Eur J Clin Pharmacol (1992) 43:55%562

© Springer-Verlag 1992

Pharmacokinetics of famotidine in patients with cirrhosis and ascites G. Vin~on I , C. Baldit 2, E C o u z i g o u 2, F. D e m o t e s - M a i n a r d 1, L. E i o u a e r - B l a n c 3, B . B a n n w a r t h 1, and B. B e g a u d 1

1Service de Pharmacologie Clinique, H6pitat Pellegrin & Universit4 de Bordeaux II, Bordeaux, France 2 Service de Gastroent6rologie, H6pital du Haut-Ldv4que, Pessac, France 3 Laboratoires Merck Sharp & Dohme-Chibret, Paris, France Received: January 10, 1992 / Accepted in revised form: June 16, 1992

Summary. T h e p h a r m a c o k i n e t i c s of famotidine has b e e n investigated in ascitic cirrhotic patients. 10 d e c o m p e n sated cirrhotic patients were studied (9 m, 1 f), w h o had n o r m a l renal function, and six healthy control subjects (4 m, 2 f), m a t c h e d for age, sex and weight. E a c h subject received on two occasions, at least f o u r days apart, a single oral (40 mg) or intravenous dose (20 mg) o f famotidine, at 21.00 h in a r a n d o m i s e d manner. Serial b l o o d samples were collected and famotidine in plasma was d e t e r m i n e d by a H P L C / U V m e t h o d . Plasma data were subjected to n o n c o m p a r t m e n t a l p h a r m a c o k i n e t i c analysis. T h e r e were no statistically significant differences in p h a r m a c o k i n e t i c p a r a m e t e r s b e t w e e n the two groups after either the intravenous or oral administration of famotidine. T h e findings suggest that the dose of famotidine m a y not require any adjustment in ascitic patients w i t h o u t renal failure.

K e y words: Famotidine, Cirrhosis; pharmacokinetics, ascites

Peptic ulceration is c o m m o n in cirrhotic patients; for instance, B u r r o u g h s et al. [1] recently r e p o r t e d a 76 % incidence in this population. Several publications have rep o r t e d higher b l o o d levels of cimetidine [2] and ranitidine [3] in cirrhotics c o m p a r e d to controls, suggesting that the dosages in such patients m a y n e e d to be reduced. Similarly, Ohnishi [4] indicated that the dosage schedule of famotidine should be r e d u c e d in patients with d e c o m p e n s a t e d cirrhosis. In contrast M o r g a n et al. [5, 6] r e p o r t e d that the p h a r m a c o k i n e t i c s of famotidine was not altered either in c o m p e n s a t e d or in d e c o m p e n s a t e d cirrhotic patients. T h e s e conflicting results p r o m p t e d the present study of the p h a r m a c o k i n e t i c s of single doses of famotidine administered either orally (40 m g nocte) or intravenously (20 m g nocte) to cirrhotic patients with ascites and to healthy adults.

Patients and m e t h o d s

Ten patients, 9 m and 1 f; mean (SD) age 52.3 (7.1) y; weight 70.8 (19.9) kg, with alcoholic cirrhosis and ascites, and six healthy subjects, 4 m and 2 f; age 46.8 (8.4) y; weight 64.1 (7.2) kg, gave their informed consent to the study. Their main characteristics are summarized in Table 1. On entering the study, all the cirrhotic patients had ascites but none had acute ulcer disease at endoscopy. The severity of hepatocellular insuficiency was assessed according to the criteria of Pugh et al. [7]; 8 patients were of Grade C and the others were Grade B. Patients with unstable haemodynamic parameters, spontaneous bacterial peritonitis (assessed by a positive ascitic fluid culture and/or polymorphonuclear leukocytes > 75/mm3) or gastrointestinal bleeding were excluded. All patients and control subjects had normal plasma creatinine and showed no evidence of renal impairment. Controls and patients abstained from alcohol consumption and concomitant drug therapy for at least five days prior to and during the study period. The protocol was approved by the local Ethics Committee of the University Hospital. Each subject was given famotidine on two occasions, at least four days apart: 40 mg orally and 20 mg IV according to a randomised, two way-crossover experimental design. Famotidine was administered at 21.00 h/2 h after the standard hospital evening dinner. It was given either as an IV bolus (20 mg within I rain), or as a 40 rag-tablet with 100 ml tap water. Venous blood samples (10 ml) were taken from the contralateral arm into dry heparinised tubes just before and 20 rain and 40 min, and 1,1.5, 2, 2.5, 3, 4, 6, 8,10,12, 24, 36, 48 h after tablet ingestion. After the i.v. injection, two additional blood samples were taken at 5 and t0 rain. Plasma samples were stored frozen at - 20 °C until drug analysis. Famotidine concentrations in plasma were measured using a slight modification of the HPLC technique of Vincek et al. [8]. Famotidine was provided by Merck Sharp & Dohme Laboratories (Paris, France. Batch L-643, 341-000 T 005). Cimetidine (Smith Kline & French Laboratories, Welwyn Garden City, Herts, U.K., Batch SK & F 92334-9R2667) was used as the internal standard. Plasma (1 ml) spiked with cimetidine (100~al of a solution of 2gg-m1-1) was added to a 2.8mi sitica gel Bond-Elut ® cartridge (Analitichem 601303). The cartidge was washed with 2 ml bidistilled water and famotidine and cimetidine were eluted with 5 ml methanol. The extract was evaporated under a mild stream of nitrogen at room temperature. The residue was redissolved in 200 gl mobile phase and conditioned in microtubes in the carousel of an automatic injector (Wisp ® 710 B). 50 gl was injected into a steel column (length 30 cm, internal diameter 3.9 mm) filled with gBondapack C 18®-10 gm (Millipore). The mobile phase consisted of 200 ml acetonitrile, 40 ml methanol and 760 ml water. A bottle of Pic-B8®

