Clinical Pharmacokinetics 8: 187-201 (1983) 0312-5963/83/0003-0187/$07.50/0 , ADIS Press Australasia Pty Ltd. All rights reserved.
Clinical Pharmacokinetics of Acyclovir Oscar L. Laskin Division of Clinical Pharmacology, Department of Medicine and Pharmacology, Cornell University Medical College, New York
Summary
Acyclovir is a selective anti-herpes virus agent. At present it is available in topical and intravenous formulations; an oral formulation is currently being developed. Absorption of acyclovir after oral administration is slow, variable and incomplete. The bioavailability of oral acyclovir is low and decreases with increasing dosage. The average time to peak concentrations is approximately 2 hours and achievable peak concentrations following oral administration (600mg every 4 hours) are less than 6 pmol/L with current oral dosage forms. Acyclovir tissue and fluid concentrations can be determined accurately and sensitively by high-performance liquid chromatography, radioimmunoassay. and by virus inhibition (bioassay). Acyclovir demonstrates biexponential elimination. with a terminal plasma halflife of 2 to 3 hours in patients with normal renal function. The volume of the central compartment (21 L/I.73m!) and the apparent volume of distribution at steady-state (48 L/ 1. 73m!) are approximately that of extracellular fluid and total body water. respectively. The drug is distributed into all tissues. with concentrations in the kidney being the highest (10 times the simultaneous plasma concentration) and in central nervous tissue the lowest (25 to 70% of the corresponding plasma concentration). Acyclovir enters the cerebrospinal fluid. saliva and vaginal secretions at concentrations inhibitory to herpes simplex virus. The drug is poorly protein bound. in the range of 9 to 22%. Acyclovir is eliminated mainly via the kidney by glomerular filtration and renal tubular secretion. with only a small percentage of the dose being oxidised to 9-carboxymethoxymethylguanine (which is the only significant metabolite of acyclovir in man). Acyclovir has dose-independent kinetics. The renal clearance of acyclovir is about 75 to 80% o/the total body clearance and approximately 3jold greater than creatinine clearance. Probenecid reduces acyclovir renal clearance by 32%. presumably by inhibiting tubular secretion of the drug. In anuric patients. acyclovir is slowly eliminated with a terminal plasma half-life of approximately 20 hours. The acyclovir total body clearance (29 ml/min/I.73m2) is only 10% of that seen in patients without renal impairment. Acyclovir is readily haemodialysable with an extraction coefficient of 0.45 and a dialysis clearance of 82 ml/min using a hollow fibre single-pass dialyser. A single haemodialysis (6h) reduces acyclovir concentrations by 60%. The pharmacokinetics of acyclovir in children (greater than 1 year of age) are similar to those in adults. In neonates. the total body clearance is about one-third 0/ that found in children and adults. The terminal plasma half-life is slightly longer in the neonate. The toxicity of acyclovir appears to be minimal and consists of local irritation after extravasation. phlebitis. and occasionally reversible elevations in serum creatinine. espe-
Clinical Pharmacokinetics of Acyclovir
188
cia//y ajier intravenous bolus doses. Other adverse effects remain to be established. Acyclovir plasma concentrations of50 to 100 Ilmol/L are easily achievable by slow intravenous administration without significant adverse effects. Dosage reduction is recommended in patients with impaired renal function. in order to achieve effective concentrations without concomitant drug accumulation.
Acyclovir [9-(2-hydroxyethoxymethyl) guanine] the herpesvirus DNA polymerase (Elion, 1982; is an acyclic nucleoside analogue of guanosine Furman et aI., 1979; St Clair et aI., 1980). which is a new potent and selective antiviral agent. Acyclovir has been found to be effective in vitro It has been found to have potent in vitro antiviral and in vivo in preclinical studies for infections activity against herpes simplex virus type I (50% caused by herpes simplex virus (Centifanto and inhibitory dose [EDso] of 0.1 ~mol/L) [Elion et aI., Kaufman, 1979; Collins and Bauer, 1979; Crum1977; Schaeffer, 1982; Schaeffer et aI., 1978]. Sub- packer et aI., 1979; Elion et aI., 1977; Field et aI., sequently, the EDso for herpes simplex virus (types 1979; Klein et aI., 1979; Park et aI., 1979), vari1 and 2) and varicella-zoster virus was found to be cella-zoster virus (Biron and Elion, 1980; Crum0.1 to 1.6 ,umol/L (Collins and Bauer, 1979; Crum- packer et at, 1979; Soike and Gerone, 1982), and packer et aI., 1979; Elion et aI., 1977) and 3 to 4 Epstein-Barr virus (Pagano and Datta, 1982). In ILmol/L (Biron and Elion, 1980; Crumpacker et aI., man, acyclovir has been shown to be of benefit in 1979), respectively, while inhibiting mammalian the prophylaxis and therapy of selected herpesvirus cell growth only at very high concentrations (> 300 infections when used topically (Corey et aI., 1982; ~mol/L) [Biron and Elion, 1980; Crumpacker et aI., Jones et at, 1979; Whitley et aI., 1982a), orally 1979; Elion et aI., 1977]. This would suggest a (Straus et aI., 1982; Wade et aI., 1982b) or parentherapeutic ratio of about 3000 for infections with terally (Meyers et aI., 1982; Mitchell et aI., 1981; herpes simplex virus. Most strains of Cytomega- Saral et aI., 1981; Spector et aI., 1982). Topicai and intravenous preparations of acyclolovirus appear to be relatively resistant (EDso > vir have recently been marketed in several coun200 ,umol/L) [Crumpacker et aI., 1979]. The selective activity of acyclovir for cells in- tries and the oral formulation is expected to be apfected with herpesviruses is due to the production proved in the not too distant future. The purpose of 2 unique herpes-specific enzymes, an isofunc- of this article is to review the clinical pharmacotional deoxynucleoside kinase and a herpes-spe- kinetics of acyclovir. cific DNA polymerase. Both of these enzymes are coded for by the herpesvirus genome (Jamieson et 1. Analytical Procedures aI., 1974; Mar and Huang, 1979; Perera and Morrison, 1970; Thouless and Skinner, 1971). AcycloDetermination of acyclovir concentrations in vir is selectively phosphorylated by the herpescoded deoxynucleoside kinase to its monophos- biological fluids can be sensitively and accurately phate form (Elion et aI., 1977; Fyfe et aI., 1978). quantitated by several methods. Cellular enzymes are then capable of converting 1.1 HPLC Methods acyclovir monophosphate to acyclovir di- and triphosphate (Elion, 1982; Miller and Miller, 1980). Acyclovir triphosphate is the active antiviral comUsing a Waters ~Bondapak CIS reverse-phase pound and is a selective substrate and inhibitor of column with 3% ethanol as the eluant, high per-
189
Clinical Pharmacokinetics of Acyclovir
formance liquid chromatography (HPLC) can be used to accurately determine acyclovir concentrations in biological fluids (de Miranda et aI., 1979; Quinn et al., 1979). Land and Bye (1981) modified the technique by using reverse-phase ion-paired HPLC and considered it was superior to the older reverse-phase method (Quinn et al., 1979). The sensitivity limit of the HPLC method is 1 J.tmol/L in plasma.
