Psychopharmacology
PsychopImrmacology54, 255-261 (t 977)
:~ by Springer-Verlag t977
Steady-State Kinetics of Imipramine in Patients LARS F. GRAM*"*, IB SONDEROAARD1, JOHANNES CHRIST!ANSEN2, GORM ODDEN PETERSEN3, PER BECH3, NIELS REISBY4, [LSE IBSEN4, .IQRGEN ORTMANN~, ADAM NAGY5, SVEN J. DENCKER 5, OVE JACOBSEN6, and OLE KRAUTWALD6 Department of Pharmacology, University of Copenhagen, Denmark 2 Department of Clinical Chemistry A, Rigshospitalet, University of Copenhagen, Denmark 3 Department of Psychiatry, Rigshospitalet, Universityof Copenhagen, Denmark 4 Department of Psychiatry, Municipai Hospital, Copenhagen, Denmark Department II, Lillhagen Hospital and Department of Clinical Chemistry, Sahlgren's Hospital, Gothenburg, Sweden 6 Department P, State Mental Hospital, Glostrup, Denmark
Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 rag/day for 2 - 5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and D M I showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of lip and/or D M I below 50 btg/1 reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2 - 3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: ~ 0 - 2 0 ~ ) . Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6 - 356 ~tg/!, D M I : 2 4 - 659 gg/1 and IP + D M I : 5 8 - 8 0 9 gg/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the I P / D M I ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state ieve!s between age groups were found. For IP: Women aged 3 0 - 39 had lower levels than women aged 2 0 - 29, 4 0 - 49, and 5 0 - 59, and men aged 50 - 59 and 60 - 65; men aged 3 0 - 3 9 had lower levels than men aged 6 0 - 6 5 . For D M I : Women aged 3 0 - 3 9 had lower levels than women aged 5 0 - 5 9 . Abstract.
Address jbr qffprint requests: L.F. Gram, M.D., Western Psychiatric Institute and Clinic University of Pittsburgh, 381l O'Hara Street, Pittsburgh, PA 15261, U.S.A. *
Key ~,,ords." t m i p r a m i n e -
D e s i p r a m i n e - Steadystate levels - Individual variation - Age differences - Hepatic elimination -- Protein binding Logaritl"mic transformation
Ten years ago it was shown tkat the steady-state plasma concentration of desipramine (DMI) and nortriptyline (NT) varies considerab!y among patients given identical doses (Hammer and Sj6qvist, 1967). A study on the urinary excretion rate of imipramine (IP) metaboiites showed a similar pronounced individual variation (Christiansen et al., 1967). A number of subsequent studies have shown that this variability in particular is due to individual variations in hepatic elimination of tricyclic antidepressants (Gram, 1974). Methods for measuring plasma levels of the secondary amines D M I and N T have been available for several years and the steady state kinetics of these compounds have been thoroughly studied (Alexanderson, 1972). Methods for determination of the tertiary amines (IP and amitriptyline AT) have only recently become available (e.g., Nagy and Treiber, 1973) and the steady-state kinetics of these compounds have so far been much less studied. There is increasing evidence indicating a clear clinical significance in measuring piasma levels of tricyc!ic antidepressants (Gram, 1977). Universal agreement on this has not been reached, but methodological problems seem to explain some of the discrepancies between the results of different groups. Some of these problems concern pharmacokinetics, and the aim of this study was to analyse some of these factors in relation to IP treatment. The data on steady-state kinetics of !P were mainly collected from a controlled study on the plasma level/effect relationship that is being reported in detail elsewhere (Gram et al., 1976a; Reisby et al., 1977).
256
Psychopharmacology 54 (1977)
DIURNAL FLUCTUATIONS OF PLASMA LEVELS DURING IMIPRAMINE TREATMENT
1 = : Oral administration of imipramine IMIPRAMINE
pg/i 100
--.'o/
/ 50 m/-
9
t
j
t
m-- 9
4"
DESIPRAMINE
pal i 150
100
50
o
f.,,~,~..~.e-.... -. ~ T
a.m.
