Fundam Clin Pharmacol (1992) 6, I 1 - 15
11
0 Elsevier, Paris
Pharmacokinetics of vidarabine in the treatment of polyarteritis nodosa F Fauvelle’, A Leon3, P Nicolasl, M Tod’, L Guillevin’, 0 Petitjean’ ‘Dkpartement de Pharmacologie HospitaliPre; lDkpartement de Mkdecine Interne; Tentre de Transfusion Sanguine, CHU Bobigny, 125, route de Sralingrad, 93009 Bobigny. France
(Received 4 July 1990; accepted 2 October 1990)
Summary - The pharmacokinetics of vidarabine were studied in 8 patients with polyarteritis nodosa related to hepatitis B virus infection. The drug was administered by continuous infusion for three weeks at doses of 15 ( I week) and 7.5 (2 weeks) mg/kg per day, during which time 15 plasma exchanges were performed. Plasma was assayed for vidarabine and its principal metabolite. hypoxanthine arabinoside by high pressure liquid chromatography. Vidarabine was not detected in the plasma of any patients. Hypoxanthine arabinoside levels were used to evaluate vidarabine kinetics. The serum levels of hypoxanthine arabinoside ranged from 3.6to 21.5 mg/l. The mean elimination half-life (f SD) was 3.0 i 1.7 h. The plasma clearance (mean + SD) was 195 270 ml/min when the dose was 7.5 mg/kg per day and 66.3 f 47 ml/min for a 15 mg/kg per day/dose (NS). Except for the elimination half-life, these results were not fully consistent with those observed in other studies. The influence of multiple plasma exchanges on vidarabine kinetics is limited and dosage adjustment is not required based on the continuous infusion of vidarabine.
*
vidanbine I pharmacokinetics I plasma exchange
Introduction
Vidarabine (9-P-D-arabinofuranosyladenine, ara A, adenine arabinoside) is a purine nucleoside with antiviral activity against varicella zoster virus and herpes simplex virus, and is potentially effective in the elimination of viral markers in chronic active hepatitis associated with hepatitis B virus (HBV). Vidarabine, which inhibits DNA polymerase, is currently used in association with an intensive course of plasma exchanges (PE) to treat polyarteritis nodosa (PN) related to HBV (Guillevin et a/, 1986). Patients rapidly deaminate vidarabine in blood to form hypoxanthine arabinoside (Hx-ara), a compound with 10 - 50-fold less antiviral activity than vidarabine (Connor et a/, 1975; Whitley et al, 1980a). In our study, patients received vidarabine doses of 15 mg/kg per day the first week and 7.5 mg/kg per day the following two weeks by slow
infusion. Data from 8 patients are presented in this report.
Materials and methods
Patients Eight patients with histologically confirmed P N and infected with HBV participated in the study. They were included over a two-year period and treated with vidarabine, vira A* (Parke-Davis, Courbevoie, France). All patients had normal renal function before entering the trial. N o patient presented liver insufficiency or hypoalbuminemia. Informed consent was obtained from the patients.
Drug infusion Vidarabine was dissolved in 5% dextrose/electrolyte solution at a concentration of 0.3 - 0.7 mg/l and was ad-
12
F Fauvelle
ministered intravenously by 24-h continuous infusion. The course of therapy lasted 3 weeks.
Plasma exchange During the 3 weeks, I5 PE were performed. The patient’s plasma volume was calculated from whole blood volume determined from the patient’s weight and hematocrit measured before PE. An equivalent volume of fluids consisting of 4% albumin and 500 ml of gelatin was infused during the procedure to restore the circulating mass. Each procedure filtered 2 200 - 4 900 ml.
Blood samples Blood was drawn from the non-infused forearm into heparinized tubes containing approximately 50 pg of adenosine deaminase inhibitor (pentotastine, WarnerLambert. Ann Arbor, MI, USA). Plasma was immediately separated by centrifugation, aliquoted and stored at - 20°C until analysis. Blood was collected before the beginning of PE, every I5 min during P E and every hour for 6 h after the end of session. At the end of the 3 weeks of infusion, 7 blood samples were collected over a period of 8 h.
