EurJ Clin Pharmacol (1991) 41:351-354 EuropeanJournalof (~[~:~(~@~

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© Springer-Verlag 1991

Pharmacokinetics of paroxetine in patients with cirrhosis K. D a l h o f f I, T. P. A l m d a l 1, K. B j e r r u m 1, S. Keiding 1, H. M e n g e l 2, and J. Lund 2

Department of Medicine A, Rigshospitalet, Copenhagen and z CNS Division, Novo Nordisk A/S, SCborg, Denmark Received: January 28, 1991/Accepted in revised form: May 4,1991

Summary, In a 14-day multiple-dose study the p h a r m a c o kinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20-30 m g paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 rag, while all six control subjects received 30 rag. D o s e - c o r r e c t e d , t r o u g h drug c o n c e n t r a t i o n at steady state (CSmSn)and d o s e - c o r r e c t e d AUC24, were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng. ml z per m g paroxetine and 89 vs 43 h (ng) - m l - 1 per m g paroxetine]. T h e elimination tl/2 was p r o l o n g e d [83 vs 36 hi, but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while n o n e of the controls had this symptom. T h e study s h o w e d slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range. K e y words:

Paroxetine,

Cirrhosis;

pharmacokinetics,

multiple-dose study, adverse effects

Paroxetine is a n e w antidepressant drug, which selectively inhibits the presynaptic r e u p t a k e of serotonin. It is well a b s o r b e d after oral administration and about 95% is b o u n d to plasma proteins [1]. The pharmacokinetics of paroxetine in patients with liver cirrhosis was previously investigated in a single-dose study by Krastev et al. [2]. N o difference was f o u n d on c o m p a r i s o n of the results with data from healthy subjects. A s paroxetine will be given to patients for several weeks or even longer, the present multiple-dose study was performed.

Material and m e t h o d s

Subjects Fifteen patients with cirrhosis, aged 28 to 69 y, entered the study together with 6 control subjects (hospital staff) aged 26 to 60 y with no signs of liver disease. All the patients had biopsy proven alcoholic cirrhosis, except one who had primary biliary cirrhosis (PBC). Three patients, including the patient with PBC, left the study after one day, due to nausea. The subjects were asked to report any adverse effects. Before and after treatment with paroxetine clinical and biochemical parameters were determined; the liver tests included alanine aminotransferase (ALT), coagulation factors 2, 7 and 10 (prothrombin index) and bilirubin. Antipyrine clearance (APC) was determined according to DCssing et al. [3], and the gatactose elimination capacity according to Tygstrup [4, 5]. Nine patients received diuretics (nos. 1, 3, 4, 5, 6, 8, 9, 10, 12), five were on cimetidine (nos.3, 4, 6, 8, 9), three on potassium chloride (nos. 6, 9, 10), three on vitamin K (nos. 6, 9, 10) and one patient (no.2) was on disulfiram. None of the patients had clinically significant ascites, encephalopathy or hepatic nephropathy during the study.

Paroxetine administration Paroxetine HC1 tablets were administered orally, in the morning, for 14 days. The daily dose of paroxetine given to each patient was adjusted according to the reduction in liver function, as assessed by the galactose elimination capacity (GEC) (GEC < 30% of expected control value according to sex and weight - 10 rag; 30% < GEC < 70% - 20 mg; GEC > 70% - 30 mg). Only patients with a GEC reduced to 80% or lower were included in the study. In all but two patients who received 30 mg (subjects 11 & 12), the daily dose of paroxetine was 20 rag. In all six control subjects the daily dose of paroxetine was 30 mg.

Sample collection and assay Daily pre-dose blood samples were taken for analysis of paroxetine trough concentrations in plasma, and further samples were collected at intervals for up to 150 h after the last dose. Urine was collected in fractions over two 24-h periods at the end of the two-week dosing cycle (Days 13 and 14). Paroxetine was assayed using an HPLC method with fluorescence detection [6]. The method was described by Brett et aI., who found a within- and between- batch variability of "generally below 10%', a limit of detection of about 0.2 ng. ml- ~,and

352

K. Dalhoff et al.: Paroxetine kinetics in cirrhosis

Table 1. Pharmacokinetic measurements, liver function tests, weight, and ages of twelve patients with cirrhosis given paroxetine p. o. daily for 14 days Patient no

Age y '