MATERIALS
~ . r ,
?
1 p.m.
AND
1"
5 p.m.
HOURS
METHODS
Seventy-six patients, 24 men and 52 women aged 2 0 - 6 5 , from four psychiatric units in Gothenburg and Copenhagen were studied. Sixty-six of these patients participated in a controlled plasma level,/ effect study (Reisby et al., :1977). Sixty-three patients were given IP 225 mg/day, 4 patients had IP 200 mg/day, and 7 patients had IP 150 mg/day. The dose was increased to maximum over a period of 3 - 4 days. Three patients who suffered from severe side effects on 225 mg/day during the first 2 weeks then had the dose reduced to 150 mg/day for the following 2 - 3 weeks. IP was given orally as tablets (Tofranil ~) in three divided doses at 8.00 a.m., 1.00 p.m., and 5.00 p.m. The patients were observed ingesting the tablets. As additional medication, nitrazepam 5 - 1 5 mg/day was permitted. Benzodiazepines have been shown not to interfere with the kinetics of tricyclic antidepressants (Silver 9 and Braithewaite, 1973; Gram et al., 1974). Blood samples for drug assay were drawn once or twice weekly from fasting patients in the morning 15 h after last drug intake. In five patients blood samples were drawn with :1-3-h intervals throughout a 24-h period at a time when they had reached steady state during IP treatment. Blood samples were taken in heparinized tubes and plasma obtained by centrifngation was stored frozen ( 20 ~ until analysis. Assay of IP and DMI in plasma was carried out by quantitative in situ thin layer chromatography as described by Nagy and Treiber (1973). Coefficient of variation of assays made in duplicate was 4 - 6 ~ for both compounds at all concentration levels. Steady-state
?
8 a.m,
Fig. 1 Fluctuations in plasma level of imipramine and desipramine throughout a 24-h period in five patients in steady state on oral imipramine treatment. ~ 0 : Pat. No. I (50 mg • 3); O - - O : Pat. No. 2 (50 m g x 3); n - - E 1 : Pat. No. 3 (50 mg• 9 9 Pat. No. 4 (75 + 75 + 50 mg); -" I1: Pat. No. 5 (75 mg x 3)
levels were calculated as the mean of the last two concentration measurements after 3 - 5 weeks treatment in most cases. In 8 patients that had low levels (IP < 50 ~tg/l, DM1 < 170 l-tg/1)the steady-state levels were calculated from samples drawn after ] 0 - 1 4 days of treatment on full dose of IP. For comparison of steady-state levels, the measurements were corrected to a dose of 3.5 mg/kg per day. The three patients that had the dose reduced after 2 weeks due to side effects all had high DMI levels. In these cases corrected steadystate levels were calculated as the mean of the measurements at the two dose levels_ For statistical analysis of differences nonparametric statistics were used (Kruskal-Wallis, Mann-Whitney U-test, Wilcoxon test for pair differences) as well as Student's t-test and F-test on logarithmically transformed data. As a measurement of intraindividual variations, SDs were calculated.
RESULTS P l a s m a levels o f I P a n d D M I t h r o u g h o u t t h e d a y i n five p a t i e n t s t r e a t e d w i t h I P f o r a t l e a s t 3 w e e k s a r e s h o w n i n F i g u r e 1. T h e I P levels v a r i e d w i t h a f a c t o r o f 2 a n d t h e D M I levels v a r i e d s l i g h t l y less. A s s h o w n in T a b l e 1, t h e m o r n i n g p l a s m a c o n c e n t r a t i o n in p e r cent of average concentration throughout the day was 6 0 - 70 ~ f o r I P , a n d 75 - 85 ~ f o r D M I . A s e x p e c t e d ,
L. F. G r a m e t a l . : Steady-State Kinetics of ~[mipramine in Patients
257
Table I. Morning plasma concentration of imipramine (IP) and desipramine (DMI) in btg/l and %; of mean concentration of the preceding 24-h period. All patients were in stead}, state Patient No.
