Psychiatry Research, 4, I47- I56 ( I98 1) Elsevier/North-Holland Biomedical Press

147

Pharmacokinetics of Clomipramine in Depressive Patients

Hugo J.A. de Cuyper, Herman M. van Praag, Wilhelmina R.E.M. Mulder- Hajonides, Herman G.M. Westenberg, and Rokus A. de Zeeuw

Received January 17, 1980; revised version received October 1, 1980; accepted January 12, 1981.

Abstract. Ten patients with a vital depressive syndrome were treated for 4 weeks with clomipramine (CI), five receiving the drug by mouth and five receiving it first intramuscularly and then by mouth. Plasma concentrations of CI and desmethyl- clomipramine (DCI) were measured daily. Both concentrations showed marked interindividual differences, especially after oral administration of the drug. The mean relative CI clearance after repeated i.m. injections was 0.441 kg-l hour-l. The route of administration proved to exert a marked influence on the plasma concen- tration ratio CI/ DCI. In this small population, no significant relationship could be demonstrated between plasma CI and DC1 concentrations, or the sum of both, and the clinical effect.

Key Words. Clomipramine, desmethylclomipramine, plasma level, first-pass effect, clinical response.

Clomipramine (Anafranil@‘), a tricyclic antidepressant (TCA) that is structurally related to imipramine, is widely used in the treatment of certain types of depression. Like other TCAs however, it has a relatively high nonresponse rate: 40-50s of depressive patients show no or no sufficient response to treatment with clomipramine (CI) (Della Corte et al., 1979). One possible factor in this high nonresponse rate might be interindividual differences in pharmacokinetics, resulting in a marked interindivid- ual variability in steady-state plasma concentrations of the active substance on stand- ard doses.

Data on the pharmacokinetics of CI are sparse, in spite of its wide use. Faigle and Dieterle (1973) studied the absorption and excretion of 14C-labeled Cl after oral and intravenous administration to volunteers. Their findings indicate that CI is almost entirely absorbed from the gastrointestinal tract, and is excreted almost exclusively in the form of metabolites. Nagy and Johansson (1977) and Westenberg et al. (1977~) studied the pharmacokinetics of CI after administration of a single oral dose to volunteers. These investigators reported a mean plasma half-life of 20.8 hours and 22.8 hours, respectively. The mean plasma clearance after a single i.m. injection was calculated to be 0.33/kg/ hr and the systemic availability of CI after oral administra- tion proved to vary from 19% to 78% ofthat after i.m. injection(Nagy and Johansson,

Hugo J.A. de Cuyper, M.D., is Resident Psychiatrist, Psychiatric Clinic Salve Mater, Louvain, Belgium. Herman M. van Praag, M.D., Ph.D., is Professor and Head, and Herman G.M. Westenberg, Ph.D., is Research Pharmacist, Department of Psychiatry, University of Utrecht, The Netherlands. Rokus A. de Zeeuw, Ph.D., is Associate Professor of Toxicology, and Wilhelmina R.E.M. Mulder-Hajonides is Research Psychologist, University of Groningen, The Netherlands. (Rey ! requests to Dr. Westenberg at Department of Psychiatry, Academic Hospital, Catharijnesingel 101, echt, The Netherlands.)

0165- 1781/81/0000~0000~$02.50 0 Elsevier/North-Holland Biomedical Press

148

1977). Nagy and Johansson (1977) have also indicated that the route of administration can influence the degree of N-desmethylation of tertiary TCA.

The primary purpose of the present study was to investigate the pharmacokinetics of CI and desmethylclomipramine (DCI) after repeated administration to depressive patients. In order to study the influence of the route of administration on the availability and metabolism of CI, some of the patients were given CI both orally and intramuscularly.

Methods

Patients. The patients studied were six women and four men who had recently been hospital- ized for treatment of depression. All showed a vital depressive syndrome (van Praag, 1978) characterized by at least the following cardinal symptoms: decreased level of mood, motor disorders, hypoasthesia, disturbed sleep, anorexia, and fatigue inconsistent with performance.

The average age was 38 (range 23-50), and the mean initial score on the Hamilton Rating Scale for depression was 32 (range 20-43). (See Table I for sample characteristics.)

Table 1. Sample characteristics

Height Patient Sex Age cm

1 M 40 178

2 M 35 185

3 F 49 172

4 F 39 161

5 F 50 165

6 M 36 172

7 F 41 180

8 F 41 152

9 F 43 165

10 M 23 197

P = mainly psychogenic. End = mainly endogenous hereditary

Initial Weight Hamilton

kg score Etiology Course

75 40 P, end Unipolar

90 26 P Unipolar

78 34 P Bipolar

96 20 P, end Unipolar

a8 24 P, end Bipolar

79 43 P Unipolar

76 34 P, end Unipolar

47 29 P, end Bipolar

80 38 P Unipolar

73 34 P Unbolar

Dosage. This was an open study. During a 5-day washout period before the study began, and throughout the period of study, no other medication was given (with the exception of benzodi- azepines as hypnotic). All patients were treated for 4 weeks with clomipramine (Anafranila, Ciba-Geigy).

