Clinical Pharmacokinetics 8: 179-185 (1983) 0312-5963/83/0003-0179/$03.50/0 © ADIS Press Australasia Pty Ltd. All rights reserved.
Original Research Article
Clinical Pharmacokinetics of Dothiepin Single-dose Kinetics in Patients and Prediction of Steady-state Concentrations
KP. Maguire, T.R. Norman, I. Mcintyre and G.D. Burrows Department of Psychiatry, University of Melbourne, Parkville, Melbourne
Summary
The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (±SD) peak plasma concentrations of dothiepin were 49 ± 27 pg/L at 3 ± 1.2h. Mean (±SD) estimates ofother parameters were asfollows: absorption half-life 1.1 ± 1.lh; distribution half-life 2.2 ± G.8h; elimination half-life 25 ± 7h; apparent volume of distribution 70 ± 62 L/kg; and oral clearance 2.1 ± 1.6 L/kg/h. The mean (± SD) peak plasma concentration of dothiepin S-oxide was 125 ± 43 pg/L at 3.5 ± l.3h with an elimination half-life of 22 ± 12h. The mean peak plasma concentration of northiaden was 6 ± 3 pg/L at 4.5 ± 1.1 h. with an elimination half-life of 31 ± 12h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained follOWing 4 weeks' treatment with dothiepin 150mg nocte.
Dothiepin is a tricyclic antidepressant similar in structure to amitriptyline and doxepin. To date, two pharmacokinetic studies have been carried out, both involving administration of single oral doses to healthy volunteers (Maguire et a!., 1981 a; Rees, 1981). The present study was undertaken to investigate the oral kinetics of the drug in depressed patients, and to compare the kinetic parameters obtained with those from the previous study in healthy volunteers (Maguire et a!., 1981a). Differ-
ences in kinetic parameters between healthy volunteers and depressed patients have been reported for another tricyclic antidepressant, nortriptyline, by Braithwaite et a!. (1978) and Dawling et a!. (1980). It has been shown in several studies that parameters obtained from single oral doses can be used to predict steady-state concentrations for nortriptyline, amitriptyline and imipramine (Alexanderson, 1972a,b, 1973; Cooper and Simpson, 1978; Brunswick et aI., 1979; Montgomery et aI., 1979;
Clinical Pharmacokinetics of Dothiepin
180
Redmond et ai., 1980; Potter et at, 1980). The use of 24-hour concentrations to predict steady-state concentrations was examined in the present study.
Methods Nine patients admitted to the Psychiatric unit at the Royal Melbourne Hospital took part in the study, after giving informed consent. They were diagnosed on clinical grounds as suffering from a primary depressive illness of such severity as to require antidepressant treatment. None was suffering from
200
any major physical illness and none was receiving any concomitant medication; however, benzodiazepines were allowed for night sedation if necessary. The patients' mean age was 51 years (range 27-78y) and their mean weight was 65kg (range 5383kg). Two hours after breakfast, the patients ingested three 25mg dothiepin capsules. Lunch was not allowed until 5 to 6 hours after administration of the drug. 20ml blood samples were taken prior to the dose, then hourly for 7 hours from an indwelling heparinised catheter in an arm vein. A further 5 samples were taken by venepuncture over the next
o
= Dothiepin concentration in blood
•
= Dothiepin concentration in plasma
o = Dothiepin S-oxide concentration in blood • = Dothiepin S-oxide concentration in plasma
100
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Time after dose (h) Fig. 1. The mean plasma and blood concentrations of dothiepin and dothiepin S-oxide obtained following oral administration of 75mg of dothiepin in 9 depressed patients.
181
Clinical Pharmacokinetics of Dothiepin
Table I. Dothiepin kinetic parameters obtained from 9 depressed patients -following a single oral dose of 75mg Pat. no.