Sex
1
f
2 3 4 5
m m f m
Table 2.
Age (years)
44 32 47 26 20
Body weight (kg)
Imipramine dose (rag)
IP
DMI
IP + D M I
~g/1
To
btg/1
o/(,
pg/'i
47 75 70 67 66
50 x 3
41
50 x 3 50 x 3 75 + 75 + 50 75 • 3
38 52 34 27
59 58 72 70 60
45 53 91 86 51
74 79 84 85 77
86 91 I43 110 78
65 69 79 81 70
Differences (A) between plasma leveis after 1st, 2nd, 3rd, and 4th week (w) on constant dose of imipramine
Steady-state level 1P 0
49pg/1
lP 50-
99 btg/t
IP 100
199 ~tg/l
I.
w/2.
w
1. w/3. w
2. w/3. w
3. w/4. w
N A +_ SD P N 3 _+ SD P
30 2.8 +_ 9.5 NS 23 4.2 • 15.9 NS
25 3.2 + 10.4 NS 18 8.3 _+ I4.2 < 0.05
25 0.2 • 9.9 NS 20 3.5 _+ !3.1 NS
23 - 0.8 _+ 7.7 NS 16 2.4 i 10.9 NS
N A _+ SD P
13 19.8 ,+ 19.5 < 0.01
11 I5.6 + 21.5 < 0.05
13 2.5 + 22.2 NS
8 7.1 _+ 14.0
DMI 0 49 big/1
N d _+ SD P
6 4.6 _+ 8.6 NS
5 7.2 • I3.2 NS
5 4.0 • !3.8 NS
4 8.8 _+ I3.4
DMI 50--991ag/1
N A _+ SD P
25 14.0 _+ 17.7 < 0.0i
2I 17.4 _+ 16.2 < 0.01
21 33 +_ 15.9 NS
17 - 4.7 ,+ 19.6 NS
DMI 100 199 ~tg/]
N d _+ SD P
23 33.8 ,+ 16.4 < 0.01
2I 36.3 ,+ 31.9 < 0.01
23 3.0 _+ 33.3 NS
17 0.1 ,+ 22.3
N A _+ SD P
i4 83.4 _+ 62.2 < 0.01
9 111.6 + 79.8 < 0,01
11 43.7 +_ 66.5 < 0.05
DMI > 200 pg/l
NS
NS 9 28.6 +_ 63.8 NS
SD : standard deviation of difference, N: number of patients, P . significance level of difference (Wilcoxon test for pair-differences)
patients with lower plasma levels tended to ha,~e the most pronounced fluctuations. In some patients a slight rise in plasma levels was seen early in the morning in spite of no additional drug intake. The time it takes to reach steady-state level and the fluctuations from week to week were analysed by comparing the concentration measurements obtained after 1, 2, 3, and 4 weeks on a constant dose of IP. As shown in Table 2, when the IP and DMI leveIs were below 50 lag/l, there was no significant further increase in levels after the first week of treatment. For patients with IP and/or DMI levels of 5 0 - 2 0 0 lag/l, there was a significant rise in plasma ievets during the second week of treatment. In patients with D M I levels above 200 lag/1 a significant further rise in
plasma levels was seen in the third week of treatment. The fluctuations from week to week expressed in terms of standard deviations (SD) were about 1 0 - 20 at all concentration levels (Table 2). The steady-state levels corrected for differences in dosage and body weight showed pronounced individual variations (Fig.2). ]P levels ranged from 6 - 3 5 6 lag/l, DMI from 24-.659 lag/l, and [P + DMI from 5 8 - 8 0 9 gg/1. The distribution of the steadystate levels was quite skewed, but as shown in Figure 3 logarithmic transformation of the concentration measurements yielded histograms close to a normal distribution. The mean values calculated in this way (ant• of mean log concentration) were close to the median values; for IP: 58 and 56 lag/i respectively,