560 Table 1. Demographic and biochemical data for patients with cirrhosis and control subjects Subjects

Cirrhotics

1 2 3 4 5 6 7 8 9 10

Sex

M M F M M M M M M M

Mean (SD) Controls

1 2 3 4 5 6 Mean (SD)

M M M F F M

Age (y)

Weight Pugh's (kg) score (grade)

Bilirubinaemia (gmol.l-~) total conjugated

Albuminaemia (g.l-l)

AST (UI/1)

55 62 55 61 50 48 39 46 57 50

62 69 48 61 58.5 90 66 118 62 73

33 101 44 35 19 211 34 45 34 275

15 34 13 14 5 137 t4 13 13 195

23.6 31.7 23.8 24.4 25.7 27.2 32.8 26 24.3 31

66 85 30 55 70 196 79 61 64 442

52.3 (7.1)

70.8 (19.9)

81.1 (93.5)

46.6 (69.3)

28.5 (3.5)

114.8 72 (123.1) (18.1)

57 35 43 46 44 56

64.5 60 54 70 74 62

11 8 7 16 25

2 1 1 2 2

34.9 45 41 38 35 45

12 16 28 15 37 30

46.8 (8.4)

64.1 (7.2)

13.6" (7.3)

1.6" (0.5)

39.8* (4.6)

23.0* (10)

C C C C B C B C C C

Creatinin- Prothromaemia bintime (gmol.l-l) (%) 97 69 53 48 78 64 59 98 82

Proaccelerin

(%)

50 44 26 52 65 49 57 61 55 42

39 50 23 45 63 48 70 47 73 42

50.1 (11.1)

50 (15.1)

111 54 37 95 68 65

87 90 100 89 90 100

74 92 9O 65 100 100

71.7 (27.1)

92.7* (5.8)

86.8* (14.3)

* Mann-Whitney P < 0.05 compared to data for cirrhotis; - data unavailable

(Millipore) was added to 1 1 of mobile phase. At a flow rate of 2 ml.min-% the retention time was 5,2 min for famotidine and 7.0 min for cimetidine. The UV-visible M490 ® detector was operated at 267 nm. Linearity of the standard curve was shown over the 0-500 ng. ml- 1concentration range, within the 95 % confidence interval. The precision estimated by the coefficient of variation, was examined at 15, 250, and 450 ng.ml 1, and the results were 10.4%, 1.8%, and 3.2% for intra-assay experiments, and 8.6 %, 2.6%, and 1.8% for inter-assay experiments, respectively. The limit of quantitation of the method (three times the SD of the lowest concentration tested with a coefficient of variation below 20%) was 5 ng.ml -t. The pharmacokinetic analysis was carried out using SIPHAR ® software (Simed Cr6teil, France) on a Vectra® microcomputer (Hewlett-Packard). The apparent rate constants (t3) of the terminal elimination phase of the IV and oral curves were calculated from the slope of the linear regression analysis of the log plasma concentration-thne data. Consequently, the corresponding elimination halflives were calculated as tV2 ]3 = In 2/]3. All other parameters are based upon observed data and are independent of a compartmental model approach. The total area under the plasma concentrationtime curves for intravenous [AUCL~] and oral [AUCpo] administrations were determined by the trapezoidal rule from zero to the last measured concentration (C~0, and were extrapolated to infinity by the term C~Jfl. Other kinetic parameters were calculated from the following formula: * After intravenous administration - Total plasma clearance (CL) = Dose/AUC - Distribution volume at steady state (V~) = CL. MRT, where MRT represents the mean residence time calculated from the observed data [9]. • After oral administration Observed maximal plasma concentration (Cm~) - Time to reach peak concentration (t,,~) - Systemic bioavailability f = [AUCpo × Dosei~]/AUQ.~. × Dosepo]. Statistical significance was evaluated using the non-parametric Mann-Whitney U test; P < 0.05 was regarded as significant. In the text, results are expressed as mean values with the absolute standard deviation in parentheses [m (SD)],

