK, L.R., and DAVIES, B. (1971). Plasma nortriptyline and clinical response. Clin. Pharm. Therap. 16: 639-644. CRESSMAN, W.A., BLANCHINE, J.R., SLVTNICK, V.B., JOHNSON, P.C. and PLOSTNIEKS, J. (1974). Plasma level profile of haloperidol in man following intramuscular administration. Europ. J. Clin. Pharmacol. !: 99-103. ERICKSEN, S.E., STEPHEN, W., HURT, M.A., and SIDNEY CHANG, M.D. (1978). Haloperidol dose, plasma levels and clinical response: a double blind study. Psydhopharmacology Bull. 14: 15-16. FORSMAN, A., OHMAN, R. (1974a). Some aspects of the distribution and metabolism of haloperidol in man. In: Antipsychotic Drugs: Pharmacodynamics and Pharmacokinetics, C. Sedwell (ed), pp. 359-365 Pergamon Press, Oxford. FORSMAN, A., MARTENSON, E., NYBERG, G. and OHMAN, R. (1974b). A gas chromatographic method for determining haloperidol. Naunyn-Schmiedeberg's Arch. Pharmaool. 286: 113-124. FORSMAN, A. and OHMAN, R. (1977a). Applied pharmacokinetics of haloperid---ol in man. Curr. Th~rap. Re8. 2_II: 396-411. FORSMAN, A., FOLSCH, G., LARSSON, M. and OHMAN, R. (1977b). On the metabolism of haloperidol in man. 6h~rr. Therap. Res. 21: 606-617. ITOH, H., YAGI, G., OHTSUKA, N., IWAMURA, K. and ICHIKAWA, K. (1980a). Serum level of haloperidol and its clinical significance. Prog. Neua~o-Psychopharmacol. 4: 171-183. ITOH, H., YAGI, G. and ICHIKAWA, K. (1980b). XII CINP Congre88, C~teborg Sweden June 22-26. LADER, M. (1976). Monitoring plasma concentration of neuroleptics. Pharmacopsychiatry 9: 170-177. MICHIELS, M., HENDRICKS, R., HEYKANTS, J. Antibodies to haloperidol: A very sencitive tool for the radioimmunologic determination of some butyrophenones. Preclinidal Research Report, Beerse, Belgium, Janssen Pharmaceutica, May (1976).
62
H. Itoh et al,
MORSELLI, P.L. and ZARIFIAN, E. (1980). Clinical significance of monitoring plasma levels of psychotropic drugs. In: Drug Conoentration8 in NeuI~opsychi~tln$. (Ciba Foundation Sympositun 74). Excerpta Medica, Amsterdam, pp. 115-139. RUBIN, R.T., TOWER, B.B., HAYS, S.E. and DOLAND, R.E. (in press), Radioimmunoassay of haloperidol. In: Van Vtmakis, H. and Langone, J.J. (eds) I ~ o c h e ~ o G l Ted~ique8 (vol. B), A volume of "Methods in Enzymology," Academic Press, New York. TUNE, L.A. (1980). Haloperidol drug level monitoring: Pharmacokinetic and methodological consideration with special emphasis on radioreceptor assay techniques. In: Ayd F.J. (ed.) H~Zope~{doZ ~6~te: 1958-1980. Ayd Med. Commun., Baltimore, pp. 220-230. ZIEGLER, V.E., TAYLOR, J.R., WETZEL, R.D. and BIGGS, J.T. (1978). Nortriptyline plasma levels and subjective side effects. B1~t, J. Psyohiat. 132: 55-60.
Inquiries and reprint requests should be addressed to: Dr. Hitoshi Itoh Department of Neuropsychiatry, School of Medicine Keio University 35 Shinanomachi, Shinjukuku Tokyo 160, Japan
0278-5846/84 $0.00 + .50
Printed in Great Britain. All rights reserved.
Copyright ~ 1984 Pergamon Press Ltd.