Weight kg

APC ° ml- min -1

GEC d mmol.min -~

ss Cmin ng-ml 1 per mg paroxetine

A U G (24 h) h(ng).ml -~ per mg paroxetine

t1/2 h

1 2b 3~ 4a 5 6a 7 8a 9a 10 11 12

52 40 69 34 61 48 54 52 37 28 48 51

45 47 49 53 61 64 66 71 72 95 95 111

27 75 8 7 13 29 36 43 21 21 50 21

0.9 1.5 0.8 1.1 0.9 1.5 1.2 1.6 1.8 1.2 1.7 1.7

3.80 1.25 2.70 2.10 4.10 5.00 3.95 3.20 0.35 6.40 1.70 6.57

97.6 31.9 76.2 49.7 109.0 127.0 99.0 95.7 9.7 164.2 48.1 162.4

42 26 73 42 152 104 56 56 17 89 28 312

4.80 1.90 3.95 2.80 5.55 7.00 4.85 4.55 0.55 7.35 3.07 7.47

1.09 0.24 0.55 0.21 1.44 0.36 0.44 054 0.35 1.86 0.45 0.56

48 (12)

69 (21)

29 (19)

1.3 (0.4)

3.43 (1.94)

89.2 (46.6)

83 (82)

4.49 (2.18)

0.67 (0.52)

Mean (SD)

CSSx ng.ml ~ per mg paroxetine

Urin. excr. mg. day -~

a Received cimetidine, b Received disuIfiram, c Antipyrine clearance (normal ranges: male > 40 ml-min- 1;female > 35 ml. min ~), d Galactose elimination capacity (normal ranges: male > 2.2 mmol-min-~; female > 1.9 mmol. min 1) Table 2. Pharmacokinetic measurements, liver function tests, weight, and ages of six control subjects given paroxetine p. o. daily for 14 days Control no

13 14 15 16 17 18 Mean (SD)

Age y

Weight kg

APC" ml.min 1

GEC b mmol.min -1

ss Groin ng.ml -~ per mg paroxetine

A U G (24 h) h ( n g ) . m l -~ per mg paroxetine

ti/2 h

CSmSax ng-ml i per mg paroxetine

Urin. excr. mg/day

39 47 26 60 41 50

58 62 65 66 78 82

68 81 54 66 37 57

1.9 2.7 2.0 2.4 3.2 2.5

0.87 0.50 1.40 2.27 2.37 1.80

24.8 17.5 39.3 51.8 73.0 48.5

21 14 25 39 45 69

1.83 1.27 2.57 2.93 3.80 2.50

0.13 0.12 0.56 0.95 0.58 0.64

44 (11)

69 (9)

61 (15)

2.5 (0.5)

1.53 (0.75)

45.6 (20.0)

36 (20)

2.48 (0.86)

0.50 (0.32)

Antipyrine clearance (normal range: male >40 ml.min-l; female >35 ml.min-~), b Galactose elimination capacity (normal range: male > 2.2 mmol.min-J; female > 1.9 mmol.min -~)

a limit of reliable determination (LRD) between 0.5 and i ng- ml 1. Analyzing samples from spiked pools of plasma over several years, standard deviations of 29, 9.6, 8.3 and 8.0% have been found at concentrations 2,10, 50 and 100 ng. ml- ~,respectively. The limit of detection was 0.2-0.5 ng. ml- 1and LRD approx 0.5 ng- ml- ~.

Pharrnacokinetic analysis In general, the plasma concentration at steady state (CSmSn)was calculated as the mean of the last three morning plasma concentrations in the second week of treatment (24 h after dosing). The elimination half-life (t~/z) was estimated from the terminal part of the plasma drug concentration vs time curve after the last dose by means of nonlinear regression, using data points from 15 to 150 h after the last dose. The area under the plasma drug concentration-time curve during one dosing interval (AUC24h) was calculated using the trapezoidal rule from the time of the last dose of paroxetine, and the maximum concentration achieved during this interval (C~S×) was noted.

Statistical analysis Differences in pharmacokinetic measurements between the two groups of subjects, and differences in liver function tests before and after paroxetine treatment, were tested using Student's t-test for

paired observations. P < 0.05 was considered statistically significant. Correlation coefficients were calculated by regression analysis.

Ethics The study was performed in accordance with the Helsinki II Declaration adopted by the 18th World Medical Assembly, Helsinki, Finland in June 1964, as amended by the 29th World Medical Assembly, Tokyo, Japan, in October 1975, and the 35th World Medical Assembly, Venice, Italy, in October 1983. Written informed consent for participation in the study was obtained from all subjects, and the protocol was approved by the Ethics Committee for the Copenhagen hospitals.