258
Psychopharmacology 54 (1977) STEADY-STATE PLASMA LEVELS CORRECTED FOR DIFFERENCES IN DOSE AND BODY WEIGHT IN 70 PATIENTS ON IMIPRAMINE
pg/I 400
300-
O
200"
I
I
Q
100-
e
iI 9
#9
9 D e
100
260
,~e
~o
560
600
700 Hg/I
Fig. 2 Corresponding plasma steady-state levels of imipramine and desipramine corrected to imipramine dose of 3.5 mg/kg per day in 76 patients
DESIPRAMINE
DISTRIBUTION OF STEADY STATE PLASMA LEVELS IN 76 PATIENTS ON IMIPRAMINE Nr
IMIPRAMINE
10
DESIPRAMINE
N IMIPRAMINE +
20,
DESIPRAMINE
10'
10
30
100
300
1000 3000 yg/i
Fig. 3. Distribution histograms (log-scale) of dose and weight corrected steady-stateplasma levelsof imipramineand desipramine in 76 patients treated with imipramine
and for DMI 116 and 111 lag/l respectively. Figure 2 shows that there was no clear positive or negative correlation between plasma levels of IP and DMI. The majority of patients (N = 60) had plasma levels of IP below 150 lag/1 and DMI below 300 lag/1. Eight patients had IP < 150 lag/1 and DMI > 300 lag/l, and another eight patients had IP > 150 gg/1 and DMI < 300 gg/1. No patients had both IP and DMI levels above these limits. The ratio IP/DMI varied from 0.07 to 5.5, and the log ratio IP/DMI showed a normal distribution (Fig. 4). Compared with AT/NT ratios measured under similar conditions as in this study (Montgomery and Braithwaite, 1975), the IP/DMI ratio (antilog mean log IP/DMI = 0.503, median value = 0.469) was significantly lower (P < 0.01) than the AT/NT ratio (antilog mean log AT/NT = 1.10, median value = 1.12). The IP/DMI ratio also showed a significantly larger individual variation than did the AT/NT ratio (F-test on log ratios: P < 0.001). Comparison of different age-sex groups (Fig. 5) showed markedly different steady-state levels, in particular with IP (Kruskal-Wallis test: P < 0.01). For IP: Women aged 3 0 - 3 9 had lower levels than women aged 2 0 - 2 9 , 4 0 - 4 9 , and 5 0 - 5 9 , and men aged 5 0 - 5 9 and 6 0 - 6 5 ; men aged 3 0 - 3 9 had lower levels than men aged 5 0 - 6 5 . For DMI: Women aged 3 0 - 39 had lower levels than women aged 5 0 - 59, and for IP + DMI women aged 3 0 - 3 9 had lower levels than women aged 5 0 - 59 and men aged 5 0 - 59 and 6 0 - 6 5 (Table 3). DISCUSSION The present data on steady-state kinetics of IP are generally in accordance with previous studies on single dose kinetics of IP and DMI (Gram and Christiansen,
L. g. Gram et al. : Steady-State Kinetics of Imipramine in Patients
259 STEADY-STATE PLASMA LEVELS OF IIlPRA,.~IINE
IN RELATION TO SEX AND
AGE AGE GROUPS (YEARS l
RATIO IN PLASMA BETWEEN TERTIARY AND
#g/l!
SECONDARY AMINES OF TRICYCLIC
300~
20-29
30-39
60-65
40-49
ANTIDEPRESSANTS o
%0i
IMIPRAMINE
o
N
20,
30 10.