MONITORING OF HALOPERIDOL SERUM LEVELS AND IT'S CLINICAL SIGNIFICANCE
HITOSHI ITOH*, GOHEI YAGI*, MASATO TATEYAMA*, YASUO FUJII*, KENICHIRO IWAMURA** and KAZUO ICHIKAWA** * Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo ** Department of Internal Medicine, School of Medicine, Tokai University, Kanagawa, Japan
(Final form, March,
1983)
Abstract Itoh, Hitoshi, Gohei Yagi, Masato Tateyama, Yasuo Fujii, Kenichiro Iwamura and Kazuo Ichikawa: Mcnitoring of halc~eridol ser~n levels and it's clinical significance. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1984, 8(1): 51-62. i.
2. 3. 4. 5. 6.
Haloperidol serum levels were determined by the recently developed radioimmunoassay technique to elucidate the relationship between serum levels and clinical effects and that between serum levels and adverse effects. The serum levels of haloperidol in divided daily doses schedule reached to the steady state more rapidly (within 7 days) than in single dose schedule. The single daily dose schedule showed significantly wider diurnal variation than the divided daily doses schedule. No remarkable differences in serum concentration was noted between different types of oral haloperidol preparation (liquid, granule, tablet). No definite relationship was established between the serum concentration of haloperidol and incidence of tardive dyskinesia. No definite positive relationship between clinical effects and serum concentration of haloperidol could obtained.
Keywords: absorption of haloperidol preparation, clinical effect, haloperidol, immunoassay, serum concentration, steady state, tardive dyskinesia. Abbreviation: area under curve pyramidal symptoms (EPS).
(AUC);
brief psychiatry
rating scale
(BPRS);
radio-
extra-
Introduction Expeditious progress has been made to the present in drug therapy for psychotic disorders, yet, the present stage still does not permit to obtain sufficient data that will facilitate assessment of clinicopharmacologic effects of drugs on scientific bases. In recent years, increasing attention has become focused on the study of measurement of plasma levels of psychotropic drugs with a view to contributing toward elucidation of the pathophysiology of psychoses as well as to expediting advances in medicinal treatment of these diseases in more scientific ways (Burrows, 1971; Lader, 1976; Ziegler, 1978; Morselli et al., 1980). Gas chromatography with a high degree of assay sensitivity modified for measurement of drug concentrations and various other techniques such as radioimmunoassay, radioreceptorassay and enzyme-immunoassay have become applied to determination of concentrations of antiepileptics, antidepressants, anxiolytics, lithium and antipsychotics in blood specimens. As yet, there is no unified view as to clinical significance of data on plasma levels of antipsychotic drugs and this still remains a subject of much controversy. The metabolism
51
52
H. Itoh et al.
of phenothiazines in human body is extremely complicated. With chlorpromazine, for example, more than I00 metabolites were shown to form besides the parent compound following administration. This made it difficult to draw a sound conclusion as to interrelation between their plasma levels and clinical and adverse effects (Lader, 1976). Administration of haloperidol yields relatively few metabolites which are devoid of psychopharmacologic activity, thus rendering it practicable to assess the interrelationship of plasma drug concentration and clinical effects. There have been intensive pursuits of clinical study on plasma concentrations of haloperidol since late in the 1970's (Forsman et al., 1974a, 1974b, 1977a, 1977b; Cressman et al., 1974; Ericksen et al., 1978; Tune, 1980). The present authors conducted a series of studies by the recently developed radioimmunoassay technique to delineate characteristics of plasma concentration patterns of haloperidol following various oral dosage schemes as well as to clarify the interrelation between plasma drug concentrations and dosage, clinical effects and adverse reactions (Rubin et al., 1980). The results were presented in part before the llth and 12th C.I.N.P. Congress as follows (Itoh et al., 1980a, b). I) The blood haloperidol concentration reaches its peak 6 hours after administration and then declines gradually to half the peak level at 12 to 24 hours; 2) In the long-term medicated patients, there exists a significant positive correlation between the blood concentration and the daily dose per kg of body weight of haloperidol; 3) The daily variation in the blood concentration is significantly narrower when haloperidol is administered in divided doses than when it is given at a time; 4) Extrapyramidal symptoms (EPS) often develop at a basal blood haloperidol level of I0 ng/m£ or over and at a peak level of 20 ng/ml or over, unless haloperidol is given in combination with antiparkinsonian drugs; and 5) Antiparkinsonian medication generally does not interfere with the blood level of haloperidol. This paper represents a further attempt to obtain blood haloperidol concentration data useful for management of haloperidol therapy in daily clinical practice.