1.2 Radioimmunoassay A radioimmunoassay (RIA) has been developed by Quinn et al. (1979) utilising an antisera from rabbits immunised with a succinyl-acyclovir rabbit serum albumin conjugate. This antisera was highly specific for acyclovir, with only slight cross-reactivity (3%) with the drug's metabolites. The RIA gave comparable results when compared with HPLC. It does not require sample extraction, is useful for many types of biological tissues and fluids, and is 20-fold more sensitive than the HPLC method. The RIA can detect concentrations of acyclovir greater than 0.05 J.tmol/L and has a coefficient of variation of approximately 5%. This sensitivity has proved useful in pharmacokinetic studies for obtaining a better estimate of the terminal rate constant. Skubitz et al. (1982) modified this radioimmunoassay by using charcoal adsorption of unbound acyclovir rather than ammonium sulphate precipitation of the bound drug to facilitate the separation of bound antigen from free antigen. This simplification allowed for a more rapid acyclovir determination, without affecting the accuracy of the sensitivity of the assay.
1.3 Bioassay Moore et al. (1981) developed a bioassay for determining acyclovir concentrations in urine and plasma. The assay is based on the inhibition by acyclovir of the cytopathic effect of a strain of
herpes simplex virus type 1 on human fibroblast cells. The assay is less sensitive (sensitivity approximately 1 J.tmol/L) than RIA and requires 48 hours of incubation time. When compared with RIA, the values obtained from the virus inhibition assay were consistently greater than those obtained from RIA. The'discrepancy was substantial when acyclovir concentrations determined by RIA were less than 7 J.tmol/L; the corresponding values determined by the virus-inhibition assay were approximately 1.5 to 3 times these levels. In the expected range for peak acyclovir concentrations during intravenous therapy, the differences were not as large and this assay would certainly be satisfactory for determining acyclovir levels during treatment. However, its use would be limited for detailed pharmacokinetic studies because of its lack of sensitivity and accuracy at concentrations less than 10 J.tmol/L.
2. Fundamental Pharmacokinetic Properties 2.1 Absorption and Bioavailability The oral absorption for acyclovir was found to vary in different animal species, ranging from 3.7 ± 0.5% (mean ± SD) in the rhesus monkey to 75.3 ± 1.3% of the oral dose in the beagle dog (de Miranda et al., 1981 b, 1982b; Krasny et al., 1981). In rodents (de Miranda et al., 1981 b), the fraction of the oral dose absorbed declined with increasing dose. Similarly, in dogs, Krasny et al. (1981) found that the mean bioavailability assessed from the ratio of the area under the plasma concentration-time curve (AVC) following oral and intravenous administration decreased with increasing dose. In man, acyclovir is slowly and poorly absorbed from the gastrointestinal tract. The time to reach peak concentrations in plasma is approximately 1.5 to 2 hours after an oral dose (Brigden et al., 1980; de Miranda et al., 1982c; Van Dyke et al., 1982a,b). Brigden et al. (1980) reported that the percent-
Clinical Pharmacokinetics of Acyclovir
age of the dose recovered in urine after oral administration of 100, 200, 400 and 600mg acyclovir was 13.2 ± 4.5% (mean ± SD), 12.1 ± 5%,7.4 ± 2.4%, and 6 ± 2.9%, respectively. With multidose administration, steady-state concentrations of acyclovir were reached within 1 to 2 days. The mean steady-state peak acyclovir concentrations following multidose oral administration of 200, 400 and 600mg 4-hourly were approximately 2.5,3.5 to 5.4, and 5.9 J.LmoljL, respectively (de Miranda et aI., 1982c; Straus et ai., 1982; Van Dyke et ai., 1982a,b). The amount of acyclovir recovered in the urine was found to be approximately 14% of the dose administered (de Miranda et aI., 1982c). The estimated total bioavailability of acyclovir in man is believed to be between 15% and 30% (Straus et aI., 1982) and it appears that the bioavailability decreases with increasing dose. Preliminary data from multidose pharmacokinetic studies using escalating oral doses suggest that peak acyclovir concentrations are linearly related to the dose administered (de Miranda et ai. 1982c; Van Dyke et aI., 1982a). Systemic absorption of acyclovir from the skin is limited. After topical administration of 5% acyclovir in polyethylene glycol for the treatment of herpes genitalis, acyclovir was not detectable (concentrations < 0.1 J.LmoljL) in plasma (Corey et ai., 1982). However, topically administered acyclovir may sometimes be detectable at very low concentrations in the blood of patients with normal renal function (Anonymous, 1982).