Sex
Fluid analysed
T
lag
(h)
(h)
2 3 4
5 6
7
8 9
Peak conc. (Jtg/L)
(h)
Peak time
t'hd
AUC
(h)
(h)
(l'g/L • h) (L/kg)
Vd,i
Clo,., (L/kg/h)
F
Plasma Blood
1.78 1.98
1.50 1.20
19 12
5 5
1.5 1.2
27 17
238 132
195.5 228.6
5.05 9.17
F
Plasma Blood
0.91 1.20
0.54 0.24
32 28
3 2.5
3.4 2.2
20 12
549 427
61.1 45.3
2.10 2.70
Plasma Blood
0.58 0.54
0.64 0.63
95 75
2.5 2.5
1.8 2.8
18 19
1778 1349
18.8 25.4
0.71 0.94
Plasma Blood
0.41 0.28
0.10 0.22
81 52
1.5 1.5
3.6 3.3
24 17
1171 789
42.7 44.1
1.21 1.79
Plasma Blood
0.18 0.99
3.85 2.30
42
4
32
4
1.5 2.3
27 19
990 658
28.2 49.8
1.20 1.84
Plasma Blood
0.96 0.97
0.53 0.35
26 19
2 2
1.8 3.3
25
313
22
205
155.6 211.2
- 4.36 6.65
Plasma Blood
0.95 0.86
1.50
40 27
4
2.00
4
1.5 2.1
25 19
595 393
50.7 67.9
1.80 2.73
Plasma Blood
1.40 1.40
0.41 0.10
38 37
2.5 2.5
1.9 3.2
17 16
660 468
38.4 49.3
1.56 2.19
Plasma Blood
0.43 0.44
0.63 0.53
72 51
2 2
2.4 3.3
42
1411 1103
39.1 49.7
0.64 0.82
M F
F
F F M F
48 hours. Samples were taken into heparinised tubes then divided into 2 parts. One part was stored frozen as whole blood, the other centrifuged and the plasma separated and stored frozen. Blood and plasma samples were analysed for dothiepin and its 2 major metabolites northiaden and dothiepin 8-oxide by gas chromatography-mass fragmentography (Maguire et aI., 1981b). The methodology showed good precision over the concentration range 2-100 J.lg/L, and the limit of sensitivity was I J.lg/L. The kinetics of dothiepin were examined using a 2-compartment open model. The blood or plasma concentrations of dothiepin were fitted to the equation:
by computer (Cyber 73) using a non-linear least squares fitting programme where T is the lag time
42
of absorption. Half-lives of absorption [tV,.bs], distribution [tv",] and elimination [t'hl1] were calculated from 0.693/k., 0.693/a, and 0.693/fJ respectively. The area under the concentration time curve (AUC) was estimated using the trapezoidal rule and the infinite part calculated as the last measured concentration divided by fJ. The apparent volume of distribution [Vd l1 ] was calculated as dose· f/AUC • {1, and the oral clearance [Cloral ] as dose' fjAUe. The fraction, f, which represents that part of the dose remaining after losses due to incomplete absorption or first-pass metabolism, was assumed to be I (see discussion). Following the single-dose study, the patients were treated with 150mg dothiepin nocte for 4 weeks. Their blood and plasma concentrations of dothiepin and its major metabolites were monitored; their relationship to clinical response is reported elsewhere (Maguire et aI., 1982).