Materials and Methods i.
subjects 166 cases material used in these study consisted of chronic inpatients from ten mental hospitals.
2.
Drug administration 166 patients had been flexible medication for various period.
3.
Study design The contents of our present study consisted of four parts. Ist study ..... comparison of the blood concentration pattern between different administration schedules. 2nd study ..... influence of alteration in form of haloperidol preparation. 3rd study ..... steady state of serum haloperidol concentration, and relationship between serum level and incidence of EPS in longitudinal observation. 4th study ..... relationship between serum concentration of haloperidol and clinical response, and serum level after withdrawal of medication.
4.
Blood level determination Serums were separated and kept in frozen storage. The r a d i o i ~ u n o a s s a y technique employed for determination of the serum level of haloperidol was a modification of the method of Michiels (Janssen group). (Michiels et al., 1976).
Results and Discussion i.
Number of daily divided poses and ~attern of daily variation in blood d ru~ co.nceqtration The blood concentration pattern of haloperidol varied with the number of daily divided doses in three groups of patients undergoing long-term oral haloperidol therapy, as
Haloperidol
serum levels and it's clinical significance
53
shown in Figure i. There was a distinct tendency for the amplitude of within-day variation (difference between peak and lowest concentrations) in serum drug concentration to diminish with increasing number of daily divided doses. Analysis of blood haloperidol concentration data from 38 patients receiving chronic oral medication disclosed a significantly higher rate of elevation of serum drug concentration (= ~peak conc.-lowest conc.)/(lowest conc.)] x I00) in a group given the drug in single daily doses than other groups receiving two or more divided doses. A further assessment of the interrelationship in an increased number of 133 cases confirmed the finding; the mean range of within-day variation in serum haloperidol level was significantly greater in a group receiving single daily doses as compared to other groups given the drug in three to four divided doses daily (Fig. 2).
Drug Administration
Drug administration
ng/ml~
ng/mlI
,°I
40.
45
//,o
Y':::. 20-
\.~ o '":~'-. "-.
,o.
",.',..
"-..-..,,-
2o-~
I0-
~
2
V" '//,o0
25
31o 3.0 40
10
6 a) once a day
b) twice a day
Drug administration
ng/mi 201
0?'5
~ 0
6
12
18
24h
C) three time a day Fig. I.
1'2 1'8
Comparison of the blood concentration pattern between different administration schedules.
24 h
54
H. Itoh et al.
.45.0 rig/.,~
so.
0
20.
~
I0.
.i 4"
.E g
|
o
L,.
~ --I0 9.6+0.0 once/day N=9 ~NS
Fig. 2.
5.0±7,5 4.5::E5,1 2.9+4.2 two times/day three times/day four times/day N=56 N=62 'P- 0.025 P, 0.051
N= 6
Comparison of the range of variation in serum concentration of haloperidol between different administration schedules.
Inasmuch as the group receiving haloperidol in daily four divided doses in that assessment, a reassessment was carried out to compare the within-day variations in a group with single daily dosage and a group of increased number of cases with four divided daily doses. Samples of blood were collected before the dose or an initial dose of the day (basal serum drug level) and at periods when a peak serum level was estimated to be seen from the preceding studies, i.e. 6-7 hours after a single daily dose or 1-2 hours after a fourth divided dose, as in the foregoing assessment. The daily dosage of haloperidol tended to be inevitably greater in the cases receiving four divided daily doses than in the single daily dose group, with a significant inter-group difference (0.162 + 0.085 mg/kg vs. 0.079 + 0.045 mg/kg, p < 0.01), since the patients were selected from among those being-treated in daily clinical practice. Their serum drug concentrations were, therefore, corrected according to actual dosage to calculate the range of within-day variations. The results are shown in Figure 3. As can be noted, the group receiving haloperidol in four divided doses daily displayed apparently smaller within-day variations, thus confirming the findings in our previous observations. It would be seen that administration of the drug in daily divided doses is more advisable in routine practice from the viewpoint that untoward side-effects such as extrapyramidal symptoms which interfere with antipsychotic drug treatment tend to arise once its blood concentration has exceeded a certain level.