190
In an earlier study in which normal human plasma was incubated with '4C-acyclovir (at acyclovir concentrations of 17.8 and 1.8 J.LmolfL) at 3rC, the protein binding of acyclovir was 22 and 33%, respectively (de Miranda et aI., 1979).
2.3 Distribution The distribution of '4C-acyclovir into tissues has been studied in several animal species (dogs, mice, rats and monkeys)[de Miranda et aI., 1978, 1981b, I 982bl. Acyclovir was found to rapidly enter all tissues examined (including the skin and brain). In most tissues, the concentrations of acyclovir were similar or greater than simultaneous concentrations in plasma. However, the brain was a notable exception; concentrations in the brain were only 10 and 33% of the corresponding plasma concentrations at 0.5 and 6 hours, respectively, after acyclovir administration (de Miranda et aI., 1982b). In dogs, acyclovir concentrations in cerebrospinal fluid (CSF) and aqueous humour were approximately 25% of those found in plasma (de Miranda et aI., 1981 b). In man, there is only limited information about the distribution of acyclovir in tissues and biological fluids. Acyclovir appears to penetrate into the CSF, where concentrations are approximately 50% of the corresponding plasma concentrations
2.2 Plasma Protein Binding When 14C-acyclovir was given to 5 subjects, de Miranda et al. (l981a, 1982a) found that the binding of acyclovir to plasma protein was relatively low and that the extent of binding is independent of the plasma concentration over the range studied (acyclovir concentrations between 1.8 and 22.8 J.LmoljL). The plasma protein binding of acyclovir ranged from 9 to 22% with a mean of 15.4%.
Acyclovir
9-Carboxymethoxy-methylguanine
Fig. 1. Structural formulae of acyclovir and its only significant metabolite in man, 9-carboxymethoxymethylguanine.
19t
Clinical Pharmacokinetics of Acyclovir
(Blum et al., 1982). At 2 hours following a dose, CSF acyclovir concentrations were 16.6 and 17.8 J.Lmol/L in 2 adults (Whitley et aI., 1982b) and 17.6 J.Lmol/L in a paediatric patient (Blum et al., 1982). Wade et al. (1982a) found at autopsy that the concentrations of acyclovir in the kidney, nervous tissue (brain and spinal cord) and lung were 1000%, 25 to 70% and 131 % of the corresponding plasma concentrations, respectively. Acyclovir concentrations in the heart and liver were similar to those in the lung. In patients with herpes zoster, acyclovir concentrations m vesicle fluid approximated the plasma concentrations after intravenous (Spector et al., 1982) or oral administration (de Miranda et al., 1982c; Van Dyke et al., 1982a,b). After oral administration of acyclovir 200mg every 4 hours, Van Dyke et al. (l982a) found the drug in both saliva (mean saliva/plasma ratio, 13%) and vaginal secretions (mean vaginal secretion/plasma ratio, 79%). The peak acyclovir concentrations in saliva (2 to 2.25 hours post-dose) and vaginal secretions (0.5 to 1.0 hour post-dose) were 0.36 ± 0.19 (mean ± SD) and 1.9 ± 1.0 J.Lmol/L, respectively. In blood, acyclovir was distributed nearly equally in the blood cells and plasma (de Miranda et aI., 1981a).
+1
2.4 Metabolism and Excretion Renal excretion is the major route of elimination of acyclovir in subjects with normal renal
+1
~ ~
C")
,......
+1
o (J)
+1
+1
+1
+1
co co LO 0 m L() Ll) ....... -.:t ....... ,.... ,......
+1
+1
P. g s; .......... N
~ ~ P6 +1
+1
~
b g
('I')
+1
("')
('I')
+1
+1
+1
+1
+1
ffi
~ ~
C\I
+1 co
tn
r-
OJ
(;t)
o
+1
~ ~
C\I
l.C)
U")
ci ci 0
ci 0
en
+1
+1
+1
C\J
.,....
CD
+1
~
ci
~
M~ ~
en
+1 0
g
,......
0
+1
+1
C")
q-
N ,.; N N N N N
C\I
+1
+1
+1
+1
+1
+1
C')
0
,....
0
0
"""':
~ ~ ~
Volume of Distribution The apparent volume of distribution of acyclovir at steady-state (V d ss) is about 70% of total bodyweight or approximately 50 L/1.73m 2 , which roughly corresponds to total body water. The volume of the central compartment (V d is about 40% of the apparent volume of distribution at steadystate and approximates the extracellular space [Laskin et al., 1982b].
+1
.q-
gg;
D
~~~~'" t.!..
ci
'0
g'"
o:g
z '"
J,
I,()
lri J,
~
0
~
N
0 dON Lri ,...:
Clinical Pharmacokinetics of Acyclovir
192
100
MAM 10
1
01
:fUS1On
001
2: (5
E .:s,
0
'"
j
i
j
10
I
I
15
I
,
j
20
25
20
25
20
25
100
co
0
.~ co
RFR
10
Q) (j
co
0
0, ,
(j
'>0
u>(j
01
III III
E
~ 001
11:
0
5
10
15
100
10
GSS
'0-
~ '0,
'-0
01
001
0
5
10
15
Time (hours)
Fig. 2. Comparison of plasma acyclovir concentration versus time profiles during and following the administration of 5.0 mg/ kg acyclovir (infused over 1 hour) in the presence (0-··-0) and absence (l'.--l'.) of prObenecid in 3 subjects (after Laskin et
al.. 1982a).