Analytical procedure Concentrations of vidarabine and Hx-ara were determined in plasma by high pressure liquid chromatography (HPLC), as described by Bowman and Kauffman (1982) with slight modifications to obtain better sensitivity. Detection limits were 0.1 mg/l for vidarabine and its metabolite Hx-ara.
Source of metabolites
el a1
clearance (CI,,)of Hx-ara was estimated by division of the infusion rate (k,) into the steady-state concentration (C,,). Clearance during plasma exchange (CIpE)can be evaluated as: CI,, = QPE/AUCPE.QPEis defined as follows, Q p E = C,, x VPE where C,, is the concentration of drug measured in the filtered volume VpE.
Results Despite the presence of an in vitro inhibitor and the rapid frozen storage ( - 20°C) of plasma, vidarabine could not be detected in the plasma of any patient during the 3 weeks of infusion and after the end of infusion. Our vidarabine assay, (0.1 mg/l) is more sensitive than other HPLC methods (Bowman and Kaufman, 1982; Buchanan et al, 1980). An HPLC method with good sensitivity for vidarabine detection has been developed (Mac Cann et al, 1985) but is not feasible in routine medical practice. The pharmacokinetic parameters of Hx-ara are presented in table I. Plasma levels of Hx-ara reached a peak of 3.6 to 21.5 mg/l. The half-life values ranged from 0.9 to 3.5 h. This half-life has no effect on drug delivery schedules, since vidarabine was continuously infused in order to assess the desirability and feasibility of maintaining effective intracellular concentrations. Figure 1 shows the plasma concentration-time profiles of Hx-ara during PE. The rebound of the plasma concentration of Hx-ara after the end of PE, due to redistribution of drug from the tissue, should be noted. Figure 2 shows the mean plasma concentrations versus time profile of Hx-ara after the end
Vidarabine and Hx-ara were obtained from Sigma Chemical Company (St Louis, MO, USA).
Pharmacokinetic and statistical analyses The terminal phase rate constant (K,) was calculated as the slope of the terminal monoexponential decline in plasma concentration-time data determined using the least squares method. Terminal T,,, = 0.693/k,. The area under curve (AUC) was calculated by application of the trapezoidal rule to the area up to sampling period. Total
Table 1. Pharmacokinetic parameters of Hx-ara in 4 patients, T,,2 and K, were determined at the end of infusion. CI, was estimated during the continuous infusion.
Dose (h)
fmg/kg per day)
7.5 15
3.0i 1.7 -
K, (h - I )
CI, fml/min)
0.34i0.32 -
195i270 66.3 f 47
13
Pharmacokinetics of vidarabine
T Y U C l
.
I?
i
I
.
.
I
'
Q
?
Y
I
I-"-
C
l
.
b
mums
I
do
I
4
wn
b
01
a-
O
i
.
.
.
MY.,
Fig 1. Plasma concentration time profiles of Hx-ara during and immediately after PE. Vidarabine was continuously infused at the following concentrations: 15 mg/kg per day ( - .) and 7.5 mg/kg per day (-).
-
A
,End
d inhricn
-P "
.-c 8
E 6
Table 11. Plasma exchange effectiveness observed in 8 patients after continuous infusion of vidarabine (IS and 7.5 mg/kg per day).
c)
C 0 0 C
8
Parameters
per day
7.5 mg/kg per day
QpE (mg/session) QPE ( m g W : a PE length (h) c 1 T (ml/min) Cl,, (ml/min)
19.5 f 14.6 10.0 f 7.3 1 . 7 5 f 0.20 66.3 f 4 7 . 0 34.2 f 3 7 . 3
7.8 It 10.2 4.0 i 5.2 1 . 7 4 f 0.38 195 f 2 7 P 22.7 f 16.8
(mg/h) : b Ratio a/b (qoo)
33.6 f 5 5 . 0 31.0 +23.0
16.8 f 2.8 26.0 i 3 5 . 0
4
I5 mg/kg
(D
5
(D
a 2
E
I0
st3
Fig 2. Mean plasma concentrations of Hx-ara plotted against time for the samples drawn after the end of 3 weeks of continuous infusion of vidarabine (IS (1 week) and 7.5 (2 weeks)).
