•
01' . , .....at ArtIcle am.
PllarmarolullCl. 19 (2): 160-166. 1990
0) 12-~963{90/0003.Q 160/103.50/0 C Ad.s Inlt rNIt lOnal L.m.ted All n&h1S rtw .... td
~-
Pharmacokinetics of Kelanserin in Patients with Cirrhosis Didier Lebrec. Antoine f1adengue, Christophe Gaudin. Jean-Claude wron. Bruno Fraitag. Pierre Berthelot and Jean-Pierre Benhamou Unile dt Recllerches de Ph ysiopathologic Ht palique (lNSER\t U-24) and Service d·Hepatologie. Hopital Beaujon. Oichy. Laboratoire: Janssen. BoulO&ne Billanooun, and Unite d'HepatolO8le (INSERM U-99), H6pital Lacnnec, Paris. France
Su mmar,.
The pharmacokinetics ofketansenn. a ncw serotonin Sl (5 HT2) antagonist. were stud· ied in 26 patients wi th cirrhosis. Patients were: randornised to receive cithcr a single oral dose of kelanserin 20mg (n - 14) or 40mg (n - 8) or an in travenous dose of kelallserin 5mg (n - 4). The plasma kinetics of ketanserin and its metabolite ketanserinol were determined O\'er 48 hours. by high pressure hquid chromatop-aphy with a nuorometric detector. Pharmacokinetic parameters were calculated using noncompanmental analySIS based on a statistical moment theory. The first·pass effect of kelanserin was markedl y decreased after oral administration compared With results previousl y obtained in healthy subjects. The peak concentration was not higher in cirrholtc patients than in controls. This resu lt could be due to an increase in the initial volume of distribution. The pre>duc tion of ketanscrinol was reduced in cirrhotics. A decreased mean ketanserin elimination half· life (t Y) - 12 ± 4 and 10 ± )h "$ 16 :t. 3 and 13 :t. 4h in healthy controls after oral ketanserin 40mg and intravenous kctanserin 5mg. respccuvely) contrasted wllh a substantial IIIcrease 111 I I'! for ketansennol (33 ::t 13 "S 19 :t. 4h). The volumn o f distribution ..... ere also markedly reduced III patients with drrbOSIS. These resullS suuest either a reduction in the oral dosa~ of ketansenn or an IIIcreasc in the in terval bet ..... een doses in patients with cirrhosis.
Ketanserin is a quinazoline derivative which has been shown to have arterial antihypertensive properties when adm inistered to animals and humans (Hedner et at 1983; Pettersson et at 1984: Van Nueten et al. 198 1). More recently, it has been demonstrated that ketanserin decreases portal pressure in patients with cirrhosis and may be used for the treatment of portal hypertension (Hadengue et at 1987). Although the exact mechanism of the hypotensive effect has not yet been fully elucidated, its action is mainly related to selective peri-
pheral serotonin S2 (5HT2) antagonism and. in pan. to associated weak a -blocking activity (Reimann & Frolich 1983). While several pharmacokinetic studies have been carried out in healthy subjects (Heykants ct a1. 1986; Reiman n ct al. 1983; Trenk et al. 1983), no information is available on ketanserin pharmacokinetics in patients with cirrhosis. The purpose of the present study was to characterise the pharmacokinetics ofketanseri n when administered either orally or intravenously in patients
Pharma(OklnChC~
ur KClanscrln In CirrhosIs
with cirrhosis. based on thc plasma kinctics of ketanserin and its mctaboli te. kctanserinol.