Haloperidol
serum levels and it's clinical
significance
55
[mean±S.D.~ pg/ml/dose 150-
[56.6_+30.0) N=24
[25.3+13.3) N=I4
| _o
100-
e
@
E e
._c
50-
II
e
I1 "6
$ e
once/day
four times/day
[__r:,. o.o1--1 Fig. 3.
2.
Comparison of the range of variation in serum concentration of haloperidol between once daily administration and four times daily administration.
Influence of alteration in form of ~reparation Haloperidol is currently available in many different forms of pharmaceutical preparation, such as tablets, powder, liquid, injectable solution and injectable depot preparation. Assessments were made to ascertain whether there might be any particular problem in alteration of the form of oral haloperidol preparation in patients undergoing treatment. Pharmaceutical manufacturers usually secure preclinical data on bioequivalence of a drug in animals and in human volunteers prior to introduction of different forms of preparation for clinical use. The following study was designed on the assumption that no such assessment of bioequivalence might have been done for haloperidol in psychiatric patients. In a series of twenty patients having been receiving a 10-fold dilution of a haloperidol liquid preparation over an extended period, the serum drug concentrations were determined following replacement of the regimen with equivalent doses of haloperidol tablets, fine granules and a higher concentration (1:5 dilution) and lower concentration (1:20 dilution) of the liquid preparation. As shown in Figure 4, there was generally no conspicuous change in blood level of the drug as assessed at 4 days after alteration in form of oral preparation. Figure 5 illustrates the patterns of serum drug level changes observed in a patient given haloperidol liquid and fine granules by cross-over design in doses of 6 mg. The peak time was slightly delayed with the liquid form but the AUC did not differ appreciably between the two forms of oral preparation. Despite our expectation that the liquid form might show a better absorption following administration , the data have indicated that both forms are absorbed at comparable rates as far as haloperidol is concerned. However, there are pharmaceutical preparations of haloperidol by several different manufactures in this country. Evaluation of such preparations to detect inter-brand differences would be necessary in view of the fact that tablet and powder forms of phenytoin and clofibrate vary in rate of absorption with some of the brands. The serum drug level that yields from administration of the depotpreparation may also become an important subject of investigation.
56
H. Itoh et al.
ng/ml
ng/,,,I
ng/ml
ng/ml 12mg/day
60-
60"
15mglday 8060
1 / 2mg/day 40 40
8mg/day
+............ +
40
60
]2rag/day
12mg/day
/ .12rag/day .---4
~.,~/day
12mg/day
~
+ ....... +
~
6 .r. . n. . . .~. . . 4. 20
20-
40
8mg/day 20
•/
(lOx)
~ Y Liquid ---*powder Liquid"--"High (10x) (10x) Liquid
15mg/day
12mg/day +..... + average Level
12rag/day
Li quid----~Tablet
Fig. 4.
~
day
Liquid (lOx)
• L;w
Liquid (20x)
(Sx)
4 days after the change of preparations•
Serum levels:
~- 50 years old body weight 50kg
ng/mE15.
--
-- Granule(G)
X. . . . "!,( Liquid (L) AUCG=108.35 55
o
2
~
.
A U C L = ]0 8
Peak time G=4 hour I L=6 hour , j G=7.2 t2 I L=7.8
,
",
5
•
,
6
,
12
,
18
i
24 hour
time after single oral administration Fig. 5.
S e r u m levels of h a l o p e r i d o l after single oral a d m i n i s t r a t i o n at a dose of 6 m g in the form of g r a n u l e and liquid.