Clinical Pharmacokinetics of Dothiepin
Results Single-dose Kinetics The mean blood and plasma concentrations of dothiepin and the major metabolite, dothiepin Soxide, obtained following the single oral dose of 75mg are shown in figure 1. The mean values for northiaden are not included because in some patients the data was incomplete due to concentrations falling below the limit of detection of the assay. The plasma and blood concentrations of dothiepin were fitted to the triexponential equation as described above. The concentrations were weighted as l/y and a good fit (r > 0.95) was obtained for all patients. The individual values for T, t'''abo, peak concentrations, time to reach the peak, t.IlP , AUC, Vdfl and Cl oral are presented in table I. The mean values for the patients are compared with those obtained previously in healthy volunteers (Maguire et al., 1981a) in table II. No significant differences were found between the patient and healthy volunteer groups for any of the parameters (p > 0.05; Mann Whitney 'U' test). Also, no correlations were found between age and any of the parameters (Spearman correlations). However, a significant difference was found between males and females (combined patient and healthy volunteer data) for t'/'/3 (p < 0.005; Mann Whitney 'U' test) and for Vd/3 (p < 0.05; Mann Whitney 'U' test). The mean values (± SD) for t'12,6 were females 28 ± 7h and males 18 ± 4h. For Vd{l, the mean values were females 83.1 ± 61.0 L/ kg and males 35.4 ± 17.2 L/kg. The patient group comprised 2 males and 7 females (table I), while the healthy volunteer group comprised 6 males and 1 female (Maguire et al., 1981a). The mean peak concentrations, time to reach the peak and t"'1l for the metabolites, northiaden and dothiepin S-oxide, are given in table III. The data for the healthy volunteers from the previous study are included for comparison. No significant differences were found between the 2 groups (p >
182
0.05; Mann Whitney 'U' test). A significant difference was found between males and females (combined patient and healthy volunteer data) for t'/'{l for northiaden (p < 0.05; Mann Whitney 'U' test) but not for t'/'{l for dothiepin S-oxide. The mean t./,,6 for northiaden in females was 31 ± 11 h and in males 25 ± 12h, while the mean t./,,6 for dothiepin S-oxide in females was 21 ± 13h and in males 21 ± 9h. Prediction of Steady-state Concentrations The steady-state dothiepin concentrations obtained during the fourth week of treatment with dothiepin 150mg nocte were highly correlated with the concentrations obtained 24 hours following the single dose [blood concentrations, r = 0.8886 (p < 0.001); plasma concentrations, r = 0.8808 (p < 0.001)]. Dothiepin S-oxide concentrations at steadystate were also correlated with the 24-hour concentrations [blood concentrations, r = 0.6995 (p < 0.02); plasma concentrations, r = 0.8331 (p < 0.01)]. Plasma northiaden concentrations at 24 hours were not measurable in some patients; hence a correlation with steady-state concentrations was not examined.
Discussion The pharmacokinetic profile of dothiepin following oral administration to depressed patients was very similar to that observed in young healthy volunteers. Following a lag time of nearly 1 hour, dothiepin was rapidly absorbed, reaching a peak at around 3 hours after administration. Distribution was also rapid, while elimination was slower with a mean t'hll of 20 hours. Estimates of the apparent volume of distribution and oral clearance were higher in the patient group but this did not reach significance. The mean age of the patient group was twice that of the volunteers but age was not correlated with any of the kinetic parameters.
Clinical Pharmacokinetics of Dothiepin
183
Table II. Comparison of parameters (mean ± SO) calculated from plasma dothiepin concentrations following a single oral dose of 75mg dothiepin to 7 healthy volunteers and 9 depressed patients
Parameter
Healthy volunteers 1
Depressed patients 2
Age (y) T(h) t wab , (h) Peak concentration ("gIL) Peak time (h) t'l," (h) t'l,P (h) AUC (l'g/Loh) Vd~ (L/kg) Clo'al (L/k9/h)
26 ± 2.4 0.81 ± 0.36 1.2 ± 1.1 47 ± 14 3 ± 1.2 2.6 ± 1.1 20 ± 7.1 821 ± 213 45.4 ± 26.6 1.36 ± 0.3
50 ± 16.5 0.84 ± 0.51 1.1 ± 1.1 49 ± 27 3 ± 1.2 2.2 ± 0.8 25 ± 7.4 856 ± 519 70.0 ± 61.8 2.08 ± 1.6
1 Data. from Maguire et al. (1981 a). 2 Present study.
In contrast, 2 studies of nortriptyline kinetics (Braithwaite et aI., 1978; Dawling et aI., 1980) have found lowered clearance in depressed patients when compared with healthy volunteers. Again, no correlation was found between age and the pharmacokinetic parameters. Factors such as previous drug exposure, preselection of patients, concomitant medication and illness (both physical and psychiatric) may have contributed to the altered kinetics in their patient groups. Although nortriptyline and dothiepin are chemically similar drugs, their metabolic pathways do differ and this may account for the conflicting finding in terms of clearance rates. Our study suggests that the factors outlined above as well as age do not significantly alter the pharmacokinetic profile of dothiepin.