Patients and Methods Patients 26 adult paticnts with cirrhosis (confirmed by Ilvcr biopsy performcd beforehand) were enrolled In thc study. Biochemical profiles. including liver tests, were carried out in all patlcnts (table I). Informed consent was obtained in the presence of a witness. Study Protocols The 26 paticnts were assigncd either I oral or I intra venous dose of kctanserin (R41468. Janssen Pharmaceuticals). 14 patients (group A) wcre allocated to oral administration of kctanserin 20mg ( I tablet). 8 (group B) to oral administration ofketanserin 40mg (2 tablcts) and the rcmaining 4 paticnts (group C) rcccived ketanserin Smg intravcnously. Blood samplcs mcasuring ketanserin concentration in group A patients were collected at 30 and 45 minutes and at 1.2. 3. 4. 6. 12. 24 and 48 hours after drug administration. Patients in group B were similarly sampled. in addition to collections aI lS minutcs and 36 hours. Group C patients were sampled at 2, 4. 6, 10.20 and 40 minutes and at 1,2, 3, 4. 6. 8. 12. 24. 36 and 48 hou rs. In a subgroup of patients. plasma concentrations ofkctanserin and ketanserinol were measured simullaneously (for 4. 8 and 4 patients in groups A. Band C. respectivcly). During hepatic vein catheterisation performcd for evaluation of portal hypertension or after transvenous liver biopsy, thc coefficient of hepatic extraction was measured after simultaneous sampling of the hepatic and periphcral veins in 5 patients receiving oral ketanserin (2 in group A and 3 in group B) after 24 hours. and in 4patients rcceiving intravenous ketanserin after 4. 10.30.60 and 180 minutes. Blood samples wcre collccted in heparinised tubes. aftcr which plasma was separated by centrifugation and stored at -20T unti l analysis. The pharmacokinetic results were com-
161
Table I. Mean (:1: SO) clinical characteris tICS and lat)ofatory values in 26 pallents With CirrhoSIS
Age (y)
S."
Welsht (kg) Heoght (em)
52 .t. 8 M _ 15: f _ ll 62 :!: 10 165 :!: 7
Serum studies alanine amlnotranslerase (IU)"
albumin (giL) alkaline phosphalases (IUIL)b bilirubin ~moIIL) protem (giL) prothrombin lime (% 0' control)
71 :1: 94 34 :!: 10 119 .t. 57 53
:!:
47
66 .t. 10 44 :!: 10
a Normal values: < 45 IU b Normal values: < 95 lUlL. AOOrevier,ons: M - male. F ~ 'emale
pared with published results obtained in health y subjects (Heykants et a!. 1986). Assay Methods Plasma concentrations ofketanserin and its metabolite. ketanscrinol, were determined using a high pressure liquid chromatographic (HPLC) system with a reversed phase column following the method described by Woestenborghs et al. (personal communication). Ketanserin , kel3nserinol and an internal sta ndard (R 46594) were extracted from previously alkalinised plasma with heptane-isoamyl alcohol (95 : 5, v/v). The analyses wert" performed on a CI8 5~m ' Hypcrsil' analytical column (I Scm x 4.6mm) fitted on a Pye 'Unicam' system equipped wi th an 'S FM25 Kontron' spectrofl uorometric detector set at 264nm (excitation) and 41 0nm (emission). The compounds were eluted using an M/ 4O phosphate buffer adjusted to pH JO with ammonium hydroxide. methanol and acetonitrile (36 : 30: 34) and readjusted to pH 10.6 after mixing. T he flow rate of thc mobile phase was 1.2 ml/min. T he retention times for ketanserin. keta nserinol and the internal standard were 3.44. 4.40 and 6.45 minutes. respecthel y. The calibration curves (0.5.200 nglml) and calculations of concentrations were performed using a 'Spcctraphysic' computcr model 4,100. For both ketanserin and its
162
elm Phormacoktnef. / 9 (1) 1990
metabolite, the recovery from spiked samples was
200
100C1b throughout the entire concentration range: and the mean coefficients of variation wert 5 and 8% for the highest (200ng) and lowest (I.5ng) concen· trated plasma samples, respectively. The standard curves wert linear. Plasma concentrations of kelanserin and ketanserinol WCrt measured in 26 and 16 palients. respectively. Phannacokinetic Methods Noncompartmental analysis based on a statistical moment theory was used to calculate the pharmacokinctic parameters. The areas under the curves (AVC) for plasma concentration (C) were determined as a function o f time. AVe (0--24) and AVe (0-48) were calculated using Ihe trapezoidal rule between time points to and 12-4 or 148, respectively. AUe (D-co) was obtained by the trapezoi. dal rule between to and the last sampling time (t n). and extrapolated to infinity using the value of the
3 6 9 12 Tme(ll)
~
0.' L,-"C"::---,-----:c--3 6 19 12 2" 36 "8 Time (h)
Flog.. 1. Plasma kUlI:l1C$ of k~tan~ri n (e : n - 10) and k~tan ~rinol (0; n - 4) In 14 pal1~nl5 wilh cirrhosis dose of k~lan ~rin 2Omg.
an~r
an oral
.