function. After an intravenous infusion of acyclovir, most of the dose is excreted unchanged in the urine (table I). The only significant metabolite that has been isolated is 9-carboxymethoxymethylguanine (fig. 1) [de Miranda et a!., 1981a], which in subjects with normal renal function accounts for 8.5 to 14% of the administered dose. In subjects with moderately reduced renal function, the percentage of dose recovered as 9-carboxymethoxymethylguanine increases (Blum et aI., 1982). As table I demonstrates, the renal clearance of acyclovir is approximately 75 to 80% of the total body clearance and is substantially greater than the estimated creatinine clearance. This indicates that renal tubular secretion as well as glomerular filtration plays a role in the elimination of acyclovir. In order to further elucidate the renal elimination of acyclovir, Laskin et al. (1982a) evaluated the influence of probenecid on the pharmacokinetics of the drug. In a crossover study, each subject received 2 infusions of acyclovir 5 mg/kg, administered in an identical manner except that 1 hour prior to the second infusion, each patient was given Ig of oral probenecid. Probenecid significantly enhanced the plasma concentrations of acyclovir' in each subject as shown in figure 2. Following probenecid, there was an 18% increase in the terminal plasma half-life (from 2.3 to 2.74h) and a 32% reduction in the renal clearance (248 to 168 ml/min/ 1. 73m 2) of acyclovir. In addition, there was a 40% increase in the area under the plasma concentration-time curve and the urinary recovery of acyclovir decreased from 79% to 69%. This implies that at least part of the renal tubular secretion of acyclovir is via the organic acid secretory system. However, since the renal clearance of acyclovir was stilI 2-fold greater than the estimated creatinine clearance, acyclovir may be secreted by other mechanisms. While investigating the effect of acyclovir on renal function, Kumor et a!. (1982) reported 1 patient (of 12) who developed a significant elevation of his serum creatinine from 1.1 to 1.8 mg/dl. This patient was found to have no changes in his
193
Clinical Pharmacokinetics of Acyclovir
100 c;
2.Smg/kg
~;; c;
10
Q)
0
c: 0
0
.s: 0
,.,
<3 0
"'",..J E:::" a
~~
0:::3
infusion 0.1
4
0
6
8
10
12
14
16
18
20
100
c:
50rng/kg
0
~
E Q)
10
0
c: 0
0
.s: 0
,.,
<3 0
"'",...J E:::"
infusion
.,0
",E
b
5:3
01
a
2
•
9
10
12
I.
16
19
20
100
c:
IO,Omg/kg
0
~
insulin. i3"-microglobulin or albumin clearances, This rise in serum creatinine in the absence of renal dysfunction suggests that acyclovir, which is both a weak acid and base (pKa of 2.27 and 9.25), may compete with the renal organic base transport of creatinine, in a manner similar to cimetidine (Dubb et al.. 1978). The metabolic fate of intravenous 14C-acyclovir (labelled on the 8 position of the purine ring) was studied in 5 subjects by de Miranda et aL (1981 a). Almost all the radioactivity was recovered in the urine with less than 2% recovered in the faeces and only negligible amounts in the expired CO 2 (estimated to be less than 0.1% of the dose). The only signficant metabolite was 9-carboxymethoxymethylguanine, which accounted for approximately 10% of the dose. There was no cleavage of acyclovir to guanine. The {3 or terminal phase plasma half-life of acyclovir is approximately 2 to 3 hours in adults with normal renal function. The pharmacokinetics of the drug are dose-dependent and are summarised in table I.
10
Q)
0
c: 0
0
'S:
2.5 Acyclovir Plasma Concentrations During Treatment
~,., 0
"'.. ..J E:::" ~~
C
0:3
infusion 0.1
a
6
2
8
10
12
I.
16
18
20
100 c; 0
IS Omg/kg
~
10
Q)
0
c: 0
0
.s: ~
..E:::"~
-'
~~
d
0::3
infusion 0,1 0
2
•
6
8
10
12
14
16
18
20
Time (hours)
Fig, 3, Mean (± SD) plasma concentration versus time profiles of acyclovir during and after a 1-hour infusion at various doses (as indicated) [after Laskin et aI., 1982b; reproduced with permission].
Acyclovir has been administered intravenously to man at doses up to 15 mg/kg. Figure 3 demonstrates that the plasma acyclovir concentrationtime profile is biexponential and is well fitted by a 2-compartment open model following intravenous infusion. Mean plasma acyclovir concentrations during and after a I-hour infusion of 2.5. 5, 10 and 15 mg/kg of acyclovir are shown in figure 3. Even at 7 hours the plasma concentrations are still greater than the ED 50 for herpes simplex virus, which is 0.1 ~mol/L. Under steady-state conditions, the mean peak acyclovir concentrations after multiple intravenous doses of 2.5, 5, 10 and IS mg/ kg every 8 hours were 22.6, 43.5, 91.9 and 104.8 ~mol/L, which are similar to those following a single dose (Blum et aI., 1982). When acyclovir was
Clinical Pharmacokinetics o.t Acyclovir
194
given as a continuous infusion of daily doses from 7.2 to 43.2 mg/kg for 3 to 5 days, the mean steadystate acyclovir concentrations ranged from 4.1 pmoljL for the lowest dose to 37 pmol/L for the highest dose (Spector et at, 1982). In bone marrow
c
30
A
0
~
25
CIl
(J
c
0
(J
'g
20
~
U >(J
"'E::::'" oJ
15
10
",0
",E
a:";!' 5
a 0
~
CIl
0
(J ~
12 10
'S:
B
~
6
0
u
"'~s. ",0
10
15
20
e
14
(J
c
~ kd~ 5
16
co
f- --+ ---~- -------
4
",E
a:";!' 2
b
1---+---1
....