Sex Differences in Elimination and Distribution When examining our combined data for healthy volunteers and patients, a significant difference was found in elimination half-lives between males and
females. Similarly, a significant difference was found in the apparent volumes of distribution between males and females. Ideally, volumes of distribution should be determined after intravenous administration of a drug. Estimates of Vd(:j following oral dosage should be corrected by f to account for incomplete absorption and first-pass metabolism. Thus the observed sex difference in VdiJ could have arisen from either differences in distribution or differences in first-pass metabolism in males and females. The fact that the same sex difference was found in the elimination half-lives of both dothiepin and northiaden suggests that the sex difference may be related to metabolism, and in particular, demethylation, since a sex difference was not found for the elimination half-life of dothiepin S-oxide. Females had longer half-lives for both dothiepin and northiaden, suggesting slower metabolism than males. In laboratory studies female rats have been shown to metabolise drugs more slowly than male rats (Curry, 1977). Although it is known that demethylation can be induced by smoking, only 5 subjects in our 2 groups were smokers (3 males, 2 females); this would probably be too few to cause a significant effect. The sex difference may also be attributed to females having a slightly slower glomerular filtration rate than males (Curry, 1977). Measurement of urinary excretion of all 3 compounds would perhaps prove interesting. Studies of the pharmacokinetics of other tricyclic antidepressants have not reported any differences between the sexes; however, the majority of studies have either been confined to healthy male volunteers or small numbers of patients (6 to to) in each study. Two larger studies, both involving nortriptyline, have reported no differences in pharmacokinetics between male and female volunteers (Alexanderson, 1973; Dawling et aI., 1980). This may be explained by the difference in metabolic pathways because nortriptyline is largely hydroxylated to lO-hYdroxynortriptyline (Alvan et aI., 1977).
Clinical Pharmacokinetics of Dothiepin
184
Further studies are necessary to confirm this sex difference in elimination half-lives of dothiepin and northiaden, as the numbers presented are still quite small (n = 16). Also, the comparison between the sexes was made using largely young male volunteers and elderly female patients. The observed differences could therefore have arisen from a combination of age and sex, or sex and disease state, and their resultant influence on distribution volume and clearance. Further studies are required to elucidate the mechanism of the differences in kinetics between males and females. However, this sex difference may not be important clinically, as all half-lives were of sufficient length to make once daily administration still appropriate. Due to the small number of male patients it was not possible to see if there was a difference in steady-state concentrations between males and females. Further
Table III. Comparison of mean (± SO) peak concentrations. peak times and elimination half-lives of dothiepin S-oxide and northiaden between healthy volunteers and depressed patients following a single oral dose of 7Smg dothiepin
Parameter
Healthy volunteers 1
Depressed patients2
Dothiepin S-oxide
Plasma peak concentration (pg/L) Blood peak concentration (Pg/L) Peak time (h) t.h , (h)
n.m.3
125 ± 43
81 ± 50
91 ± 38
5 ± 1.1 19 ± 9
3.5 ± 1.3 22 ± 12
10 ± 6
6±3
11 ± 5
11 ± 6
NorthiBden
Plasma peak concentration (l'g/L) Blood peak concentration (l'g/L) Peak time (h) tv.,. (h)
6 ± 2.2 27 ± 12
4.5 ± 1.1 31 ± 12
studies with larger numbers of patients are required to examine this.
Blood/Plasma Concentrations Both blood and plasma concentrations of dothiepin and its 2 metabolites were determined. Dothiepin and dothiepin S-oxide concentrations were higher in plasma than in blood, whereas northiaden concentrations were higher in blood than in plasma. Since the distribution of the 3 compounds in blood and plasma were not equal, blood-derived parameters should be used. However, plasma-derived parameters are used for comparison with previous studies. Dothiepin S-oxide was the major metabolite in both groups. The relationship between steady-state plasma and blood concentrations of dothiepin, dothiepin S-oxide and northiaden, and clinical effect in these patients has been reported elsewhere (Maguire et aI., 1982).