10IP/DMI - )
%
I
pg/~ 300-
ANBTRIPTYLINE *
3oI
o
(N:2e)
F
0.1
PsychopImrmacology54, 255-261 (t 977)
:~ by Springer-Verlag t977
Steady-State Kinetics of Imipramine in Patients LARS F. GRAM*"*, IB SONDEROAARD1, JOHANNES CHRIST!ANSEN2, GORM ODDEN PETERSEN3, PER BECH3, NIELS REISBY4, [LSE IBSEN4, .IQRGEN ORTMANN~, ADAM NAGY5, SVEN J. DENCKER 5, OVE JACOBSEN6, and OLE KRAUTWALD6 Department of Pharmacology, University of Copenhagen, Denmark 2 Department of Clinical Chemistry A, Rigshospitalet, University of Copenhagen, Denmark 3 Department of Psychiatry, Rigshospitalet, Universityof Copenhagen, Denmark 4 Department of Psychiatry, Municipai Hospital, Copenhagen, Denmark Department II, Lillhagen Hospital and Department of Clinical Chemistry, Sahlgren's Hospital, Gothenburg, Sweden 6 Department P, State Mental Hospital, Glostrup, Denmark
Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 rag/day for 2 - 5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and D M I showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of lip and/or D M I below 50 btg/1 reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2 - 3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: ~ 0 - 2 0 ~ ) . Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6 - 356 ~tg/!, D M I : 2 4 - 659 gg/1 and IP + D M I : 5 8 - 8 0 9 gg/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the I P / D M I ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state ieve!s between age groups were found. For IP: Women aged 3 0 - 39 had lower levels than women aged 2 0 - 29, 4 0 - 49, and 5 0 - 59, and men aged 50 - 59 and 60 - 65; men aged 3 0 - 3 9 had lower levels than men aged 6 0 - 6 5 . For D M I : Women aged 3 0 - 3 9 had lower levels than women aged 5 0 - 5 9 . Abstract.
Address jbr qffprint requests: L.F. Gram, M.D., Western Psychiatric Institute and Clinic University of Pittsburgh, 381l O'Hara Street, Pittsburgh, PA 15261, U.S.A. *
Key ~,,ords." t m i p r a m i n e -
D e s i p r a m i n e - Steadystate levels - Individual variation - Age differences - Hepatic elimination -- Protein binding Logaritl"mic transformation
Ten years ago it was shown tkat the steady-state plasma concentration of desipramine (DMI) and nortriptyline (NT) varies considerab!y among patients given identical doses (Hammer and Sj6qvist, 1967). A study on the urinary excretion rate of imipramine (IP) metaboiites showed a similar pronounced individual variation (Christiansen et al., 1967). A number of subsequent studies have shown that this variability in particular is due to individual variations in hepatic elimination of tricyclic antidepressants (Gram, 1974). Methods for measuring plasma levels of the secondary amines D M I and N T have been available for several years and the steady state kinetics of these compounds have been thoroughly studied (Alexanderson, 1972). Methods for determination of the tertiary amines (IP and amitriptyline AT) have only recently become available (e.g., Nagy and Treiber, 1973) and the steady-state kinetics of these compounds have so far been much less studied. There is increasing evidence indicating a clear clinical significance in measuring piasma levels of tricyc!ic antidepressants (Gram, 1977). Universal agreement on this has not been reached, but methodological problems seem to explain some of the discrepancies between the results of different groups. Some of these problems concern pharmacokinetics, and the aim of this study was to analyse some of these factors in relation to IP treatment. The data on steady-state kinetics of !P were mainly collected from a controlled study on the plasma level/effect relationship that is being reported in detail elsewhere (Gram et al., 1976a; Reisby et al., 1977).
256
Psychopharmacology 54 (1977)
DIURNAL FLUCTUATIONS OF PLASMA LEVELS DURING IMIPRAMINE TREATMENT
1 = : Oral administration of imipramine IMIPRAMINE
pg/i 100
--.'o/
/ 50 m/-
9
t
j
t
m-- 9
4"
DESIPRAMINE
pal i 150
100
50
o
f.,,~,~..~.e-.... -. ~ T
a.m.