------~
1
1 1
T
+ 5
10
15
20
Study day
Fig. 4, a: Mean (± SD) plasma acyclovir concentrations during prophylactic therapy in bone marrow transplant recipients, • = mean peak concentrations; 0 = mean trough concentrations. b: Mean (± SD) plasma acyclovir concentrations normalised for changes in renal function (symbols as in a), The plasma acyclovir concentrations were adjusted tor changes in renal function by the equation: Cnorm Caev x (Clerlday,1 + Clerlda , 11)
=
where Cnorm is the normalised acyclovir concentration, Caev is the plasma acyclovir concentrations on study day x, and Clerlda, ,I and Clerlday 11 are the creatinine clearances of the patient on study day x and day 1, respectively (after Laskin et aI., 1982e; reproduced with permission),
transplant recipients who received acyclovir for 18 days (Laskin et at, 1982e), there was an increase in the plasma acyclovir levels with therapy (fig. 4a). However, these patients had a 37% reduction'in renal function during therapy. This decrease in renal function was not considered to be due to acyclovir but rather to other nephrotoxic agents and events (e.g. amphotericin B, aminoglycosides, hypotension) since a similar decrease was seen in the placebo-treated group. Acyclovir concentrations remained relatively constant over time when normalised for the changes in creatinine clearance (fig. 4b).
3. Effect of Disease States and Age on Acyclovir Pharmacokinetics 3.1 End-Stage Renal Failure and Haemodialysis One would expect that a drug which exhibits the pharmacokinetic profile of acyclovir to have its kinetics influenced by significant changes in renal function. Acyclovir (2.5 mg/kg) was given intravenously to 6 patients with end-stage renal disease who required chronic haemodialysis (Laskin et aI., 1982). Figure 5 demonstrates the biphasic decay and the plasma acyclovir concentration-tiine profiles for each subject following a I-hour infusion and during haemodialysis. The mean peak acyclovir concentration at the end of the infusion was found to be 37.5 pmoljL. This compares with 20 ILmoljL seen in a previous single-dose study in normal subjects, where acyclovir was administered in an identical fashion (fig. 6). At 8 hours, there was a 5-fold greater plasma acyclovir concentration in those with end-stage renal disease compared with those with normal kidneys. In addition, acyclovir persisted in the plasma of the subjects with renal insufficiency, so that the plasma concentration was greater than I pmol/L in every subject after 48 hours. In patients with normal renal function, acyclovir concentrations fell below 1 pmoljL by 11 hours and were undetectable at 36 hours.
195
Clinical Pharmacokinetics of Acyclovir
The pharmacokinetic parameters of acyclovir in subjects with end-stage renal disease and during haemodialysis are shown in table II. In patients with end-stage renal disease the terminal plasma half-life was found to be 19.5 hours. This is a 7fold increase over the terminal plasma half-life seen in the presence of normal renal function. The apparent volume of distribution at steady-state was
Patient 1
2: "0 E
..:;,
41.2 Lil. 73m 2, which was statistically different from that seen in patients with normal renal function (Laskin et ai., 1982c). The total body clearance of acyclovir in the absence of renal function was only about 10% of that observed in previous subjects who had relatively normal glomerular filtration and represents the non-renal clearance in normal subjects.
Patient 2
10
10
1.0
1.0
Patient 3
.,o C
Jg c ~ c o
~
'> o
~ o
'"
OJ
~
'"
-
InfusIon
DialYSIS
InfuSion
0:: 0.1
+-----.--~-~~-c:;:='____,
40
50
60
0.1
Infusion
DIOlyslS
+-----.----,~~,-~-=~;:::...~
o
10
20
30
40
50
0.1
60
100
o
10
20
30
40
50
60
100
Patient 6
Patient 5
Patient 4
2:
"0 E 10 ..:;,
OIOIYSIS
+---,~___r_-~--,--=-;=--,
°0
10
10
c
o
~
<= ~
c
~
os;
1.0
1.0
1.0
.Q u >u
'"
OJ
~
£
InfuSion
0.1
DlolyslS
+--,r---.--.----,r-....:-r=-----,
o
10
20
30
Time (hours)
40
50
60
Intullon
0.1
o
10 20 30 Time (hours)
Infu"on
DiQI~111
+---.--....--..--.,..--'T=--. 40
~O
60
0-1
DiQI~lil
+--.---..--r--.--....:-~~
o
10 20 30 Time (hours)
40
~O
60
Fig. 5. Individual plasma acyclovir concentration versus time profiles after a 1-hour infusion of 2.5 mg/kg acyclovir in 6 anuric subjects. At 48 hours each subject underwent haemodialysis for 6 hours. The last data point was obtained following haemodialysis.
The line represents the best-fit biexponential equation for each subject (after Laskin et aI., 1982d; reproduced with permission).
Clinical Pharmacokinetics of Acyclovir
196
100
:J
'5
E .5 c
i
10
1
Q) ()
c 0
()
I
.>
I
0
13 >()
'"
'"E a::''""
Infusion 0.1
0
-
Dialysis
x 10 20 Time (hours)
patients with severe renal insufficiency, an effect of concomitant hepatic dysfunction on acyclovir kinetics would be expected since the site of biotransformation of acyclovir to its metabolite, 9carboxymethoxymethylguanine, is in the liver. While elevations in AST (SOOT) and ALT (SOPT) have been observed in patients receiving acyclovir (Laskin et aI, 1982e; Van der Meer and Versteeg, 1982; Keeney et aI., 1982), the clinical significance of these elevations is not known.
30
40
3.3 Pharmacokinetics in Infants and Children
SO
Fig. 6. Comparison of the mean (± SO) plasma acyclovir concentration versus time profiles in 6 subjects with end-stage renal disease (t>--LI) and 3 subjects with normal renal function (..........) after receiving a single i-hour infusion of acyclovir (2.S mg/kg) [after Laskin et al., i982c; reproduced with permission].