FIg. 2. Plasma kincuC$ of ketan~nn (e ) and ketanscrinol (0 ) in 8 pal1~nlS WIth CI rrhOSIS an~ an oral dO$(' or k~lansenn
-.
slope (J (last linear segment) and the concentration at the final sampling time such that AVC - AVC ln + C,,/tJ. The elimination half-life (t'h) was estimated by nonlinear regression on logarithmic (In) curves of plasma concentrations as a function of time. In patients receiving intravenous ketanserin. total plasma clearance was expressed as C l "" d~/ AVC (0-00). while total blood clearance (Cl) was estimated using the ratio o f the concentrations of blood/ plasma. where CL - CL/ r with r ... 0.70 for ketanserin (Heykanu et al. 1986). The coefficient of hepatic extraction (E) was calculated using the formula Ecal "" CLIO (intravenous route) with representing hepatic blood flow. Furthermore. Ereal "" Cpv - CHV/CPV. where Cpv and C HV represent the plasma concentrations from a peripheral and the hepatic vein, respectively. This assumes that the concentratIon in the portal vein following oral drug intake is similar to that in the peripheral venous or arterial s~tems at the m" ment of sampling (24h). The mean volume of distribution at steady-state (Vss) was calculated according to the following equation: Vss "" Dose x AVMC (o-oo)/ AVC (20-00)
0
~ 0.2
"
PharmaCO~lnC\lC$
of Kelanscnn
In
CirrhosIs
163
where AUMC (0-00) is the area under the first moment curve for the plasma/ time concentrations (Benet & Galeazzi 1979). was measured by continuous infusion (Caesar et al. 1961). Six peripheral and hepatic blood samples were drawn simultaneously al 2-minute intervals during intravenous infusion of indocyanine green (leG) [0.2 was calculated from the formula: mg/min]. ICG clearanee/ ICG extraction
OH
OH
I - haemalrocrit All resuits are expressed as mean ± SD.
Results The main pharmacokinetic results for the 3 cirrhotic groups stud ied, and comparative values for healthy subjects from a study ( Heykants et a1. 1986) performed by the same analytical method. arc shown in table II. Following oral administration. ketanserin plasma kinetics showed a mean peak concentration at 1.07 ± 0.80 and 2.38 ± l.00h after doses of 20mg and 40mg. respectively. Although the mean peak concentratIOns (Cma,) observed were within the range of values reported for healthy subjects (table II ). the mean times 10 C max
(Imax) were greater than those obtained in healthy subjects (p < 0.001. 40mg dose). The AUC (0--00) averaged approximately 3-fold higher with the 20mg dose. and 2- to 4-fold higher with the 40mg dose, than in healthy subjects. Both t'h and mean volume of distribution (Vd) were lower in cirrhotic patients than in health y controls. Pharmacokinellc values of ketanserinol following oral or inlravenQusadministrat ion in ci rrhotics and healthy subjects are indicated in figures I to 3 and in table 111 . Mean AUC ketanserinolketanserin ratios were markedl y decreased in cirrhotics: 0.24 ± 0.15 [AUC (o--24h)] following intravenous injection (- 7Mb) and after oral ketanserin intake (-68%). The mean t 'h for ketanserin was significantly decreased for the 40mg oral dose (p < 0.0 1). After the 5mg intravenous injection , no statistical comparison could be carried out since there were only 4 subjects in the cirrhotic group, butt", and Vd were noticeably lower in the patients than in healthy subjects. The Ereal measured in patients with cirrhosis was 0.30 ± 0.05 (24h after oral administration) and 0.53 ± 0. 11 (after intravenous administration): £cal after intravenous administration was 0.47 ± 0.18. In healthy subjects (Heykants et al. 1986). Ereal was not meas-
Table II. Mean (;! SO) ptlarmacoklnetlC parameters 01 ketanse"n In pallenlS WIth CirrhoSIS. Values for conlrQj S are laken from Heykants et al (1986); headIngs indlCale dose and route of admlOistratlOll Parameter
Cma • (;.g/l ) 1m.. (h) t ,~
(h)
AUC (0 ' co) [l'glL' hi CL (L/ hJ V.. (l/kg) V, ILl kg)
.""" PO
''''''' PO
pallenlS (n - 14)
controls (n .. 10)
98 !c 197 .,. 15.2 ;! 925 :!
110 1: 0.66 !: 165 ;t 279 .!:
46 080 49
359"
29 025 3.3 59
pallenlS (n .. 8)
conlrols In • 10)
158 :! 86 2.38 :! 100119 1: 36 D 1535 1: 802 D
193 :! 98 060 :! 024 178 :! 38 625 1: 99
pallents
conlrols
(n .. 4)
(n -
101 !: 29 287 !: 31 175 !: 1.9 25 .,. 0.5
298 33.9
4.7
!:
1.0
10)
143 ;! 4.4 ;!