aNS (Student's t-test); bNS (Student's r-test)
14
F Fauvelle er ol
of infusion. Only 4 patients were investigated after the end of infusion. The corresponding equation for this mean curve was: C(t) = 4.245 e- 3.41r + 4.49 e- 0 . 3 8 1 r . PE effectiveness and the most relevant data are given in table 11. At a first glance, interindividual variations are large. PE participated in the elimination of Hx-ara as shown by the Hxara plasma concentration time profile during and after the PE. Thirty percent of the drug was removed during PE.
Discussion The results showed that vidarabine was quickly deaminated by adenosine deaminase. Virtually all of the drug present in the plasma was in the form of Hx-ara. If the deamination of vidarabine by plasma is so rapid, even during the intravenous infusion of the drug, that only the metabolite Hx-ara can be found, then it is possible that vidarabine never reaches the cellular site of viral replication and, therefore, that Hx-ara is important therapeutically. Confirming this hypothesis, our findings showed that the plasma concentration of Hx-ara was 20 - 200 - fold (levels of Hx-ara/limit of detection (LD)) higher than the plasma concentration of vidarabine (LD = 0.1 mg/l). In addition, the MICs for a prototype strain of herpes simplex virus in a sensitive in vifro system were 1.5 mg/l for vidarabine and 75 mg/l for Hx-ara (Connor et a/, 1975) thus vidarabine was 50 times more potent than its metabolite. In another study (Shope er a/, 1983), the MIC for vidarabine was 10 times lower than that for Hx-ara. These concentrations are well in excess of those obtained in plasma with therapeutic doses. The undetectable levels of vidarabine may be related to an extremely rapid cellular uptake of vidarabine during administration. Intracellular levels are most important in the antiviraI effect of vidarabine an Hx-ara ; plasma levels alone may not accurately reflect therapeutic efficacy. The measurement of intracellular concentrations of vidarabine mono-, di- and tri-phosphates may explain such differences, but, at the present time, we cannot resolve this point.
The Hx-ara half-lives (mean 3.0 f 1.7 h) observed in our study were similar to those reported in other papers (Buchanan ef a/, 1980; Shope ef a/, 1983). Hx-ara levels in our 8 patients with PN related to HBV were higher (3.6 to 21.5 mg/l) than those measured in other studies using similar doses in patients herpes with zoster (3 to 6 mg/l) (Buchanan eta/, 1980; Shope el a/, 1983 ; Whitley el a/, 1980b). The plasma clearance of Hx-ara was not significantly different, using Student’s t-test for the two doses (7.5 and 15 mg/kg per day); this parameter was not reported in other publications, apart from that of Aronoff et a/ (1980) in which the plasma clearance reached 87.9 ml/min in a patient with renal failure. We found an extremely large intersubject varaibility. The differences in the circulating Hx-ara levels noted between our patients and the subjects described in other reports may be explained by the disease afflicting these individuals ; PN causes extensive vascular complications leading t o hemodynamic disorders. The second purpose of the study was to assess the effect of PE on the pharmacokinetics of vidarabine. The volume of distribution and protein binding are two relevant parameters for PE. The plasma protein binding for vidarabine and Hx-ara are, respectively, 20 and C 5% (data on file, ParkeDavis Laboratories). Our data on 8 patients show that Hx-ara is cleared by PE and that the plasmapheretic clearance represents, respectively, 30 and 50% (7.5 and 15 mg/kg per day) of the total clearance. The fraction of the drug removed during PE ie, 30%, represents less than 8% of a daily dosage of vidarabine. In patients with polyarteritis nodosa associated with HBV, the effect of repeated PE on the steady-state kinetics of vidarabine is limited and a dosage adjustment is not necessary. However, controlled studies are needed to quantify the effects of PE on other drug therapies and in other pathological situations.