The patients were randomly divided into two equal groups: Group l-patients received Cl orally in tablet form throughout the study, starting with 25 mg three times daily and gradually increasing to 200 mg per day on day 6 of the study, whereafter the dose was kept constant. Group 2-patients were given Cl intramuscularly for the first 14 days, starting with 25 mg twice daily and increasing within 2 days to 100 mg per day in two injections. After 14 days, injections were replaced by a daily dose of 200 mg, orally administered in three fractional doses given at 0830, 1630, and 2200h (the i.m. injections were given at 0830 and 1600h).

Plasma Measurements. During the first 2 weeks ofthe study, twice-daily blood samples were obtained immediately before the morning medication and 60 minutes (group I) or 30 minutes (group 2) after the afternoon medication. During the third and the fourth weeks, blood samples

149

were obtained once a day in both groups, 60 minutes after the afternoon medication. The blood was collected in heparinized glass tubes and, after centrifugation, stored as plasma at -20°C until analysis.

The plasma Cl and DC1 concentrations were determined by the liquid chromatography technique described by Westenberg et al. (1977b).

Behavior Rating. Two depression rating scales, the Hamilton Rating Scale (HRS; Hamilton, 1960) and the Zung Self-rating Scale (ZSRS; Zung, 1965) were used to evaluate therapeutic effectiveness. The HRS was done by the attending psychiatrist, while the ZSRS was completed by the patient. Both ratings were always made on the same day, in the morning hours before the study began and every 4 days throughout the study.

Data Analysis. The mean steady-state plasma concentration is described in the equation (Wagner et al., 1965):

C= D.F

Clp T (1)

in which c represents the “average” steady-state plasma concentration, F the systemic availability-that is, the fraction of the dose that reaches the systemic circulation unchanged (after i.v. injection, F = 1 by definition)&D the dose, Clp the plasma clearance and T the dose interval.

The systemic availability (F) of a drug is determined by the amount absorbed from the gastrointestinal tract unchanged and the amount eliminated or metabolized during the first passage through the liver. The latter, so-called first-pass effect is of particular importance for drugs cleared chiefly via the liver.

The systemic availability F during repeated oral administration can be calculated with the aid of the equation:

c F= oral ’ ‘oral x D i.v.

‘iv ’ ’ i.v. D . . oral

As no iv. doses were given in this study, plasma clearance and systemic availability during repeated oral administration were estimated with the aid of equations (1) and (2), respectively, using i.m. data, assuming that the dose is completely systemically available.

The “average” steady-state plasma concentrations were calculated during the second and the fourth weeks of medication, as the mean of the plasma concentrations during the period in question.

The therapeutic effect was established during the second and the fourth weeks of medication by calculating for both depression scales the differences from the initial score. The percentage of reduction on the HRS was also calculated.

For statistical analysis of the mean values of the “average” steady-state plasma concentra- tions of Cl, DCI, and CI + DCI, and of the therapeutic effects, use was made of an analysis of variance with two factors: method of administration (groups) and weeks with repeated mea- sures on one factor (weeks).

Results

Pharmacokinetics. The difference between morning and afternoon plasma concen-

trations of CI and DC1 was generally rather small in Group 1 (see Fig. 1, upper panel,

days l-l 5). Day-to-day fluctuations were quite pronounced in some subjects, but these

variations were small compared to the interindividual variations in the steady-state

plasma concentrations (Table 2). DC1 appeared in the plasma of all subjects after oral

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administration of Cl. The ratio between the plasma concentrations of CI and DC1 varied from 0.3 to 2.0 during the second week and from 0.2 to 1.3 during the fourth week of treatment in this group.

Fig. 1. Plasma concentration-time curves of clomipramine (0) and desmethyl- clomipramine (0) in two representative patients from Group 1

plasma concentration ( nglml ; log scale )

500. subject l-6.

jq, 4 0,’ ‘..* ,*w-.c* : I *\ ,+

/k* ,*/ \d’ 200 d’ \XW’

/d P

10. 1 , 0 5 10 15 20 25 days

plasma concentration ( nglml ; log scale 1

500. subject B.U

200.

100.

50.

10; 0 5 10 15 20

Clomlpramine was given by mouth in daily doses increasing up to 200 mg.