36
3.4 3.7 ;! 0.9 97 ;! J .J ;!
a SIgnificantly dlfferenl from controls (p < O.OOt). b Sognlficantly dille.enl 'rom controls (p < 0.01). AbOtevI,/r()tl$. C"", • • peak plasma drug concentratlOll. Itr,u .. tIme to C"", • . I" , .. ehmlnabOn nalf·hfe. AUC (O~ co ) - area under the coocentrallOrl-llme CUNe from lIme zero 10 InfiOlty; CL - 10lal plasma drug clearance. Vss • volume of dlSlflDl/1IOrl at Sleadystate; V, - vQjume 01 distll00tlOll during Itle terminal phase; PO • oral; IV - IntravltnOUS
164
elm. pJ,armacoklnf'{, 19 (1) /990
500
200 HXl
50
T ime (h)
FIg. 3. Plasma kine lics ofkctanscrin (e ) and kct8nscrinol (0 ) in 4 patients with cirrhosis aficr an int ravenolls dose of kelanscrin 5mg.
ured, but estimated values can be derived from the bioavailability for oral route (0.48 ± 7.3) and from the clearance for intravenous administration (0.53 ± 0.05).
Di3CUJS;on Previous studies in healthy subjccts have shown thai ketanserin is completely absorbed by the gas. trointestinal tract after oral administration, and has an absolute bioavailability (f) ofapproximateiy 50% (Heykants e t al. 1986; Rei mann et al. 1983; Trcnk el al. 1983). In contrast, in cirrhotic patients, kelanserin absorption has not been evaluated. Only a relatively minor proportion of the drug is eliminated in unchanged form , consisting of about 1% in the faeces and 3% in the urine. In this trial, the increase in AUC (0---00) among pat ients with cirrhosis was not due to a longer ketanserin t'h, indicating a reduction in the effect of the initial passage of the drug (first-pass effect) through the liver. This phenomenon may be explained by a reduced E following alterations i n h epatic metabolic capac-
ity, and/o r a decrease in O.
While there arc no forma l eontraind ications for treating ctTrhotlC patIents with oral doses of ketanserino the results obtained in this study suggest the need for a reduction in the oral dosage or an increase in Ihe interval between administration of kelanserin in patients with cirrhosis. A ckn o,..,ledgem~ntf
Tht authors graterully acknowkdge the edllonal and ttthmcal assIstance prOVided by Mr and Mrs F. ShapIro, and also thank Mrs P. Stephan and Mrs P. Penchon for performing the plasma concentralion determlnalion and Drs B. Babany. S. Chaussade. C. Mouquct, S,S, Lee and R. Moreau ror their medical assistance.
ReJerencef 1k~1 1.2 G~k;t.ul RL "':onoIume of d,smOOilOO. Journal of Pharma~u"cal
SmllCn 68. 1011·1074. 1979 Cana. J. Sh31(\on S. (lilandussl L Gue>ara L SMrloc~ S The uSC of ondoc)·anl~ ~n In !he masuremtnt ofhepallc blood no ... lind as I ttS! of MpallC funclOon , Clinical Sc:lelltt 21 ~). 37. 196t Hadenguf A. l« SS, Moreau R. 8rallion .... u,b= D &ndicoal Mmod)nllmlC eff«ts of ketanscnn In pallents ... "h CIlTh~IS pOnlbk role ofscrOLonlnCl'il( m«hanl~m~ on pOl1al h)Pfl1enslon. Hcp.inolol)' 7: 644-647.1987 Hcdlltr T. ~nson 8. &rcJund G_ Kctanscnn, I no>e! 3-h)-
elm Pho,,,,oro/../lu't. 19 (}) 1990
166
dro~yII')Ptam IlK' antalOnls\: monolhtrapy m C'SKn hal hyper· l~n510n. Brill\h Journal ofClmlcal PIIlIrmarolocy 16: 121·1 H.
1983 HC'ykanls J. van Ptn A. Woalenbor&hs R. Gould S. Mills J. Pharmarokl~l,"of kcunsenn and liS ~tabohle ~cunKTlnol ,n man after ontravenou5 InlramuklIlar Ind oral admlnlslra· 1100. European Joumll orCl,nocal PIoarmaroloir)1 )
01' . , .....at ArtIcle am.