Haloperidol
3.
serum levels and it's clinical significance
Steady state of serum ha loperidolconcentration in longitudinal observation Serum basal levels of haloperidol were followed serially (days O, 3, 7, 14 and 28) after initiation of oral medication with tablets in single daily doses or in three divided daily doses in 23 patients. The dosage was 6 mg per day as a rule but might be individualized according to the patient's conditions, although kept fixed at least for the first one-month period in every case. No restriction was posed on concomitant use of other neuroleptios while the use of antiparkinsonian drugs was withheld until development of extrapyramidal symptoms. The observation revealed that the basal serum level of haloperidol attained a plateau 7 days after start of oral medication (Figure 6). In Figure 7, the data from the cases stratified according to the number of divided daily doses are illustrated. With single oral doses, the blood level appeared to have not necessarily reached a steady state by Day 7 of medication but to be slightly delayed, whereas with three divided doses, it can be said that a steady state was accomplished by this period. Thus, administration in divided daily doses affords a faster attainment of a steady state of basal serum drug concentration.
ng/ml
~ mean_+S. E. N=23
I o
-}
io
doses a day (mean_+S. D) 1
I
0.101_+0.043mg/kg J
0
days of drug treatment Fig. 6.
4.
57
day.
Time required to reach steady state serum level of haloperidol after successive oral administration.
Interrelation between serum level and incidence of extrapyramidal symptoms Twenty of these patients excluding 3 who had extrapyramidal symptoms already at initiation of the oral haloperidol therapy were classified into two groups, i.e. those who developed any of such symptoms as akathisia, parkinsonism and acute dystonic reaction following the treatment and those who did not, and their patterns of changes in serum basal level compared. The latter group exhibited a mean basal level of about
58
H. Itoh et al.
three tiros daily administration ng/mt
N=15
20
÷ Fig. 7.
•.,e... once daily administration N=7
Comparison of the time required to reach steady-state serm. level of haloperidol between different administration schedules.
mean-i-S. E.
I.
T
o
.c
10-
"6 I I I I I I • I I I I
S Doses a day (mean-t-S D )
I
l
three times daily administration : 0 112-10.043mg/kg once daily administration : 0. 088 + 0 033mg/kg
0|
o
ng/ml
~
~
,'4 days of drug treatment
2,
20-
2'e day
Fig. 8. + Serum levels of haloperidol in patients after successive oral administration in relation to the incidence of EPS.
o
EPS (--) cases
"5 10'
E
/
I !
0 0
mean-f S E.
~
1'4
2',
~8 N.S.
t-test days of drug treatment
Haloperidol serum levels and it's clinical significance
59
I0 ng/m£ during the observation period of 28 days, compared to a mean level in the region of 20 ng/m£ in the former group (Figure 8). The mean serum drug concentration of the patients during manifestation of extrapyramidal symptoms was calculated to be 20.0 + 4.0 ng/mZ. In contrast, the mean of highest serum basal levels was 11.7 + 2.4 ng/m£ in the patients who did not develop such reactions and their serum levels at Day 28 averaged at 10.4 + 2.6 ng/m£. The data seem to show that monitoring of blood haloperidol concentration provides adequate information for prediction of development of extrapyramidal symptom. 5.
Relation between serum haloperidol level and incidence of tardive dyskinesia Tardive dyskinesia was found p r e s e n t in 14 patients and suspected in 7 patients among those who were undergoing long-term treatment with haloperidol. We assessed their basal serum levels of haloperidol in comparison with those of patients without such complication. As shown in Figure 9, no definite relationship is established between the serum concentration of haloperidol and the incidence of tardive dyskinesia. The mean of haloperidol serum level in the tardive dyskinesia-positiv e group is 26.7 + 18.4 ng/m£, in the tardive dyskinesia-suspected group 17.9 + 9.7 ng/m£, and in the tardive dyskinesia-negative group 39.4 + 36.9 ng/m£. And, the mean daily doses of haloperidol in these groups were 174 ~ 94 ~g/kg and, 116 ~ 63 ~g/kg and 217 + 197 ~g/kg, respectively. A variety of factors may probably be involved in the development of side-effects that are associated with long-term therapy; hence unpredictable merely from serum drug concentration data.
6.