25 days

151

Table 2. Mean plasma clomipramine (Cl) and desmethylclomipramine (DCI) concentrations in Groups 1 and 2 during weeks 2 and 41

Cl DCI Cl + DCI

Patient # 2nd 4th 2nd 4th 2nd 4th

Group 1 1 49 a0 143 344 192 424 2 97 93 48 187 145 280 3 158 195 122 la3 280 378 4 139 209 239 540 378 749 5 197 296 110 234 307 530

Mean 128 175 132 298 260 472

SD 57 a9 69 150 93 179

Group 2 6 156 191 28 262 la4 453

7 115 75 30 41 145 116 a 142 131 ND2 137 142 268

9 131 la7 ND2 76 131 254 10 151 131 36 75 la7 206

Mean 139 141 ~23 118 158 259 SD 16 46 aa 26 123

Analyses of variance3

F

P

Cl DCI

Groups Weeks Groups Weeks

<l 4.06 7.69 21.11

NS NS co.05 co.01

Groups X weeks Groups X weeks

Cl + DCI

Groups Weeks

5.61 a.00 co.05 co.05

Groups X weeks

F 3.36 1.51 2.49

D NS NS NS

1. Plasma concentration ng/ml. 2. ND = not detectable (~10 ng/ml-1 ). In the computations we used a value of 10 ng/ml-1 3. Degrees of freedom = 1. 8.

In Group 2 there was a considerable difference between morning and afternoon plasma concentrations of CI after i.m. injection, suggesting substantial 24-hour fluctuations (Fig. 2). DC1 appeared in the plasma of three subjects 5 to 10 days after i.m. administration of CI. In two subjects no detectable amounts of DC1 (< 10 mg/ ml) were observed during i.m. administration. The switch from i.m. to oral administration resulted in a substantial increase in the plasma DC1 concentration in four of the five subjects (Table 2). The mean relative plasma clearance in Group 2 was 0.44 + 0.11 /kg/ hr (mean Ifr SD). The systemic availability was estimated to average 50%

(32% to 67%). There was no significant difference between the plasma concentrations of CI in the

second week as compared with the fourth week (Table 2). Neither was there a significant difference between the plasma CI concentrations of Group 1 as compared to those of Group 2. The N-desmethylation of CI, however, was significantly less for Group 2 than for Group 1 (F = 21.11, df = 1,8, p < 0.01). For both Groups 1 and 2,

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there was a significant increase in the mean plasma DC1 concentration from week 2 to week 4 (F = 7.69, df = 1, 8, p < 0.05). The results for the sum of CI and DC1 are identical to the results for DC1 alone.

Fig. 2. Plasma concentration-time curves of clomipramine (0) and desmethyl- clomipramine (0) in two representative patients from Group 2

plasma concentration (nglml; log scale)

500 subject A.0.

I

101 0 5 10 1 1’5 20 25 days

i.m. -j- oral

plasma concentration ( nglml ; log scale)

5001 subject Z.L.

200. p-.. 8 9

loo-

50-

20- i

lo-? 0 5 10 --l- 15 20 25 days

i.m . oral Clomipramine was first given intramuscularly G.m.) and then by mouth, in daily doses of 100 mg and 200 mg, respectively.

153

Therapeutic Effects. Table 3 presents the differences in HRS and ZSRS scores from the initial scores and the ?Jr reduction on the HRS (% improvement) per individual patient in Group 1 (patients l-5) and Group 2 (patients 6-10). All patients in Group 1 showed distinct improvement on the HRS during CI medication. The mean HRS improvement at completion of medication was 15.2 points, corresponding to 49% improvement. The improvement on the ZSRS was much less pronounced: only two of the five patients rated themselves as improved. In Group 2, HRS improvement was seen in four of the five patients. The mean HRS improvement at completion of medication in this group was 10.2 points (i.e., 27% improvement). Three of the four patients (one did not complete the ZSRS) rated themselves as slightly improved.

For all therapeutic variables, Groups 1 and 2 showed comparable significant increases from the second to the fourth weeks.

Table 3. TheraDeutic effects in Groups 1 and 2

Patient #

A HRS A ZSRS2 VO Improvements

2nd 4th 2nd 4th 2nd 4th

Group 1 1 2 3 4 5

SD 9 3.5

Group 2 6 7 6 9

10

9

9 0

12 6

Mean 7.2

9 6

15 a 7

20 11

30

a 7

15

9.7

17

11

-1

15

9

10.2

-3

10

12

-4

-2

2.6

7.7

4

-1

7

9 -

4.8 6.8 19 27

1

11

15

-1

5.4

7.1

5 21 40

6 26 32

5 0 -4

11 32 39 - ia 28

23 50

23 42

44 a3

40 40

29 29

32 49

10 21

SD 4.6 7.0 4.4 2.9 12 la

Analyses of variance

F df D

A HRS’ A ZSRSz O/O Improvements

Groups Weeks Groups Weeks Groups Weeks

Cl 7.67 1 6.54 3.62 a.41

13 13 1,7 1,7 i,a i,a NS co.05 NS dO.05 NS co.05

Groups X weeks Groups X weeks Groups X weeks

F Cl 1

df i,a 1,7

P NS NS

1. A HRS = difference in HRS score from initial score. 2. A ZSRS = difference in ZSRS score from initial score. 3. % Improvement = % reduction on the HRS.