MATERIALS
~ . r ,
?
1 p.m.
AND
1"
5 p.m.
HOURS
METHODS
Seventy-six patients, 24 men and 52 women aged 2 0 - 6 5 , from four psychiatric units in Gothenburg and Copenhagen were studied. Sixty-six of these patients participated in a controlled plasma level,/ effect study (Reisby et al., :1977). Sixty-three patients were given IP 225 mg/day, 4 patients had IP 200 mg/day, and 7 patients had IP 150 mg/day. The dose was increased to maximum over a period of 3 - 4 days. Three patients who suffered from severe side effects on 225 mg/day during the first 2 weeks then had the dose reduced to 150 mg/day for the following 2 - 3 weeks. IP was given orally as tablets (Tofranil ~) in three divided doses at 8.00 a.m., 1.00 p.m., and 5.00 p.m. The patients were observed ingesting the tablets. As additional medication, nitrazepam 5 - 1 5 mg/day was permitted. Benzodiazepines have been shown not to interfere with the kinetics of tricyclic antidepressants (Silver 9 and Braithewaite, 1973; Gram et al., 1974). Blood samples for drug assay were drawn once or twice weekly from fasting patients in the morning 15 h after last drug intake. In five patients blood samples were drawn with :1-3-h intervals throughout a 24-h period at a time when they had reached steady state during IP treatment. Blood samples were taken in heparinized tubes and plasma obtained by centrifngation was stored frozen ( 20 ~ until analysis. Assay of IP and DMI in plasma was carried out by quantitative in situ thin layer chromatography as described by Nagy and Treiber (1973). Coefficient of variation of assays made in duplicate was 4 - 6 ~ for both compounds at all concentration levels. Steady-state
?
8 a.m,
Fig. 1 Fluctuations in plasma level of imipramine and desipramine throughout a 24-h period in five patients in steady state on oral imipramine treatment. ~ 0 : Pat. No. I (50 mg • 3); O - - O : Pat. No. 2 (50 m g x 3); n - - E 1 : Pat. No. 3 (50 mg• 9 9 Pat. No. 4 (75 + 75 + 50 mg); -" I1: Pat. No. 5 (75 mg x 3)
levels were calculated as the mean of the last two concentration measurements after 3 - 5 weeks treatment in most cases. In 8 patients that had low levels (IP < 50 ~tg/l, DM1 < 170 l-tg/1)the steady-state levels were calculated from samples drawn after ] 0 - 1 4 days of treatment on full dose of IP. For comparison of steady-state levels, the measurements were corrected to a dose of 3.5 mg/kg per day. The three patients that had the dose reduced after 2 weeks due to side effects all had high DMI levels. In these cases corrected steadystate levels were calculated as the mean of the measurements at the two dose levels_ For statistical analysis of differences nonparametric statistics were used (Kruskal-Wallis, Mann-Whitney U-test, Wilcoxon test for pair differences) as well as Student's t-test and F-test on logarithmically transformed data. As a measurement of intraindividual variations, SDs were calculated.
RESULTS P l a s m a levels o f I P a n d D M I t h r o u g h o u t t h e d a y i n five p a t i e n t s t r e a t e d w i t h I P f o r a t l e a s t 3 w e e k s a r e s h o w n i n F i g u r e 1. T h e I P levels v a r i e d w i t h a f a c t o r o f 2 a n d t h e D M I levels v a r i e d s l i g h t l y less. A s s h o w n in T a b l e 1, t h e m o r n i n g p l a s m a c o n c e n t r a t i o n in p e r cent of average concentration throughout the day was 6 0 - 70 ~ f o r I P , a n d 75 - 85 ~ f o r D M I . A s e x p e c t e d ,
L. F. G r a m e t a l . : Steady-State Kinetics of ~[mipramine in Patients
257
Table I. Morning plasma concentration of imipramine (IP) and desipramine (DMI) in btg/l and %; of mean concentration of the preceding 24-h period. All patients were in stead}, state Patient No.