Results P h a r m a c o k i n e t i c p a r a m e t e r s a r e listed in T a b l e 2. M e a n p l a s m a c o n c e n t r a t i o n - t i m e curves a f t e r a single e v e n i n g d o s e of f a m o t i d i n e in c o n t r o l s a n d c i r r h o t i c p a t i e n t s are s h o w n in Fig. 1 a (20 m g I V ) a n d Fig. l b (40 m g P O ) . F a m o t i d i n e c o u l d n o t b e d e t e c t e d b e y o n d t h e 12th h in t h e controls a n d the 24th h in t h e c i r r h o t i c patients. A f t e r t h e I V injection, t h e m a x i m u m f a m o t i d i n e conc e n t r a t i o n s w e r e q u i t e similar in t h e c i r r h o t i c p a t i e n t s [548.1 (189.5) ng. m1-1] a n d c o n t r o l subjects [499.3 (149) ng. ml-1; p > 0.05]. A t t h e t w e l f t h hour, the m e a n p l a s m a c o n c e n t r a t i o n s w e r e h i g h e r in cirrhotics [13.6 (14.5) ng. ml-1] t h a n in h e a l t h y subjects [7.2 (8.2) ng. ml-1], b u t d u e to t h e m a r k e d o v e r l a p , t h e d i f f e r e n c e was n o t statistically significant. T h e m e a n p l a s m a e l i m i n a t i o n half-life was 2.96 (0.48) h, t h e d i s t r i b u t i o n v o l u m e at s t e a d y s t a t e 88.6 (19.4)1, a n d t h e t o t a l p l a s m a c l e a r a n c e 25.3 (8.2) I - h ~ in the c o n t r o l g r o u p . T h e s e p a r a m e t e r s w e r e n o t significantly a l t e r e d in t h e cirrhotics [tl/2 ]3: 4.24 (1.72) h; V~: 109 (24.8) I; e l : 24.9 (8.6) I - h - l ] . After the oral dose, the mean systemic bioavailability was 39.8 (19.1) % in c o n t r o l s a n d 47.8 (13.2) % in cirrhotics ( P > 0.05). Similarl), n o significant d i f f e r e n c e b e t w e e n cirrhotics a n d c o n t r o l s was o b s e r v e d in e i t h e r tmax [3.6 (1.9) h vs 2.3 (1.05) hi o r Cm,x [95.2 (26.2) vs 100.5 (36.4) rig. m l - i ] . Finally, n o significant d i f f e r e n c e b e t w e e n t h e two g r o u p s was f o u n d in any o f t h e m e a s u r e d o r d e r i v e d p h a r m a c o k i n e t i c p a r a m e t e r s e v e n on a w e i g h t basis.

Discussion F a m o t i d i n e is a specific H 2 - r e c e p t o r a n t a g o n i s t with a l o n g d u r a t i o n of action. O n an e q u i m o l a r basis, its gastric antis e c r e t o r y effect after a c o n v e n t i o n a l m e a l has b e e n s h o w n

561 Table 2. Pharmacokinetic parameters after single intravenous and oral doses of famotidine 20 mg IV

Cirrhotics

Controls

40 mgPO

Subjects

Dose t~/zfl (mg.kg -1) (h)

AUC CL (ng-h-ml -~) (1.h i)

V,~ (1)

Dose tt/2fl (mg.kg -~) (h)

C~.x tm~ (ng.ml z) (h)

AUC f (ng.h-mt -~) (%)

1 2 3 4 5 6 7 8 9 10 Mean (SD) 1 2 3 4 5 6 Mean (SD)

0.32 0.29 0.42 0.33 0.34 0.22 0.3 0.17 0.32 0.27 0.3 (0.07) 0.3t 0.33 0.37 0.29 0.27 0.32 0.32 (0.03)