PllarmarolullCl. 19 (2): 160-166. 1990
0) 12-~963{90/0003.Q 160/103.50/0 C Ad.s Inlt rNIt lOnal L.m.ted All n&h1S rtw .... td
~-
Pharmacokinetics of Kelanserin in Patients with Cirrhosis Didier Lebrec. Antoine f1adengue, Christophe Gaudin. Jean-Claude wron. Bruno Fraitag. Pierre Berthelot and Jean-Pierre Benhamou Unile dt Recllerches de Ph ysiopathologic Ht palique (lNSER\t U-24) and Service d·Hepatologie. Hopital Beaujon. Oichy. Laboratoire: Janssen. BoulO&ne Billanooun, and Unite d'HepatolO8le (INSERM U-99), H6pital Lacnnec, Paris. France
Su mmar,.
The pharmacokinetics ofketansenn. a ncw serotonin Sl (5 HT2) antagonist. were stud· ied in 26 patients wi th cirrhosis. Patients were: randornised to receive cithcr a single oral dose of kelanserin 20mg (n - 14) or 40mg (n - 8) or an in travenous dose of kelallserin 5mg (n - 4). The plasma kinetics of ketanserin and its metabolite ketanserinol were determined O\'er 48 hours. by high pressure hquid chromatop-aphy with a nuorometric detector. Pharmacokinetic parameters were calculated using noncompanmental analySIS based on a statistical moment theory. The first·pass effect of kelanserin was markedl y decreased after oral administration compared With results previousl y obtained in healthy subjects. The peak concentration was not higher in cirrholtc patients than in controls. This resu lt could be due to an increase in the initial volume of distribution. The pre>duc tion of ketanscrinol was reduced in cirrhotics. A decreased mean ketanserin elimination half· life (t Y) - 12 ± 4 and 10 ± )h "$ 16 :t. 3 and 13 :t. 4h in healthy controls after oral ketanserin 40mg and intravenous kctanserin 5mg. respccuvely) contrasted wllh a substantial IIIcrease 111 I I'! for ketansennol (33 ::t 13 "S 19 :t. 4h). The volumn o f distribution ..... ere also markedly reduced III patients with drrbOSIS. These resullS suuest either a reduction in the oral dosa~ of ketansenn or an IIIcreasc in the in terval bet ..... een doses in patients with cirrhosis.
Ketanserin is a quinazoline derivative which has been shown to have arterial antihypertensive properties when adm inistered to animals and humans (Hedner et at 1983; Pettersson et at 1984: Van Nueten et al. 198 1). More recently, it has been demonstrated that ketanserin decreases portal pressure in patients with cirrhosis and may be used for the treatment of portal hypertension (Hadengue et at 1987). Although the exact mechanism of the hypotensive effect has not yet been fully elucidated, its action is mainly related to selective peri-
pheral serotonin S2 (5HT2) antagonism and. in pan. to associated weak a -blocking activity (Reimann & Frolich 1983). While several pharmacokinetic studies have been carried out in healthy subjects (Heykants ct a1. 1986; Reiman n ct al. 1983; Trenk et al. 1983), no information is available on ketanserin pharmacokinetics in patients with cirrhosis. The purpose of the present study was to characterise the pharmacokinetics ofketanseri n when administered either orally or intravenously in patients
Pharma(OklnChC~
ur KClanscrln In CirrhosIs
with cirrhosis. based on thc plasma kinctics of ketanserin and its mctaboli te. kctanserinol.