Acyclovir is readily haemodialysable as shown in figure S and table II. During haemodialysis, the mean apparent plasma half-life of acyclovir was 5.7 hours and the dialysis clearance was found to be approximately 82 mljmin using a hollow fibre single-pass system with an approximate blood flow of 200 ml/min and a dialysate flow of 800 ml/min (Laskin et aI., 1982d). The total clearance of acyclovir during haemodialysis (Cl tot + Cldia1 ) was approximately lID ml/min/1.73m 2 (Krasny et aI., 1982; Laskin et aI., 1982d). The coefficient of extraction of acyclovir was found to be 0.45. A single 6-hour course of haemodialysis reduced acyclovir concentrations by approximately 60%. 3.2 Liver Disease Little is known about the pharmacokinetics of acyclovir in patients with liver disease or their tolerance to the drug. Since subjects with normal renal function eliminate acyclovir mostly via urinary excretion, elimination of acyclovir is unlikely to be significantly affected by liver dysfunction. In
The pharmacokinetics of acyclovir has been established in both neonates (0 to 3 months) and in Table II. Pharmacokinetic parameters of acyclovir in subjects with end-stage renal disease between (interdialysis period) and during haemodialysis (after Laskin et aI., 1982c,d)
Pharmacokinetic parameter
Interdialysis period (mean ± SO)
During haemodialysis (mean ± SO)
Terminal half-life (h)
19.5 ± 5.9
5.7 ± 0.9
Vc (L/l.73m2)
15.3 ± 8.1
Vd ss (L/i.73m2)
4; ± 2.3 81.8 ± 12.6
Cl doal (ml/min) Clio, (ml/min/1.73m2 )
28.6 ± 9.S
110 ± 14"
k., (L/h)b
0.15 ± 0.09
0.69 ± 0.6 0.45 ± 0.12
Coefficient of extraction
Acyclovir pre-dialysis conc. (Cp,.) = 2.74 ± 1.4 "mol/L. Acyclovir post-dialysis conc. (Cpos,) = 1.11 ± 0.6 Ilmol/L. Mean (Cpo. - Cpost)jCpte
= 0.6.
a Represents the total clearance during dialysis; value includes the clearance due to extracorporeal removal of drug [Le. the dialyser (Cl d",)] and the clearance due to non-renal corporeal elimination (e.g. biotransformation). b
=
During dialysis ka' = kal
+
kdla"
Abbreviations: Vc = volume of the central compartment; Vd s•
apparent volume of distribution at steady-state; Gldlal = dialysis clearance; CI,o' total body clearance; k., = apparent firstorder rate constant of elimination.
=
197
Clinical Pharmacokinetics of Acyclovir
Table 11/. Summary of paediatric pharmacokinetic studies with acyclovir following multidose intravenous administration (mean values :t SO)
Reference
Age group
Dose (mg/kg)
(h)
Vd ss (L/l.73m2)
Cl tot (ml/min/l.73m2)
t,/2rl
Hintz et al. (1982)
Neonates (0-3 months)
5.0 10.0 15.0
4.0 ± 1.6 4.1 ± 1.5 3.2 ± 0.7
30.0 ± 2.0 28.9 ± 11.3 24.1 ± 6.3
122 ± 51 98 ± 34 108 ± 43
Blum et al. (1982)
Neonates (0-3 months) Children (1-17 years)
5-15
4.1 ± 1.2
28.8 ± 9.3
105 ± 42
6-12"
2.5 ± 1.0
44.7 ± 15.4
335 ± 109
a
Actual dosage was 250 to 500 mg/m 2 which is approximately 6 to 12 mg/kg.
children (1 to 17 years), as summarised in table III. In neonates, the plasma half-life was slightly longer (4.0 hours) and the total body clearance was much less (105 to 122 ml/min/1.73m 2) than that found in either children or adults. This significant decrease in clearance seen in neonates is consistent with the changes that occur in the kidney during the first year oflife. Hintz et al. (1982) found that the mean peak acyclovir plasma concentrations in neonates following doses of 5, 10 and 15 mg/kg increased directly proportional to the dose administered (30.0, 61.2 and 86.1 J.tmol/L, respectively). These values were similar to those found by Yeager (1982) in premature and term neonates. After 1 year of age, the pharmacokinetics in children were found to be similar to that of adults as were the peak acyclovir concentrations following infusion.
4. Potential Drug Interactions As discussed above (section 2.4), the renal clearance of acyclovir is decreased by probenecid, presumably by competitive inhibition of organic acid secretion. Therefore theoretically, other drugs which are secreted by the organic acid secretory pathway in the renal tubules should have a similar effect to probenecid in decreasing acyclovir clearance. These drugs would include the penicillins, cephalosporins
and para-aminohippuric acid (PAH). However, the influence of probenecid (and presumably these other agents) on acyclovir kinetics, while statistically signficant, is small and probably of limited clinical importance. On the other hand, acyclovir, by competing for this pathway, may decreage the renal clearance of other drugs which are eliminated by active renal secretion. This could be very important for methotrexate (Calabresi and Parks, 1980). Because of its low protein binding, drug interactions with acyclovir resulting from competition for protein binding sites are not anticipated.
5. Adverse Effects Acyclovir appears to have a very large therapeutic index. The toxicity to date with acyclovir has been minor. Phlebitis and local intravenous injection site irritation have been observed (Keeney et al., 1982; Laskin et al., 1982b; Meyers et aL, 1982); this may be related to the rather high pH of the infusing solution (pH> 9.0) raiher than a direct effect of the drug. Acyclovir, which has a maximal solubility in urine of 1.3 mg/ml, uncommonly causes a reversible elevation in the serum creatinine; this renal dysfunction may be due to crystallisation of the drug in the renal tubules or collect-
198
Clinical Pharmacokinetics of Acyclovir
ing ducts (Brigden, et aI., 1982; Keeney et aI., 1982). The development of renal dysfunction seems to be related to the method of administration. It appears to be more likely when the drug is given as a bolus injection rather than as a I-hour infusion (Brigden et aI., 1981, 1982). Acyclovir has caused an elevation in the liver transaminases (AST, ALT) [Laskin et aI., 1982e; Soike and Gerone, 1982; Van der Meer and Versteeg, 1982; Whitley et aI., 1982b], but the clinical importance of this has not been established. Central nervous system toxicity (delirium, tremors, abnormal EEG) has occurred during therapy with acyclovir (Saral et aI., 1981; Wade et aI., 1982a), but these tend to occur in extremely complicated cases and a causal relationship can not be established. Acyclovir has not been shown to have any bone marrow suppressive toxicity at clinical relevant concentrations (Laskin et aI., 1982e; McGuffin et aI., 1980).