860 1125 690 609 661 1020 479 929 1670 930 896 (336) 904 857 484 922 1120 783 846 (210)

109 149 73.1 122 94.5 104 146 108 109 78.4 109 (24.8) 83.2 72.1 120 104 71.8 80.5 88.6 (i9.4)

0.64 0.58 0.83 0.67 0.68 0.44 0.61 0.34 0.64 0.55 0.6 (0.13) 0.62 0.66 0.74 0.58 0.54 0.64 0.63 (0.07)

112 116 62 54 89 71 121 97 132 98 95.2 (26.2) 90 94 77 56 156 130 100.5 (36.4)

1150 1200 578 319 626 817 618 1090 1130 836 837.1 (300) 618 440 742 540 980 458 630 (204)

4.05 7.32 2.41 3.5 2.93 4.19 3.51 4.05 7.35 3.08 4.24 (1.72) 2.82 2.71 2.54 3.81 3.25 2.66 2.96 (0.48)

23.3 17.8 28.9 32.8 30.3 19.7 41.8 21.5 12 21.5 24.9 (8.6) 22.1 23.4 41.3 21.7 17.8 25.5 25.3 (8.2)

to be approximately 7.5- and 40-times more potent than that of ranitidine and cimetidine, respectively [10]. The pharmacokinetics offamotidine have been extensively studied in healthy subjects. Following a single oral dose, its syst e m i c b i o a v a i l i b i l i t y h a s b e e n r e p o r t e d t o average43 % and the peak plasma concentration has been attained within

~1000t

+

Cirrhotics

100

t0

1

0

6

12

18

24

Time(h) ~1000-

--o- Cirrhotics • Controls

100

F~ B

1 i

0

--.

6

1'2

1'8

24

Time( h ) Fig.1. A Mean (SEM) plasma concentration-time curves in control subjects and in cirrhotic patients following famotidine 20 mg IV. B Mean (SEM) plasma concentration-time curves in control subjects and in cirrhotic patients following famotidine 40 mg PO

5.77 6.58 4.75 3.57 3.74 6.92 2.7 5.57 6.8 4.72 5.11 (1.46) 3.65 2.56 5.27 4.86 2.81 2.66 3.64 (1.18)

6.2 2.5 3 2,6 2.5 4 2.5 8 3 2 3.6 (1.9) 2.5 3 3 2 3 0.33 2.3 (1.05)

67 53.3 41.9 26.1 47.3 40.2 64.6 58.9 34 44.9 47.8 (13.2) 34.2 25.7 76.6 29.3 43.6 29.3 39.8 (19.1)

2.5 h; the elimination half-life was approximately 3 h after oral or intravenous administration; the total body clearance ranged from4.1 to 6.97 ml. m n -1. kg -t and the apparent volume of distribution was about 1.2 1- k g - ~after 20 mg IV [11-14]. The present findings are in good agreement with those results. Famotidine is excreted in urine mainly as unchanged drug. Its renal clearance exceeds the glomerular filtration rate, indicating tubular secretion of the drug [14]. As a result, the terminal elimination half-life of famotidine is significantly reduced in patients with m o d e r a t e to severe renal impairment [15,16]. H u c k e r et al. [17] reported substantial interindividual variability in the extent of hepatic biotransformation of famotidine, ranging from 10 to 50 %. Their results suggest that liver disease might alter the disposition of famotidine. Indeed, Ohnishi [4] found that the terminal half-fife of famotidine was significantly prolonged and the total body clearance markedly reduced in patients with G r a d e C (Pugh) decompensated cirrhosis. On the other hand, its disposition was not altered in chronic hepatitis or in Grade A or B cirrhosis. In contrast, the present results are in agreement with those of Morgan et al. [6], suggesting that decompensated cirrhosis had no significant effect on the pharmacokinetics of famotidine. The conflicting data do not appear to be related to the relative severity of the drrhosis in the different patient populations. Thus, the Pugh's scores in our series were quite similar to those in Ohnishi's decompensated cirrhotic patients. The latter did have concomitant m o d e r a t e renal impairment, whereas the present patients and those of Morgan et al. [6] showed no evidence of renal failure. Moreover, Ohnishi [4] found a weak but significant correlation between the total body clearance of famotidine and creatinine clearance. It is likely that the disposition of famotidine would be altered by concomitant renal failure rather than by hepatic dysfunction in patients with chronic liver disease.

562 Finally, the dosage schedule for famotidine m a y not require modification in cirrhotic patients in the absence of significant renal impairment.

Acknowledgements. We thank Mrs B. Martinez and E. Deridet for their technical assistance in completion of study.

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