Sex
1
f
2 3 4 5
m m f m
Table 2.
Age (years)
44 32 47 26 20
Body weight (kg)
Imipramine dose (rag)
IP
DMI
IP + D M I
~g/1
To
btg/1
o/(,
pg/'i
47 75 70 67 66
50 x 3
41
50 x 3 50 x 3 75 + 75 + 50 75 • 3
38 52 34 27
59 58 72 70 60
45 53 91 86 51
74 79 84 85 77
86 91 I43 110 78
65 69 79 81 70
Differences (A) between plasma leveis after 1st, 2nd, 3rd, and 4th week (w) on constant dose of imipramine
Steady-state level 1P 0
49pg/1
lP 50-
99 btg/t
IP 100
199 ~tg/l
I.
w/2.
w
1. w/3. w
2. w/3. w
3. w/4. w
N A +_ SD P N 3 _+ SD P
30 2.8 +_ 9.5 NS 23 4.2 • 15.9 NS
25 3.2 + 10.4 NS 18 8.3 _+ I4.2 < 0.05
25 0.2 • 9.9 NS 20 3.5 _+ !3.1 NS
23 - 0.8 _+ 7.7 NS 16 2.4 i 10.9 NS
N A _+ SD P
13 19.8 ,+ 19.5 < 0.01
11 I5.6 + 21.5 < 0.05
13 2.5 + 22.2 NS
8 7.1 _+ 14.0
DMI 0 49 big/1
N d _+ SD P
6 4.6 _+ 8.6 NS
5 7.2 • I3.2 NS
5 4.0 • !3.8 NS
4 8.8 _+ I3.4
DMI 50--991ag/1
N A _+ SD P
25 14.0 _+ 17.7 < 0.0i
2I 17.4 _+ 16.2 < 0.01
21 33 +_ 15.9 NS
17 - 4.7 ,+ 19.6 NS
DMI 100 199 ~tg/]
N d _+ SD P
23 33.8 ,+ 16.4 < 0.01
2I 36.3 ,+ 31.9 < 0.01
23 3.0 _+ 33.3 NS
17 0.1 ,+ 22.3
N A _+ SD P
i4 83.4 _+ 62.2 < 0.01
9 111.6 + 79.8 < 0,01
11 43.7 +_ 66.5 < 0.05
DMI > 200 pg/l
NS
NS 9 28.6 +_ 63.8 NS
SD : standard deviation of difference, N: number of patients, P . significance level of difference (Wilcoxon test for pair-differences)
patients with lower plasma levels tended to ha,~e the most pronounced fluctuations. In some patients a slight rise in plasma levels was seen early in the morning in spite of no additional drug intake. The time it takes to reach steady-state level and the fluctuations from week to week were analysed by comparing the concentration measurements obtained after 1, 2, 3, and 4 weeks on a constant dose of IP. As shown in Table 2, when the IP and DMI leveIs were below 50 lag/l, there was no significant further increase in levels after the first week of treatment. For patients with IP and/or DMI levels of 5 0 - 2 0 0 lag/l, there was a significant rise in plasma ievets during the second week of treatment. In patients with D M I levels above 200 lag/1 a significant further rise in
plasma levels was seen in the third week of treatment. The fluctuations from week to week expressed in terms of standard deviations (SD) were about 1 0 - 20 at all concentration levels (Table 2). The steady-state levels corrected for differences in dosage and body weight showed pronounced individual variations (Fig.2). ]P levels ranged from 6 - 3 5 6 lag/l, DMI from 24-.659 lag/l, and [P + DMI from 5 8 - 8 0 9 gg/1. The distribution of the steadystate levels was quite skewed, but as shown in Figure 3 logarithmic transformation of the concentration measurements yielded histograms close to a normal distribution. The mean values calculated in this way (ant• of mean log concentration) were close to the median values; for IP: 58 and 56 lag/i respectively,