1.23

i,a NS

154

Discussion

It has become increasingly evident in recent years that the clinical effect of many medications correlates better with the plasma concentration than with the dose administered. The steady-state plasma concentration at a given dosage is determined by clearance and by the fraction of the dose administered that reaches the systemic circulation unchanged (equation 1). These pharmacokinetic factors are usually deter- mined after administration of a single dose to volunteers. However, pharmacokinetic factors can be time-dependent-i.e., subject to changes after repeated administration of the compound in question (Westenberg et al., 1978). Study of the pharmacokinetics during repeated administration is therefore always advisable.

Currently available data on the pharmacokinetics of Cl after repeated administra- tion to depressive patients are in accord with data previously reported after adminis- tration of a single dose to volunteers (Nagy and Johansson, 1977). Both the mean clearance after repeated i.m. injections and the mean systemic availability after repeated oral administrations were not significantly different from the corresponding values after a single dose. These pharmacokinetic factors would therefore not seem to be time-dependent. However, because the range around these mean values was substantial, interindividual variations in the disposition of CI are evidently significant.

The switch from i.m. to oral administration resulted in a significant increase in plasma DC1 concentration, This is in line with a similar observation reported by Nagy and Johansson (1977). This fact, together with the low availability (mean value 500/c) after oral administration, suggests that a significant fraction of the oral CI dose is metabolized in the liver during the first passage after absorption.

Since CI is eliminated almost exclusively via metabolic conversion, including N-desmethylation, this so-called “first-pass” effect results in an influence of the route of administration, not only on the availability of the parent compound but also on the plasma DC1 concentration. Although CI and DC1 are both pharmacologically active (Sigg et al., 1963, 1965; Carlsson et al., 1969a), they differ in their effect on the central monoamine metabolism (Carlsson et al., 1969~ 1969b; Traskman et al., 1979): CI proves to be a relatively selective inhibitor of 5-hydroxytryptamine (5-HT) uptake, whereas DCI-as secondary amine-is a strong inhibitor of noradrenaline (NA) uptake. The route of administration, therefore, influences the clinical effect not only quantitatively, but possibly also qualitatively.

Biotransformation chiefly takes place by the microsomal enzymes in the liver. Changes in the capacity of the drug-metabolizing enzyme system (as a result of enzyme inhibition or enzyme induction and/ or changes in hepatic blood flow) can therefore markedly influence plasma CI and DC1 concentrations. When other drugs are admin- istered simultaneously, the possibility of changes in the plasma concentration ratio CI/DCI should always be taken into account.

The “average” plasma concentration, as calculated by employing equation 1, equals the area under the plasma concentration-time curve between the doses divided by the dose interval, and therefore must represent some value between the maximum and minimum steady-state concentration. For this reason the mean values of the morning and afternoon plasma concentrations were used to estimate the “average” steady-state concentrations during the second week of treatment. During the fourth week, only

155

afternoon plasma concentrations were available, but as the difference between the morning and afternoon plasma concentrations after oral doses appeared to be small, these values closely approximate the “average” steady-state concentration.

The interindividual variations in plasma CI and DC1 concentrations, particularly after oral CI administration, might largely be ascribed to variability both in absorp- tion and in first-pass effect. The differences in first-pass effect probably reflect differences in enzyme activity.

The intraindividual day-to-day fluctuations observed in some subjects are less readily explained. Apart from patient noncompliance-a factor that can never be excluded with certainty in oral medication-the fluctuations might be caused by physiological variables such as blood flow or food uptake.

In this small population, no statistically significant linear relation (product moment correlation) could be demonstrated between clinical effect and plasma CI, DCI, or CI + DC1 concentrations. Because of the small number of patients involved, no tests for a curvilinear relationship could be completed. Although the mean clinical effect, partic- ularly as measured by the HRS, was more pronounced at completion of the treatment in Group 1 than in Group 2, this difference was not statistically significant.

Comparison of all mean values for Group 1 versus Group 2 reveals that only the plasma DC1 and CI + DC1 concentrations in Group 1 were significantly higher than those in Group 2. This might suggest that DC1 makes an important contribution to the overall clinical effect. A similar observation has been recently reported by Della Corte et al. (1979) and Trlskman et al. (1979), who found a significant correlation between amelioration of depression and plasma DC1 concentration. According to Traskman et al. (1979), this correlation was best in patients with “high” pretreatment concentra- tions of 5-hydroxyindolacetic acid in the cerebrospinal fluid. Therefore, particularly in this subgroup of depressive patients, the degree of desmethylation and consequently the route of administration may be very important.

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