Patients and Methods Patients 26 adult paticnts with cirrhosis (confirmed by Ilvcr biopsy performcd beforehand) were enrolled In thc study. Biochemical profiles. including liver tests, were carried out in all patlcnts (table I). Informed consent was obtained in the presence of a witness. Study Protocols The 26 paticnts were assigncd either I oral or I intra venous dose of kctanserin (R41468. Janssen Pharmaceuticals). 14 patients (group A) wcre allocated to oral administration of kctanserin 20mg ( I tablet). 8 (group B) to oral administration ofketanserin 40mg (2 tablcts) and the rcmaining 4 paticnts (group C) rcccived ketanserin Smg intravcnously. Blood samplcs mcasuring ketanserin concentration in group A patients were collected at 30 and 45 minutes and at 1.2. 3. 4. 6. 12. 24 and 48 hours after drug administration. Patients in group B were similarly sampled. in addition to collections aI lS minutcs and 36 hours. Group C patients were sampled at 2, 4. 6, 10.20 and 40 minutes and at 1,2, 3, 4. 6. 8. 12. 24. 36 and 48 hou rs. In a subgroup of patients. plasma concentrations ofkctanserin and ketanserinol were measured simullaneously (for 4. 8 and 4 patients in groups A. Band C. respectivcly). During hepatic vein catheterisation performcd for evaluation of portal hypertension or after transvenous liver biopsy, thc coefficient of hepatic extraction was measured after simultaneous sampling of the hepatic and periphcral veins in 5 patients receiving oral ketanserin (2 in group A and 3 in group B) after 24 hours. and in 4patients rcceiving intravenous ketanserin after 4. 10.30.60 and 180 minutes. Blood samples wcre collccted in heparinised tubes. aftcr which plasma was separated by centrifugation and stored at -20T unti l analysis. The pharmacokinetic results were com-
161
Table I. Mean (:1: SO) clinical characteris tICS and lat)ofatory values in 26 pallents With CirrhoSIS
Age (y)
S."
Welsht (kg) Heoght (em)
52 .t. 8 M _ 15: f _ ll 62 :!: 10 165 :!: 7
Serum studies alanine amlnotranslerase (IU)"
albumin (giL) alkaline phosphalases (IUIL)b bilirubin ~moIIL) protem (giL) prothrombin lime (% 0' control)
71 :1: 94 34 :!: 10 119 .t. 57 53
:!:
47
66 .t. 10 44 :!: 10
a Normal values: < 45 IU b Normal values: < 95 lUlL. AOOrevier,ons: M - male. F ~ 'emale
pared with published results obtained in health y subjects (Heykants et a!. 1986). Assay Methods Plasma concentrations ofketanserin and its metabolite. ketanscrinol, were determined using a high pressure liquid chromatographic (HPLC) system with a reversed phase column following the method described by Woestenborghs et al. (personal communication). Ketanserin , kel3nserinol and an internal sta ndard (R 46594) were extracted from previously alkalinised plasma with heptane-isoamyl alcohol (95 : 5, v/v). The analyses wert" performed on a CI8 5~m ' Hypcrsil' analytical column (I Scm x 4.6mm) fitted on a Pye 'Unicam' system equipped wi th an 'S FM25 Kontron' spectrofl uorometric detector set at 264nm (excitation) and 41 0nm (emission). The compounds were eluted using an M/ 4O phosphate buffer adjusted to pH JO with ammonium hydroxide. methanol and acetonitrile (36 : 30: 34) and readjusted to pH 10.6 after mixing. T he flow rate of thc mobile phase was 1.2 ml/min. T he retention times for ketanserin. keta nserinol and the internal standard were 3.44. 4.40 and 6.45 minutes. respecthel y. The calibration curves (0.5.200 nglml) and calculations of concentrations were performed using a 'Spcctraphysic' computcr model 4,100. For both ketanserin and its
162
elm Phormacoktnef. / 9 (1) 1990
metabolite, the recovery from spiked samples was
200
100C1b throughout the entire concentration range: and the mean coefficients of variation wert 5 and 8% for the highest (200ng) and lowest (I.5ng) concen· trated plasma samples, respectively. The standard curves wert linear. Plasma concentrations of kelanserin and ketanserinol WCrt measured in 26 and 16 palients. respectively. Phannacokinetic Methods Noncompartmental analysis based on a statistical moment theory was used to calculate the pharmacokinctic parameters. The areas under the curves (AVC) for plasma concentration (C) were determined as a function o f time. AVe (0--24) and AVe (0-48) were calculated using Ihe trapezoidal rule between time points to and 12-4 or 148, respectively. AUe (D-co) was obtained by the trapezoi. dal rule between to and the last sampling time (t n). and extrapolated to infinity using the value of the
3 6 9 12 Tme(ll)
~
0.' L,-"C"::---,-----:c--3 6 19 12 2" 36 "8 Time (h)
Flog.. 1. Plasma kUlI:l1C$ of k~tan~ri n (e : n - 10) and k~tan ~rinol (0; n - 4) In 14 pal1~nl5 wilh cirrhosis dose of k~lan ~rin 2Omg.
an~r
an oral
.