258
Psychopharmacology 54 (1977) STEADY-STATE PLASMA LEVELS CORRECTED FOR DIFFERENCES IN DOSE AND BODY WEIGHT IN 70 PATIENTS ON IMIPRAMINE
pg/I 400
300-
O
200"
I
I
Q
100-
e
iI 9
#9
9 D e
100
260
,~e
~o
560
600
700 Hg/I
Fig. 2 Corresponding plasma steady-state levels of imipramine and desipramine corrected to imipramine dose of 3.5 mg/kg per day in 76 patients
DESIPRAMINE
DISTRIBUTION OF STEADY STATE PLASMA LEVELS IN 76 PATIENTS ON IMIPRAMINE Nr
IMIPRAMINE
10
DESIPRAMINE
N IMIPRAMINE +
20,
DESIPRAMINE
10'
10
30
100
300
1000 3000 yg/i
Fig. 3. Distribution histograms (log-scale) of dose and weight corrected steady-stateplasma levelsof imipramineand desipramine in 76 patients treated with imipramine
and for DMI 116 and 111 lag/l respectively. Figure 2 shows that there was no clear positive or negative correlation between plasma levels of IP and DMI. The majority of patients (N = 60) had plasma levels of IP below 150 lag/1 and DMI below 300 lag/1. Eight patients had IP < 150 lag/1 and DMI > 300 lag/l, and another eight patients had IP > 150 gg/1 and DMI < 300 gg/1. No patients had both IP and DMI levels above these limits. The ratio IP/DMI varied from 0.07 to 5.5, and the log ratio IP/DMI showed a normal distribution (Fig. 4). Compared with AT/NT ratios measured under similar conditions as in this study (Montgomery and Braithwaite, 1975), the IP/DMI ratio (antilog mean log IP/DMI = 0.503, median value = 0.469) was significantly lower (P < 0.01) than the AT/NT ratio (antilog mean log AT/NT = 1.10, median value = 1.12). The IP/DMI ratio also showed a significantly larger individual variation than did the AT/NT ratio (F-test on log ratios: P < 0.001). Comparison of different age-sex groups (Fig. 5) showed markedly different steady-state levels, in particular with IP (Kruskal-Wallis test: P < 0.01). For IP: Women aged 3 0 - 3 9 had lower levels than women aged 2 0 - 2 9 , 4 0 - 4 9 , and 5 0 - 5 9 , and men aged 5 0 - 5 9 and 6 0 - 6 5 ; men aged 3 0 - 3 9 had lower levels than men aged 5 0 - 6 5 . For DMI: Women aged 3 0 - 39 had lower levels than women aged 5 0 - 59, and for IP + DMI women aged 3 0 - 3 9 had lower levels than women aged 5 0 - 59 and men aged 5 0 - 59 and 6 0 - 6 5 (Table 3). DISCUSSION The present data on steady-state kinetics of IP are generally in accordance with previous studies on single dose kinetics of IP and DMI (Gram and Christiansen,
L. g. Gram et al. : Steady-State Kinetics of Imipramine in Patients
259 STEADY-STATE PLASMA LEVELS OF IIlPRA,.~IINE
IN RELATION TO SEX AND
AGE AGE GROUPS (YEARS l
RATIO IN PLASMA BETWEEN TERTIARY AND
#g/l!
SECONDARY AMINES OF TRICYCLIC
300~
20-29
30-39
60-65
40-49
ANTIDEPRESSANTS o
%0i
IMIPRAMINE
o
N
20,
30 10.
10IP/DMI - )
%
I
pg/~ 300-
ANBTRIPTYLINE *
3oI
o
(N:2e)
F
0.1