References Aronoff C R , Szwed JJ, Nelson RL, Marcus ED, Kleit SA (1980) Hypoxanthine-arabinoside pharmacokinetics
Pharmacokinetics of vidarabine
after adenine arabinoside administration to a patient with renal failure. Antimimb Agents Chemother, 18,212-214 Bowman DB, Kauffman RE (1982) Reversed phase high performance liquid chromatographic method to determine vidarabine and hypoxanthine arabinoside in biological fluids. J Chromatrogr 229, 487-491 Buchanan R, Kindel A, Alford C , Whitley R (1980) Plasma levels and urinary excretion of vidarabine after repeated dosing. Clin Pharmacol Ther 27, 690-696 Connor J , Sweetman L, Carey S , Stuckey M, Buchanan R (1975) An antiviral agent. In: Adenine Arabinoside (Pavan-Langston D, Buchanan RA, Alford CA, eds) Raven Press, NY, 177-196 Guillevin L, Trepo C , Aouate JM, Royer I, Ouzan D, Barrier J, Wechsler B (1986) Polyarteritis nodosa related to hepatitis B virus. Treatment with plasma exchange and vidarabine. In: Progress in Artificial Organs (Nose Y, Kjellstrand C , lvanovich P , eds) ISAO Press, Cleveland, p 827-829
15
Mac Cann W, Hall L, Siler W, Barton N. Whitley R (1985) High pressure liquid chromatographic methods for determining arabinosyladenine-5’-monophosphate, arabinosyladenine and arabinosylhypoxanthine in plasma and urine. Antimicrob Agents Chemother 28, 265 - 273 Shope TC, Kauffman RE, Bowman D, Marcus EL (1983) Pharmacokinetics of vidarabine in the treatment of infants and children with infections due to herpes virus. J Infect Dis 148, 721-725 Whitley RJ, Tucker B, Kindel AW, Barton N, Pass R, Whelchel J , Cobbs CG, Diethelm A , Buchanan R (1980a) Pharmacology, tolerance and antiviral activity of vidarabine monophosphate in humans. Antimicrob Agents Chemother 18, 709-715 Whitley RJ, Alford C , Hess F, Buchanan R (1980b) Vidarabine : a preliminary review of its pharmacological properties and therapeutic use. Drugs 20, 267-282
11
0 Elsevier, Paris
Pharmacokinetics of vidarabine in the treatment of polyarteritis nodosa F Fauvelle’, A Leon3, P Nicolasl, M Tod’, L Guillevin’, 0 Petitjean’ ‘Dkpartement de Pharmacologie HospitaliPre; lDkpartement de Mkdecine Interne; Tentre de Transfusion Sanguine, CHU Bobigny, 125, route de Sralingrad, 93009 Bobigny. France
(Received 4 July 1990; accepted 2 October 1990)
Summary - The pharmacokinetics of vidarabine were studied in 8 patients with polyarteritis nodosa related to hepatitis B virus infection. The drug was administered by continuous infusion for three weeks at doses of 15 ( I week) and 7.5 (2 weeks) mg/kg per day, during which time 15 plasma exchanges were performed. Plasma was assayed for vidarabine and its principal metabolite. hypoxanthine arabinoside by high pressure liquid chromatography. Vidarabine was not detected in the plasma of any patients. Hypoxanthine arabinoside levels were used to evaluate vidarabine kinetics. The serum levels of hypoxanthine arabinoside ranged from 3.6to 21.5 mg/l. The mean elimination half-life (f SD) was 3.0 i 1.7 h. The plasma clearance (mean + SD) was 195 270 ml/min when the dose was 7.5 mg/kg per day and 66.3 f 47 ml/min for a 15 mg/kg per day/dose (NS). Except for the elimination half-life, these results were not fully consistent with those observed in other studies. The influence of multiple plasma exchanges on vidarabine kinetics is limited and dosage adjustment is not required based on the continuous infusion of vidarabine.