FIg. 2. Plasma kincuC$ of ketan~nn (e ) and ketanscrinol (0 ) in 8 pal1~nlS WIth CI rrhOSIS an~ an oral dO$(' or k~lansenn
-.
slope (J (last linear segment) and the concentration at the final sampling time such that AVC - AVC ln + C,,/tJ. The elimination half-life (t'h) was estimated by nonlinear regression on logarithmic (In) curves of plasma concentrations as a function of time. In patients receiving intravenous ketanserin. total plasma clearance was expressed as C l "" d~/ AVC (0-00). while total blood clearance (Cl) was estimated using the ratio o f the concentrations of blood/ plasma. where CL - CL/ r with r ... 0.70 for ketanserin (Heykanu et al. 1986). The coefficient of hepatic extraction (E) was calculated using the formula Ecal "" CLIO (intravenous route) with representing hepatic blood flow. Furthermore. Ereal "" Cpv - CHV/CPV. where Cpv and C HV represent the plasma concentrations from a peripheral and the hepatic vein, respectively. This assumes that the concentratIon in the portal vein following oral drug intake is similar to that in the peripheral venous or arterial s~tems at the m" ment of sampling (24h). The mean volume of distribution at steady-state (Vss) was calculated according to the following equation: Vss "" Dose x AVMC (o-oo)/ AVC (20-00)
0
~ 0.2
"
PharmaCO~lnC\lC$
of Kelanscnn
In
CirrhosIs
163
where AUMC (0-00) is the area under the first moment curve for the plasma/ time concentrations (Benet & Galeazzi 1979). was measured by continuous infusion (Caesar et al. 1961). Six peripheral and hepatic blood samples were drawn simultaneously al 2-minute intervals during intravenous infusion of indocyanine green (leG) [0.2 was calculated from the formula: mg/min]. ICG clearanee/ ICG extraction
OH
OH
I - haemalrocrit All resuits are expressed as mean ± SD.
Results The main pharmacokinetic results for the 3 cirrhotic groups stud ied, and comparative values for healthy subjects from a study ( Heykants et a1. 1986) performed by the same analytical method. arc shown in table II. Following oral administration. ketanserin plasma kinetics showed a mean peak concentration at 1.07 ± 0.80 and 2.38 ± l.00h after doses of 20mg and 40mg. respectively. Although the mean peak concentratIOns (Cma,) observed were within the range of values reported for healthy subjects (table II ). the mean times 10 C max
(Imax) were greater than those obtained in healthy subjects (p < 0.001. 40mg dose). The AUC (0--00) averaged approximately 3-fold higher with the 20mg dose. and 2- to 4-fold higher with the 40mg dose, than in healthy subjects. Both t'h and mean volume of distribution (Vd) were lower in cirrhotic patients than in health y controls. Pharmacokinellc values of ketanserinol following oral or inlravenQusadministrat ion in ci rrhotics and healthy subjects are indicated in figures I to 3 and in table 111 . Mean AUC ketanserinolketanserin ratios were markedl y decreased in cirrhotics: 0.24 ± 0.15 [AUC (o--24h)] following intravenous injection (- 7Mb) and after oral ketanserin intake (-68%). The mean t 'h for ketanserin was significantly decreased for the 40mg oral dose (p < 0.0 1). After the 5mg intravenous injection , no statistical comparison could be carried out since there were only 4 subjects in the cirrhotic group, butt", and Vd were noticeably lower in the patients than in healthy subjects. The Ereal measured in patients with cirrhosis was 0.30 ± 0.05 (24h after oral administration) and 0.53 ± 0. 11 (after intravenous administration): £cal after intravenous administration was 0.47 ± 0.18. In healthy subjects (Heykants et al. 1986). Ereal was not meas-
Table II. Mean (;! SO) ptlarmacoklnetlC parameters 01 ketanse"n In pallenlS WIth CirrhoSIS. Values for conlrQj S are laken from Heykants et al (1986); headIngs indlCale dose and route of admlOistratlOll Parameter
Cma • (;.g/l ) 1m.. (h) t ,~
(h)
AUC (0 ' co) [l'glL' hi CL (L/ hJ V.. (l/kg) V, ILl kg)
.""" PO
''''''' PO
pallenlS (n - 14)
controls (n .. 10)
98 !c 197 .,. 15.2 ;! 925 :!
110 1: 0.66 !: 165 ;t 279 .!:
46 080 49
359"
29 025 3.3 59
pallenlS (n .. 8)
conlrols In • 10)
158 :! 86 2.38 :! 100119 1: 36 D 1535 1: 802 D
193 :! 98 060 :! 024 178 :! 38 625 1: 99
pallents
conlrols
(n .. 4)
(n -
101 !: 29 287 !: 31 175 !: 1.9 25 .,. 0.5
298 33.9
4.7
!:
1.0
10)
143 ;! 4.4 ;!