Results A g e , b o d y w e i g h t , l i v e r f u n c t i o n tests a n d p h a r m a c o k i n e t i c m e a s u r e m e n t s in t h e c i r r h o t i c p a t i e n t s a n d t h e c o n t r o l s u b j e c t s are s h o w n in T a b l e s i a n d 2, r e s p e c t i v e l y . T h e r e was n o c o r r e l a t i o n b e t w e e n age, w e i g h t , G E C o r A P C a n d t h e p h a r m a c o k i n e t i c s o f p a r o x e t i n e (tl/2, AUC24h, C~n a n d CSmSx)in t h e p a t i e n t s . I n t h e c o n t r o l subjects, h o w e v e r , A P C w a s c o r r e l a t e d w i t h b o t h A U C 2 4 a n d

K. Dalhoff et al.: Paroxetine kinetics in cirrhosis CSSax(r = - 0.88; P < 0.05 and r = - 0.90; P < 0.05, respectively). Patients and controls were well matched regarding age and weight. GEC and APC were significantly lower in the patients than in the control group (P < 0.01 and P < 0.01, respectively), corresponding to the selection of patients. Albumin, too, (reference value 40-51 g. 1-1) was significantly lower in the patients (32 (6) g. 1-i) than in the control group (46 (4) g. 1-~; P < 0.01). Some patients were co-prescribed cimetidine or disulfiram, two drugs which can affect plasma levels of highlymetabolised drugs, of which paroxetine is an example. Therefore, the pharmacokinetic data were analyzed with or without patients treated with either of the two drugs. C~n, AUC24and CSmSxwere significantly higher in the patients than in the control subjects if cimetidine and disulfiram-treated patients were excluded (P < 0.01, P < 0.01 and P < 0.05, respectively). The pharmacokinetic measurements were still significantly different, except CSSax (P > 0.05), if all the patients were included in the data analysis. Also, the mean elimination tl/2 was longer in the patients than in the control group with or without exclusion of the cimetidine and disulfiram-treated patients, but the difference was not significant (P > 0.05 and P > 0.05, respectively). In the control group routine liver tests (ALT, bilirubin and prothrombin index) did not change during drug administration. In six patients (subjects 1, 2, 3, 4, 6, 9) with cirrhosis only bilirubin was significantly changed during paroxetine administration. However, all changes were within normal range. All but one patient (subject 3) completing the trial experienced symptoms, which were regarded as paroxetineinduced adverse reactions. The most frequently reported symptom was transient nausea, lasting up to three days after the start of treatment. This symptom was not correlated with CSSx,neither was there any correlation between CSSx and the degree of adverse reactions, i.e. CSSxof the patient with no adverse reactions was not in the lower end of the CSmSxrange. Next to nausea tiredness was the most prominent symptom in the patients (31%) as well as in the control subjects (100%). Discussion

The pharmacokinetics of paroxetine in patients with hepatic impairment has been investigated in a single dose study by Krastev et al. [2]. Krastev et al. found no particular difference in plasma concentration or pharmacokinetic measurements in cirrhotic patients when compared with the data from healthy subjects receiving the same dose (20 rag). However, as paroxetine will be administered to patients over a period of several weeks or more, a multiple dose study is more clinically relevant. In a multiple dose studyof30 mg. d ~,for30 days [1], in young adults with normal liver function AUC24h and Groin was the same as the control group values here, but the mean tlj2 was longer than the mean tl/2 at steady state reported by Kaye et al. (36 vs 21 h, respectively). Large interindividual variation could partly explain the finding and also the present control subjects were older; it has pre-

353 viously been found that t~/2tends to be longer in elderly people [7]. Age may also have contributed to the trend towards a longer half-life in the cirrhotic patients (mean age 48 y). Kaye et al., reporting half-lives in healthy subjects after single oral 30 mg doses, quoted a range of 7.3-65.1 h [1]. Steady state half-lives beyond this range were observed in 5 of our 12 patients, although the longest values will have been imprecisely determined. It cannot be excluded that the other medicines taken by the patients in the study may have influenced the metabolism and pharmacokinetic parameters of paroxetine. However, the patient who took disulfiram, which is known to induce liver enzymes, did not have extreme kinetic parameters. Five patients were receiving cimetidine, an inhibitor of certain microsomal oxidative drug metabolizing enzymes [8]. Its effect on paroxetine pharmacokinetics in healthy males was studied by Greb et al. [9]; after administration of cimetidine 200 mg four times daily for 7 days, a single dose of paroxetine 30 mg was given and its pharmacokinetics was compared with measurements made prior to the cimetidine treatment. The bioavailability and kinetic parameters of paroxetine were not changed. In another study [10], the two drugs were administered together (paroxetine 30 mg o.d. daily on Days 1-28 and cimetidine 300 mg t. i. d. on Days 22-28) and the effect of cimetidine on the established steady state level of paroxetine was examined. The plasma paroxetine levels were increased by about 50% when cimetidine was added to the dosing regimen, demonstrating inhibition of paroxetine metabolism by cimetidine. It is not known what the paroxetine level in the 5 patients in the present study would have been if they had not taken cimetidine, but the levels in them were not unusually high. It is concluded, therefore, that the difference between the control subjects and patients was probably not due to the possible effect of cimetidine in the sub-group of patients receiving it. Further, it is not likely that the remaining drugs given concurrently with paroxetine would have changed the availability, metabolism or excretion of paroxetine. The reduced metabolic liver function in the twelve patients was illustrated by their decreased galactose elimination capacity and by their lower antipyrine clearance. Even though there was no correlation between these two liver tests and any of the pharmacokinetic measurements of paroxetine, it appears that the hepatic dysfunction in some way had affected the metabolic capacity for paroxetine. Reduced plasma protein concentration in liver disease patients may lead to an increased concentration of unbound drug and consequently to an increase in the socalled unbound hepatic intrinsic clearance of the drug [11], partly compensating for the decrease in metabolic capacity. However, the effect of reduced protein binding at physiological protein concentrations is a question of current debate [12]. Urinary excretion of unchanged paroxetine in the patients was low and was not significantly different from the urinary excretion in the control subjects. Thus, even during hepatic impairment, almost all the dose was still cleared by metabolism. Previous investigations [1] have shown that paroxetine exhibits non-linear kinetics and indicate that in certain individuals there is disproportionate relationship between