6. Dosage Adjustment in Renal Insufficiency When acyclovir is administered to patients with renal insufficiency, dosage modification will be necessary to maintain the plasma acyclovir concentration at an effective level without concomitant drug accumulation. Blum et al. (1982) explored the linear relationship of total body clearance of acyclovir and creatinine clearance by pooling all the adult data and derived that the Cl tot = 28.7 + 3.37 x Cler . Based on this relationship, guidelines for adjustment of the dose for patients with varying degrees of renal dysfunction were devised. The current recommendations are: a) For Cler > 50 ml/min/1.73m2, the usual dose of acyclovir (250 to 500 mg/m2) should be given b) For Cler of 25 to 50 mlfmin/1.73m 2, the usual c) For Cler of 10 to 25 ml/min/1.73m 2, the usual d) For Clcr < 10 mlfmin/1.73m2, half the usual dose of acyclovir should be given every 24 hours. In subjects with end-stage renal disease, Laskin
et ai. (1982c, 1982d), suggested that an alternative to changing the interval was to give an initial loading dose and then to give a reduced maintenance dose every 8 hours. Computer simulation using a 2-compartment model indicated that a loading dose of 37% and an 8-hourly maintenance dose of 14% of the dosage recommended for similar patients with normal renal function should produce and maintain similar mean plasma concentrations. During dialysis about 60% of acyclovir in the body will be removed and should be replaced. Depending on when dialysis occurs relative to the preceding dose, this will be 60 to 100% of the loading dose.
7. Conclusions Acyclovir is a new effective antiherpetic agent with selective activity against herpesviruses. Its mechanism of action has recently been established. The pharmacokinetics of acyclovir have been well described in neonates, children and adults and in patients with renal insufficiency. These data have enabled a rational dose regimen to be used in phase II and III studies. Acyclovir has been shown to be effective in numerous ciinical studies, many of which were double-blind, randomised, controlled trials. While a considerable wealth of knowledge about the clinical pharmacology of acyclovir has accumulated, much still remains to be learned about the optimum use of the drug in the treatment of viral diseases.
Acknowledgements The author would like to gratefully thank Dr Marcus M. Reidenberg and Dr Dennis Drayer for their critical reading of this manuscript and for their helpful suggestions. Dr Oscar L. Laskin is a Rockefeller Brothers Clinical Scholar.
Clinical Pharmacokinetics of Acyclovir
References Anonymous: Topical acyclovir for herpes simplex. Medical Letter 24: 55-56 (1982). Biron, K.K. and Elion, G.B.: In vitro susceptibility of VaricellaZoster virus to acyclovir. Antimicrobial Agents and Chemotherapy 18: 443-447 (1980). Blum. M.R.: Liao, S.H.T. and de Miranda, P.: Overview of acyclovir pharmacokinetic disposition in adults and children. American Journal of Medicine 73 (Supp!.): 186-192 (July 1982). Brigden, D.: Bye, A.: Fowle, AS.E. and Rogers, H.: Human pharmacokinetics of acyclovir (an antiviral agent) following rapid intravenous injection. Journal of Antimicrobial Chemotherapy 7: 399-404 (1981). Brigden, D.: Fowle, A. and Rosling, A.: Acyclovir, a new antiherpetic drug: Early experience in man with systemically administered drug; in Collier and Oxford (Eds) Developments in Antiviral Therapy, pp. 53-62 (Academic Press, New York 1980). Brigden, D.; Rosling, A.E. and Woods, N.C: Renal function after acyclovir intravenous injection. American Journal of Medicine 73 (Supp!.): 182-185 (Jul 1982). Calabresi, P. and Parks, R.E.: Antiproliferative agents and drugs used for immunosuppression; in Goodman et a!. (Eds) The Pharmacological Basis of Therapeutics pp. 1274 (Macmillan Publishing Co, New York 1980). Centifanto, Y.M. and Kaufman, H.E.: 9-(2-Hydroxyethoxymethyl)guanine as an inhibitor of herpes simplex virus replication. Chemotherapy 25: 279-281 (1979). Collins, P. and Bauer, D.J.: The activity in vitro against herpes virus of 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine), a new antiviral agent. Journal of Antimicrobial Chemotherapy 5: 431-436 (1979). Corey, L.: Benedetti, J.K.; Critchlow, CW.; Remington, M.R.; Winter, CA: Fahnlander, A.L.; Smith, K.; Salter, D.L.; Keeney, R.E.: Davis, L.G.; Hintz, M.; Connor, J.D. and Holmes, K.K.: Double-blind controlled trial of topical acyclovir in genital herpes simplex virus infections. American Journal of Medicine 73 (Supp!.): 326-334 (Jul 1982). Crumpacker, CS.: Schnipper, L.E.; Zaia, J.A. and Levin, M.J.: Growth inhibition by acycloguanosine of herpes viruses isolated from human infection. Antimicrobial Agents and Chemotherapy 15: 642-645 (1979). de Miranda, P.; Good, 5.5.; Krasny, H.C; Connors, J.D.; Laskin, O.L. and Lietman, P.S.: Metabolic rate of radioactive acyclovir in humans. American Journal of Medicine 73 (Supp!.): 215-220 (Jul I 982a). de Miranda, P.; Good, S.S.; Laskin, O,L.; Krasny, H.C; Connors, J.D.; and Lietman, P.S.: Disposition of intravenous radioactive acyclovir. Clinical Pharmacology and Therapeutics 30: 662-672 (l98Ia). de Miranda, P.; Krasny, H.C. and Elion, G.B.: Metabolic disposition of 9-(2-hydroxyethoxymethyl)guanine, a new anti-