Prediction of Steady-state Concentrations The 24-hour concentrations of both dothiepin and dothiepin S-oxide were good predictors of the steady-state concentrations achieved after 4 weeks' treatment. This is in agreement with studies of other tricyclic antidepressants which have shown that 12hour, 24-hour and 48-hour concentrations, oral clearance, or AUC can be used to predict steadystate concentrations (Alexanderson, 1972a,b; 1973; Cooper and Simpson, 1978; Brunswick et ai., 1979; Montgomery, 1979; Redmond et aI., 1980; Potter et ai., 1980). This study examined only the 24-hour level because this is the most practical as far as outpatient treatment is concerned.
Therapeutic Implications 1 Data from Maguire et a!. (1981a). 2 Present study. 3 n.m. = not measured.
Prediction of whether the patient will develop either very low or very high steady-state levels
Clinical Pharmacokinetics ot Dothiepin
would save the patient from developing side effects which may result from excessive levels, or ensure that the patient receives a large enough dose to give the drug a fair trial. Modification of the usual 40sage may also be necessary if the patient has any physical illnesses or is taking other drugs which may alter dothiepin kinetics. Prediction of steady-state concentrations from single doses thus saves time for the patient and clinician. If future studies find a 'therapeutic window' for dothiepin, then this will become an integral part of therapy. Studies to date on the question of clinical response and dothiepin concentrations are not in agreement, and are reviewed elsewhere (Maguire et aI., 1982).
Acknowledgements The authors would like to thank Ms Pauline Gorhan for technical assistance, and the Boots Co. (Aust.) Pty Ltd for financial assistance.
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Brunswick, D.J.; Amsterdam, J.D.; Mendels, J.; and Stem, S.L: Prediction of steady-state imipramine and desmethylimipramine plasma concentrations from single-dose date. Clinical Pharmacology and Therapeutics 25: 605-610 (1979). Cooper, T.B. and Simpson, G.M.: Prediction of individual dosage of nortriptyline. American Journal of Psychiatry 135: 333-335 (1978). Curry, S.H.: Drug disposition and pharmacokinetics with a consideration of pharmacological and clinical relationships. (Blackwell Scientific Publications, London 1977). Dawling, S.; Crome, P. and Braithwaite, R.: Pharmacokinetics of single oral doses of nortriptyline in depressed elderly hospital patients and young healthy volunteers. Clinical Pharmacokinetics 5: 394-40 I (1980). Maguire, K.P.; Burrows, G.D.; Norman, T.R. and Scoggins, B.A.: Metabolism and Pharmacokinetics of dothiepin. British Journal of Clinical Pharmacology 12: 405-409 (l98Ia). Maguire, K.P.; Norman, T.R.; Burrows, G.D., and Scoggins, B.A.: Simultaneous measurement of dothiepin and its major metabolites in plasma and whole blood by gas-chromatographymass fragmentography. Journal of Chromatography 222: 399408 (l98Ib). Maguire, K.P.; Norman, T.R.; McIntyre, I.; Burrows, G.D. and Davies, B.: Blood and plasma concentrations of dothiepin and its major metabolites and clinical response. Journal of Affective Disorders 4: 41-48 (1982). Montgomery, S.A.; McAuley, R.; Montgomery, D.B.; Braithwaite, R.A. and Dawling, S.: Dosage adjustment from simple nortriptyline spot level predictor tests in depressed patients. Clinical Pharmacokinetics 4: 129-136 (I 979). Potter, W.Z.; Zavadil, A.P.; Kopin, l.J. and Goodwin, F.K.: Single-dose kinetics predict steady-state concentrations of imipramine and desipramine. Archives of General Psychiatry 37: 314-320 (1980). Redmond, F.e.; Bowden, e.L. and Lehman, L.D.: Single-dose prediction of amitriptyline and nortriptyline requirement in unipolar depression. Current Therapeutic Research 27: 635642 (1980). Rees, j.A.: Clinical interpretation of pharmacokinetic data on dothiepin hydrochloride (Dosulepin, Prothiaden). journal of International Medical Research 9: 98-\02 (1981).
Author's address: Dr KP. Maguire, Department of Psychiatry. University of Melbourne, Parkville, Victoria 3052 (Australia).