36
3.4 3.7 ;! 0.9 97 ;! J .J ;!
a SIgnificantly dlfferenl from controls (p < O.OOt). b Sognlficantly dille.enl 'rom controls (p < 0.01). AbOtevI,/r()tl$. C"", • • peak plasma drug concentratlOll. Itr,u .. tIme to C"", • . I" , .. ehmlnabOn nalf·hfe. AUC (O~ co ) - area under the coocentrallOrl-llme CUNe from lIme zero 10 InfiOlty; CL - 10lal plasma drug clearance. Vss • volume of dlSlflDl/1IOrl at Sleadystate; V, - vQjume 01 distll00tlOll during Itle terminal phase; PO • oral; IV - IntravltnOUS
164
elm. pJ,armacoklnf'{, 19 (1) /990
500
200 HXl
50
T ime (h)
FIg. 3. Plasma kine lics ofkctanscrin (e ) and kct8nscrinol (0 ) in 4 patients with cirrhosis aficr an int ravenolls dose of kelanscrin 5mg.
ured, but estimated values can be derived from the bioavailability for oral route (0.48 ± 7.3) and from the clearance for intravenous administration (0.53 ± 0.05).
Di3CUJS;on Previous studies in healthy subjccts have shown thai ketanserin is completely absorbed by the gas. trointestinal tract after oral administration, and has an absolute bioavailability (f) ofapproximateiy 50% (Heykants e t al. 1986; Rei mann et al. 1983; Trcnk el al. 1983). In contrast, in cirrhotic patients, kelanserin absorption has not been evaluated. Only a relatively minor proportion of the drug is eliminated in unchanged form , consisting of about 1% in the faeces and 3% in the urine. In this trial, the increase in AUC (0---00) among pat ients with cirrhosis was not due to a longer ketanserin t'h, indicating a reduction in the effect of the initial passage of the drug (first-pass effect) through the liver. This phenomenon may be explained by a reduced E following alterations i n h epatic metabolic capac-
ity, and/o r a decrease in O.
While there arc no forma l eontraind ications for treating ctTrhotlC patIents with oral doses of ketanserino the results obtained in this study suggest the need for a reduction in the oral dosage or an increase in Ihe interval between administration of kelanserin in patients with cirrhosis. A ckn o,..,ledgem~ntf
Tht authors graterully acknowkdge the edllonal and ttthmcal assIstance prOVided by Mr and Mrs F. ShapIro, and also thank Mrs P. Stephan and Mrs P. Penchon for performing the plasma concentralion determlnalion and Drs B. Babany. S. Chaussade. C. Mouquct, S,S, Lee and R. Moreau ror their medical assistance.
ReJerencef 1k~1 1.2 G~k;t.ul RL "':onoIume of d,smOOilOO. Journal of Pharma~u"cal
SmllCn 68. 1011·1074. 1979 Cana. J. Sh31(\on S. (lilandussl L Gue>ara L SMrloc~ S The uSC of ondoc)·anl~ ~n In !he masuremtnt ofhepallc blood no ... lind as I ttS! of MpallC funclOon , Clinical Sc:lelltt 21 ~). 37. 196t Hadenguf A. l« SS, Moreau R. 8rallion .... u,b= D &ndicoal Mmod)nllmlC eff«ts of ketanscnn In pallents ... "h CIlTh~IS pOnlbk role ofscrOLonlnCl'il( m«hanl~m~ on pOl1al h)Pfl1enslon. Hcp.inolol)' 7: 644-647.1987 Hcdlltr T. ~nson 8. &rcJund G_ Kctanscnn, I no>e! 3-h)-
elm Pho,,,,oro/../lu't. 19 (}) 1990
166
dro~yII')Ptam IlK' antalOnls\: monolhtrapy m C'SKn hal hyper· l~n510n. Brill\h Journal ofClmlcal PIIlIrmarolocy 16: 121·1 H.
1983 HC'ykanls J. van Ptn A. Woalenbor&hs R. Gould S. Mills J. Pharmarokl~l,"of kcunsenn and liS ~tabohle ~cunKTlnol ,n man after ontravenou5 InlramuklIlar Ind oral admlnlslra· 1100. European Joumll orCl,nocal PIoarmaroloir)1 )