*
vidanbine I pharmacokinetics I plasma exchange
Introduction
Vidarabine (9-P-D-arabinofuranosyladenine, ara A, adenine arabinoside) is a purine nucleoside with antiviral activity against varicella zoster virus and herpes simplex virus, and is potentially effective in the elimination of viral markers in chronic active hepatitis associated with hepatitis B virus (HBV). Vidarabine, which inhibits DNA polymerase, is currently used in association with an intensive course of plasma exchanges (PE) to treat polyarteritis nodosa (PN) related to HBV (Guillevin et a/, 1986). Patients rapidly deaminate vidarabine in blood to form hypoxanthine arabinoside (Hx-ara), a compound with 10 - 50-fold less antiviral activity than vidarabine (Connor et a/, 1975; Whitley et al, 1980a). In our study, patients received vidarabine doses of 15 mg/kg per day the first week and 7.5 mg/kg per day the following two weeks by slow
infusion. Data from 8 patients are presented in this report.
Materials and methods
Patients Eight patients with histologically confirmed P N and infected with HBV participated in the study. They were included over a two-year period and treated with vidarabine, vira A* (Parke-Davis, Courbevoie, France). All patients had normal renal function before entering the trial. N o patient presented liver insufficiency or hypoalbuminemia. Informed consent was obtained from the patients.
Drug infusion Vidarabine was dissolved in 5% dextrose/electrolyte solution at a concentration of 0.3 - 0.7 mg/l and was ad-
12
F Fauvelle
ministered intravenously by 24-h continuous infusion. The course of therapy lasted 3 weeks.
Plasma exchange During the 3 weeks, I5 PE were performed. The patient’s plasma volume was calculated from whole blood volume determined from the patient’s weight and hematocrit measured before PE. An equivalent volume of fluids consisting of 4% albumin and 500 ml of gelatin was infused during the procedure to restore the circulating mass. Each procedure filtered 2 200 - 4 900 ml.
Blood samples Blood was drawn from the non-infused forearm into heparinized tubes containing approximately 50 pg of adenosine deaminase inhibitor (pentotastine, WarnerLambert. Ann Arbor, MI, USA). Plasma was immediately separated by centrifugation, aliquoted and stored at - 20°C until analysis. Blood was collected before the beginning of PE, every I5 min during P E and every hour for 6 h after the end of session. At the end of the 3 weeks of infusion, 7 blood samples were collected over a period of 8 h.
Analytical procedure Concentrations of vidarabine and Hx-ara were determined in plasma by high pressure liquid chromatography (HPLC), as described by Bowman and Kauffman (1982) with slight modifications to obtain better sensitivity. Detection limits were 0.1 mg/l for vidarabine and its metabolite Hx-ara.
Source of metabolites
el a1
clearance (CI,,)of Hx-ara was estimated by division of the infusion rate (k,) into the steady-state concentration (C,,). Clearance during plasma exchange (CIpE)can be evaluated as: CI,, = QPE/AUCPE.QPEis defined as follows, Q p E = C,, x VPE where C,, is the concentration of drug measured in the filtered volume VpE.
Results Despite the presence of an in vitro inhibitor and the rapid frozen storage ( - 20°C) of plasma, vidarabine could not be detected in the plasma of any patient during the 3 weeks of infusion and after the end of infusion. Our vidarabine assay, (0.1 mg/l) is more sensitive than other HPLC methods (Bowman and Kaufman, 1982; Buchanan et al, 1980). An HPLC method with good sensitivity for vidarabine detection has been developed (Mac Cann et al, 1985) but is not feasible in routine medical practice. The pharmacokinetic parameters of Hx-ara are presented in table I. Plasma levels of Hx-ara reached a peak of 3.6 to 21.5 mg/l. The half-life values ranged from 0.9 to 3.5 h. This half-life has no effect on drug delivery schedules, since vidarabine was continuously infused in order to assess the desirability and feasibility of maintaining effective intracellular concentrations. Figure 1 shows the plasma concentration-time profiles of Hx-ara during PE. The rebound of the plasma concentration of Hx-ara after the end of PE, due to redistribution of drug from the tissue, should be noted. Figure 2 shows the mean plasma concentrations versus time profile of Hx-ara after the end
Vidarabine and Hx-ara were obtained from Sigma Chemical Company (St Louis, MO, USA).