Clinical response and serum haloperidol level Some of the studies reported in the literature purport to demonstrate correlation of the clinical effect and serum levels of haloperidol while others present data which defy such interrelationship; there has been no unified conclusion in this respect. Investigations on this subject are also in progress at the author's department. The results heretofore obtained have failed to show any definite interrelationship between the BPRS total score and the serum basal level of haloperidol in a series of 20 cases under treatment. That is, the patients with lower BPRS total scores did not necessarily show higher serum levels of the drug, nor did those with higher scores display lower serum concentrations (Fig. i0). A previous clinical observation of 9 patients undergoing haloperidol therapy with oral dosage of 3-9 mg q.d. over periods of several months revealed that the psychotic condition was markedly improved in 1 case, moderately improved in i, unimproved in 4 and worsened in 4 by overall assessments of the therapeutic response. And, there was no significant interrelation between the clinical response to haloperidol therapy and the serum level of the drug. These findings seem to stress importance of further pursuit of study in full detail on the relationship of blood levels and serial changes in BPRS and other parametric scoring on various psychiatric and behavioral rating scales in order to attain a more precise conclusion as to interrelation of serum concentrations and clinical effects of the drug.
7.
Serum level after withdrawal of medication Another problem of profound interest to the clinician would be the question of how long the drug administered remains in the circulating serum after the medication is discontinued. Figure Ii shows pertinent data from 4 patients followed in our clinic by periodic measurements of serum levels. As can be noted, it took 2-4 days after withdrawal for the serum haloperidol level to decline to half the basal level during 2- to 4-week medication, and it was not until more than i0 days had elapsed after withdrawal that the drug became scarcely demonstrable in the circulation.
60
H. Itoh et al.
ng/m~ 150"
o. o --~ 1"
100Tardlve Dyskmesla • Negat,ve N=24 ,~. Suspected N----7 O Positwe N~I4
o
u') ~'
5og
•
o
o
o
÷ Fig. 9. R e l a t i o n b e t w e e n serum conc e n t r a t i o n of h a l o p e r i d o l and i n c i d e n c e of tardive dyskinesia.
•
|
,60
26o
360
4oo
5/)0
6i)o
7/)0
800ng/kg
daily dose of Haloperidol/body weight ng/ml
ng/ml 40.
•
stop medication stop medication / 3.0m~!day
•
I0-
6.0mg/ly
~ / d a y i ~ ~
30" -6 o
2
,0
"5 20-
~o
~5
day
"lFig. 11.
00
E
2o
ee
N=20 ~/=--0.011
10"
Serum levels of h a l o p e r i d o l a f t e r w i t h drawal o f haloperidol.
Fig. I0.
e
e •
0 ~0
io
•
~o
R e l a t i o n s h i p b e t w e e n B P R S total score and serum level of haloperidol.
~o
9
/o
~o
BPRS total score
Haloperidol
serum levels and it's clinical
significance
61
Summary and Conclusion The results of the present study have demonstrated
the following:
i) From the practical advantage of haloperidol showing modest within-day variations in serum concentration and a fast attainment of a steady state of serum level, it is more advisable to administer the compound in divided daily doses rather than in single daily doses. This may effect prevention of evoking such undesirable reactions as extrapyramidal symptoms. 2) Absorption of the compound by oral administration does not vary noticeably whichever the form of pharmaceutical preparations, i.e. liquid, granules or tablets. 3) A steady state of serum basal concentration of the drug is usually reached about one week after initiation of medication in divided daily oral doses. It is delayed slightly with single oral daily dosage. 4) The lowest serum haloperidol level at which, practically, extrapyramidal symptoms may develop is estimated to be in the region of i0 ng/m£. 5) No significant correlation has been noted to exist between the incidence of tardive dyskinesia and the serum level of haloperidol. 6) Analysis of the data failed to reveal any appreciable correlationship between clinical effects and serum levels of the drug, but this remains to be further investigated in full detail.