354 plasma drug concentration and dose. Thus, in such subjects the plasma concentration following a 30 mg dose will be more than 1.5-times higher than that following a 20 mg dose, adding further weight to the significantly greater dose-corrected AUC24h and Cmin ss in the patients with cirrhosis (mostly receiving 20 mg) c o m p a r e d to the control subjects (receiving 30 rag), but this cannot be evaluated in detail from the present data. The results suggest that patients with hepatic impairment may exhibit a longer half-life of paroxetine than is seen in healthy subjects. Consequently, at a given dose level, plasma concentrations are likely to be significantly higher in such patients. In the present study, a daily dose of 20 mg in patients with hepatic impairment resulted in plasma paroxetine levels which were similar to or marginally higher than those observed in subjects with normal liver function given 30 mg daily. The laboratory tests for liver impairment were not affected by administration ofparoxetine for 14 days, neither in patients nor in control subjects, supporting the assumption that paroxetine is a safe drug in patients with liver dysfunction. However, the initial dose should be at the lower end of the range r e c o m m e n d e d for subjects without liver disease.

Acknowledgements. Fr. M. Clausen, U. Laursen and M. Pedersen are thanked for their excellent technical assistance and E. Kj¢lbye for language revision.

References 1. Kaye CM, Haddock RE, Langley PF et al. (1989) A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand 80 [Supp1350]: 60-75 2. Krastev Z, Terziivanov D, Vlahov Vet al. (1989) The pharmacokinetics of paroxetine in patients with liver cirrhosis. Acta Psychiatr Scand 80 [Supp1350]: 91-92

K. Dalhoff et al.: Paroxetine kinetics in cirrhosis 3. D0ssing M, Poulsen HE, Andreasen PB, Tygstrup N (1982) A simple method for determination of antipyrine clearance. Clin Pharmacol Ther 32:392-397 4. Tygstrup N (1966) Determination of the hepatic elimination capacity (Lm) of galactose by single dose injection. Scand J Clin Lab Invest 18 [Suppl 92]: 118-125 5. Tygstrup N (1977) Effect of sites for blood sampling in determination of the galactose elimination capacity. Scand J Clin Lab Invest 37:333-338 6. Brett MA, Dierdorf HD, Zussman BD, Coates PE (1987) Determination of paroxetine in human plasma, using high-performance liquid chromatography with fluorescence detection. J Chromatogr 419:438444 7. Lundmark J, Thomsen IS, Fjord-Larsen T et al. (1989) Paroxetine: pharmacokinetic and antidepressant effect in the elderly. Acta Psychiatr Scand 80 [Supp1350]: 76-80 8. D0ssing M, Pilsgaard H, Rasmussen B, Poulsen HE (1983) Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism. Eur J Clin Pharmaco125:215-222 9. Greb WH, Buscher G, Dierdorf HD, K0ster FE, Wolf D, Mellows G (1989) The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine. Acta Psychiatr Scand 80 [Suppl 350]: 95-98 10. Bannister SJ, Houser VR Hulse JD, Kisicki JC, Rasmussen JGC (1989) Evaluation of the potential for interactions of paroxetine with cimetidine, warfarin and digoxin. Acta Psychiatr Scand 80 [Supp1350]: 102-106 11. Bass L, Keiding S (1988) Physiologically based models and strategic experiments in hepatic pharmacology. Biochem Pharmaco137:1425-1431 12. Sorrentino D, Potter BJ, Berk PD (1990) From albumin to the cytoplasm: the hepatic uptake of organic anions. In: Popper H, Schaffner F (eds) Progress in liver diseases. Saunders, Philadelphia

K. D alhoff, MD Rigshospitalet A-2152 Blegdamsvej 9 DK-2100 Copenhagen Denmark

Pharmacokinetics of paroxetine in patients with cirrhosis.

In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without ...
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