Pharmacokinetic and statistical analyses The terminal phase rate constant (K,) was calculated as the slope of the terminal monoexponential decline in plasma concentration-time data determined using the least squares method. Terminal T,,, = 0.693/k,. The area under curve (AUC) was calculated by application of the trapezoidal rule to the area up to sampling period. Total
Table 1. Pharmacokinetic parameters of Hx-ara in 4 patients, T,,2 and K, were determined at the end of infusion. CI, was estimated during the continuous infusion.
Dose (h)
fmg/kg per day)
7.5 15
3.0i 1.7 -
K, (h - I )
CI, fml/min)
0.34i0.32 -
195i270 66.3 f 47
13
Pharmacokinetics of vidarabine
T Y U C l
.
I?
i
I
.
.
I
'
Q
?
Y
I
I-"-
C
l
.
b
mums
I
do
I
4
wn
b
01
a-
O
i
.
.
.
MY.,
Fig 1. Plasma concentration time profiles of Hx-ara during and immediately after PE. Vidarabine was continuously infused at the following concentrations: 15 mg/kg per day ( - .) and 7.5 mg/kg per day (-).
-
A
,End
d inhricn
-P "
.-c 8
E 6
Table 11. Plasma exchange effectiveness observed in 8 patients after continuous infusion of vidarabine (IS and 7.5 mg/kg per day).
c)
C 0 0 C
8
Parameters
per day
7.5 mg/kg per day
QpE (mg/session) QPE ( m g W : a PE length (h) c 1 T (ml/min) Cl,, (ml/min)
19.5 f 14.6 10.0 f 7.3 1 . 7 5 f 0.20 66.3 f 4 7 . 0 34.2 f 3 7 . 3
7.8 It 10.2 4.0 i 5.2 1 . 7 4 f 0.38 195 f 2 7 P 22.7 f 16.8
(mg/h) : b Ratio a/b (qoo)
33.6 f 5 5 . 0 31.0 +23.0
16.8 f 2.8 26.0 i 3 5 . 0
4
I5 mg/kg
(D
5
(D
a 2
E
I0
st3
Fig 2. Mean plasma concentrations of Hx-ara plotted against time for the samples drawn after the end of 3 weeks of continuous infusion of vidarabine (IS (1 week) and 7.5 (2 weeks)).
aNS (Student's t-test); bNS (Student's r-test)
14
F Fauvelle er ol
of infusion. Only 4 patients were investigated after the end of infusion. The corresponding equation for this mean curve was: C(t) = 4.245 e- 3.41r + 4.49 e- 0 . 3 8 1 r . PE effectiveness and the most relevant data are given in table 11. At a first glance, interindividual variations are large. PE participated in the elimination of Hx-ara as shown by the Hxara plasma concentration time profile during and after the PE. Thirty percent of the drug was removed during PE.
Discussion The results showed that vidarabine was quickly deaminated by adenosine deaminase. Virtually all of the drug present in the plasma was in the form of Hx-ara. If the deamination of vidarabine by plasma is so rapid, even during the intravenous infusion of the drug, that only the metabolite Hx-ara can be found, then it is possible that vidarabine never reaches the cellular site of viral replication and, therefore, that Hx-ara is important therapeutically. Confirming this hypothesis, our findings showed that the plasma concentration of Hx-ara was 20 - 200 - fold (levels of Hx-ara/limit of detection (LD)) higher than the plasma concentration of vidarabine (LD = 0.1 mg/l). In addition, the MICs for a prototype strain of herpes simplex virus in a sensitive in vifro system were 1.5 mg/l for vidarabine and 75 mg/l for Hx-ara (Connor et a/, 1975) thus vidarabine was 50 times more potent than its metabolite. In another study (Shope er a/, 1983), the MIC for vidarabine was 10 times lower than that for Hx-ara. These concentrations are well in excess of those obtained in plasma with therapeutic doses. The undetectable levels of vidarabine may be related to an extremely rapid cellular uptake of vidarabine during administration. Intracellular levels are most important in the antiviraI effect of vidarabine an Hx-ara ; plasma levels alone may not accurately reflect therapeutic efficacy. The measurement of intracellular concentrations of vidarabine mono-, di- and tri-phosphates may explain such differences, but, at the present time, we cannot resolve this point.