Acknow!edgements This work was supported in part by Grant-in-Aid for Scientific Research No. 448248 from the Japanese Ministry of Education. The analytical-reagents for radioimmunoassay were kindly supplied by Dai-Nippon Pharmaceutical Co., Ltd. We are grateful to H. Suzuki, M. Iwasaki, Y. Sekine, M. Hashimoto, A. Kagemoto and Y. Utsui for their excellent technical assistance.
References BURROWS, G., SCOGGINS, B.A., TURECEK, L.R., and DAVIES, B. (1971). Plasma nortriptyline and clinical response. Clin. Pharm. Therap. 16: 639-644. CRESSMAN, W.A., BLANCHINE, J.R., SLVTNICK, V.B., JOHNSON, P.C. and PLOSTNIEKS, J. (1974). Plasma level profile of haloperidol in man following intramuscular administration. Europ. J. Clin. Pharmacol. !: 99-103. ERICKSEN, S.E., STEPHEN, W., HURT, M.A., and SIDNEY CHANG, M.D. (1978). Haloperidol dose, plasma levels and clinical response: a double blind study. Psydhopharmacology Bull. 14: 15-16. FORSMAN, A., OHMAN, R. (1974a). Some aspects of the distribution and metabolism of haloperidol in man. In: Antipsychotic Drugs: Pharmacodynamics and Pharmacokinetics, C. Sedwell (ed), pp. 359-365 Pergamon Press, Oxford. FORSMAN, A., MARTENSON, E., NYBERG, G. and OHMAN, R. (1974b). A gas chromatographic method for determining haloperidol. Naunyn-Schmiedeberg's Arch. Pharmaool. 286: 113-124. FORSMAN, A. and OHMAN, R. (1977a). Applied pharmacokinetics of haloperid---ol in man. Curr. Th~rap. Re8. 2_II: 396-411. FORSMAN, A., FOLSCH, G., LARSSON, M. and OHMAN, R. (1977b). On the metabolism of haloperidol in man. 6h~rr. Therap. Res. 21: 606-617. ITOH, H., YAGI, G., OHTSUKA, N., IWAMURA, K. and ICHIKAWA, K. (1980a). Serum level of haloperidol and its clinical significance. Prog. Neua~o-Psychopharmacol. 4: 171-183. ITOH, H., YAGI, G. and ICHIKAWA, K. (1980b). XII CINP Congre88, C~teborg Sweden June 22-26. LADER, M. (1976). Monitoring plasma concentration of neuroleptics. Pharmacopsychiatry 9: 170-177. MICHIELS, M., HENDRICKS, R., HEYKANTS, J. Antibodies to haloperidol: A very sencitive tool for the radioimmunologic determination of some butyrophenones. Preclinidal Research Report, Beerse, Belgium, Janssen Pharmaceutica, May (1976).
62
H. Itoh et al,
MORSELLI, P.L. and ZARIFIAN, E. (1980). Clinical significance of monitoring plasma levels of psychotropic drugs. In: Drug Conoentration8 in NeuI~opsychi~tln$. (Ciba Foundation Sympositun 74). Excerpta Medica, Amsterdam, pp. 115-139. RUBIN, R.T., TOWER, B.B., HAYS, S.E. and DOLAND, R.E. (in press), Radioimmunoassay of haloperidol. In: Van Vtmakis, H. and Langone, J.J. (eds) I ~ o c h e ~ o G l Ted~ique8 (vol. B), A volume of "Methods in Enzymology," Academic Press, New York. TUNE, L.A. (1980). Haloperidol drug level monitoring: Pharmacokinetic and methodological consideration with special emphasis on radioreceptor assay techniques. In: Ayd F.J. (ed.) H~Zope~{doZ ~6~te: 1958-1980. Ayd Med. Commun., Baltimore, pp. 220-230. ZIEGLER, V.E., TAYLOR, J.R., WETZEL, R.D. and BIGGS, J.T. (1978). Nortriptyline plasma levels and subjective side effects. B1~t, J. Psyohiat. 132: 55-60.
Inquiries and reprint requests should be addressed to: Dr. Hitoshi Itoh Department of Neuropsychiatry, School of Medicine Keio University 35 Shinanomachi, Shinjukuku Tokyo 160, Japan