The Hx-ara half-lives (mean 3.0 f 1.7 h) observed in our study were similar to those reported in other papers (Buchanan ef a/, 1980; Shope ef a/, 1983). Hx-ara levels in our 8 patients with PN related to HBV were higher (3.6 to 21.5 mg/l) than those measured in other studies using similar doses in patients herpes with zoster (3 to 6 mg/l) (Buchanan eta/, 1980; Shope el a/, 1983 ; Whitley el a/, 1980b). The plasma clearance of Hx-ara was not significantly different, using Student’s t-test for the two doses (7.5 and 15 mg/kg per day); this parameter was not reported in other publications, apart from that of Aronoff et a/ (1980) in which the plasma clearance reached 87.9 ml/min in a patient with renal failure. We found an extremely large intersubject varaibility. The differences in the circulating Hx-ara levels noted between our patients and the subjects described in other reports may be explained by the disease afflicting these individuals ; PN causes extensive vascular complications leading t o hemodynamic disorders. The second purpose of the study was to assess the effect of PE on the pharmacokinetics of vidarabine. The volume of distribution and protein binding are two relevant parameters for PE. The plasma protein binding for vidarabine and Hx-ara are, respectively, 20 and C 5% (data on file, ParkeDavis Laboratories). Our data on 8 patients show that Hx-ara is cleared by PE and that the plasmapheretic clearance represents, respectively, 30 and 50% (7.5 and 15 mg/kg per day) of the total clearance. The fraction of the drug removed during PE ie, 30%, represents less than 8% of a daily dosage of vidarabine. In patients with polyarteritis nodosa associated with HBV, the effect of repeated PE on the steady-state kinetics of vidarabine is limited and a dosage adjustment is not necessary. However, controlled studies are needed to quantify the effects of PE on other drug therapies and in other pathological situations.
References Aronoff C R , Szwed JJ, Nelson RL, Marcus ED, Kleit SA (1980) Hypoxanthine-arabinoside pharmacokinetics
Pharmacokinetics of vidarabine
after adenine arabinoside administration to a patient with renal failure. Antimimb Agents Chemother, 18,212-214 Bowman DB, Kauffman RE (1982) Reversed phase high performance liquid chromatographic method to determine vidarabine and hypoxanthine arabinoside in biological fluids. J Chromatrogr 229, 487-491 Buchanan R, Kindel A, Alford C , Whitley R (1980) Plasma levels and urinary excretion of vidarabine after repeated dosing. Clin Pharmacol Ther 27, 690-696 Connor J , Sweetman L, Carey S , Stuckey M, Buchanan R (1975) An antiviral agent. In: Adenine Arabinoside (Pavan-Langston D, Buchanan RA, Alford CA, eds) Raven Press, NY, 177-196 Guillevin L, Trepo C , Aouate JM, Royer I, Ouzan D, Barrier J, Wechsler B (1986) Polyarteritis nodosa related to hepatitis B virus. Treatment with plasma exchange and vidarabine. In: Progress in Artificial Organs (Nose Y, Kjellstrand C , lvanovich P , eds) ISAO Press, Cleveland, p 827-829
15
Mac Cann W, Hall L, Siler W, Barton N. Whitley R (1985) High pressure liquid chromatographic methods for determining arabinosyladenine-5’-monophosphate, arabinosyladenine and arabinosylhypoxanthine in plasma and urine. Antimicrob Agents Chemother 28, 265 - 273 Shope TC, Kauffman RE, Bowman D, Marcus EL (1983) Pharmacokinetics of vidarabine in the treatment of infants and children with infections due to herpes virus. J Infect Dis 148, 721-725 Whitley RJ, Tucker B, Kindel AW, Barton N, Pass R, Whelchel J , Cobbs CG, Diethelm A , Buchanan R (1980a) Pharmacology, tolerance and antiviral activity of vidarabine monophosphate in humans. Antimicrob Agents Chemother 18, 709-715 Whitley RJ, Alford C , Hess F, Buchanan R (1980b) Vidarabine : a preliminary review of its pharmacological properties and therapeutic use. Drugs 20, 267-282