199
viral drug. Abstracts of the 7th International Congress of Pharmacology, p. 354 (1978). de Miranda, P.: Krasny, H.C.; Page, D.A and Elion, G.B.: The disposition of acyclovir in different species. Journal of Pharmacology and Experimental Therapeutics 219: 309-315 (198Ib). de Miranda, P.: Krasny, H.C.; Page, D.A, and Elion, G.B.: Species differences in the disposition of acyclovir. American Journal ~f Medicine 73 (Supp!.): 31-35 (Jul 1982b). de-Miranda, P.; Whitley, R.I.: Barton, N.; Page, D.; Creagh-Kirk, T.; Liao, S. and Blum, R.: Systemic absorption and pharmacokinetics of acyclovir (Zovirax) capsules in immunocompromised patients with herpesvirus infections. Twenty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, Miami, Abstract 418 (l982c). de Miranda, P.; Whitley, R.I.; Blum, M.R.; Keeney, R.E.; Barton, N.: Cocchetto, D.M.; Good, S.; Hemstreet, G.P.; Kirk, L.E.; Page. B.S. and Elion, G.B.: Acyclovir kinetics after intravenous infusion. Clinical Pharmacokinetics and Therapeutics 26: 718-728 (1979). Dubb. J.W.: Stote, R.M.; Familar, R.G.; Lee, K. and Alexander, F.: Effect of cimetidine on renal function in normal man. Clinical Pharmacology and Therapeutics 24: 76-83 (1978). Elion, G.B.: Mechanism of action and selectivity of acyclovir. American Journal of Medicine 73 (Supp!.): 7-13 (Jul 1982). Elion. G.B.; Furman, P.A.; Fyfe, J.A.; de Miranda, P.; Beauchamp, L. and Schaeffer, H.J.: Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proceedings of the National Academy of Science (USA) 74: 57165720 (1977). Field. H.1.: Bell. S.E.; Elion, G.B.; Nash, A.A. and Wi\dy, P.: Effect of acydoguanosine treatment on acute and latent herpes simplex infections in mice. Antimicrobial Agents and Chemotherapy 15: 554-561 (1979). Furman. P.A.; SI. Clair, M.H.: Fyfe, J.A.; Rideout, J.L.; Keller, P.M. and Elion, G.B.: Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate. Journal of Virology 32: 72-77 (1979). Fyfe. J.A.; Keller, P.M.; Furman, P.A.; Miller, R.L. and Elion, G.B.: Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound 9-(2-hydroxyethoxymethyl)guanine. Journal of Biological Chemistry 253: 8721-8727 (1978). Hintz, M.: Connor, J.D.; Spector, S.A.; Blum, M.R.; Keeney, R.E. and Yeager, A.S.: Neonatal acyclovir pharmacokinetics in patients with herpes virus infections. American Journal of Medicine 73 (Suppl.): 210-214 (Jul 1982). Jamieson. A.T.; Gentry, G.A and Subak-Sharpe, J.H.: Induction of both thymidine and deoxycytidine kinase activity by herpes virus. Journal of General Virology 24: 465-480 (1974). Jones. B.R.: Coster, OJ.; Fison, P.N.; Thompson, G.M.; Cabo, L.M. and Falcon, M.G.: Efficacy of acydoguanosine (Well-
Clinical Pharmacokinetics of Acyclovir
come 248U) against herpes-simplex corneal ulcers. Lancet I: 243-244 (1979). Keeney. R.E.; Kirk, L.E. and Brigden, D.: Acyclovir tolerance in humans. American Journal of Medicine 73 (Supp!.): 176-181 (Jul 1982). Klein. R.J.; Friedman-Kien, A.E. and DeStefano, E.: Latent herpes simplex virus infections in sensory ganglia of hairless mice prevented by acycloguanosine. Antimicrobial Agents and Chemotherapy 15: 723-729 (1979). Krasny. H.e.; de Miranda, P.; Blum, M.R. and Elion, G.B.: Pharmacokinetics and bioavailability of acyclovir in the dog. Journal of Pharmacology and Experimental Therapeutics 216: 281288 (1981). Krasny. H.e.; Liao, S.H.T.; de Miranda, P.; Laskin, O.L.; Whelton. A. and Lietman, P.S.: Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure. American Journal of Medicine 73 (Supp!.): 202-204 (Jul 1982). Kumor. K.M.; Woo, J. and Conklin, R.: Renal function in immunocompromised patients receiving acyclovir for herpes virus infections (abstract). Clinical Research 30: 253A (1982). Land. G. and Bye, A.: Simple high-performance liquid chromatographic method for the analysis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) in human plasma and urine. Journal of Chromatography 224: 51-58 (1981). Laskin. O.L.; de Miranda, P.; King, D.H.; Page, D.A.; Longstreth, J.A.; Rocco. L. and Lietman, P.S.: Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans. Antimicrobial Agents Chemotherapy 21: 804-807 (1982a). Laskin. O.L.; Longstreth, J.A.; Saral, R.; de Miranda, P.; Keeney, R. and Lietman, P.S.: Pharmacokinetics and tolerance of acyclovir. a new anti-herpes virus agent, in humans. Antimicrobial Agents and Chemotherapy 21: 393-398 (1982b). Laskin. O.L.; Longstreth, J.A.; Whelton, A.; Krasny, H.C.; Keeney. R.E.; Rocco, L. and Lietman, P.S.: Effect of renal failure on the pharmacokinetics of acyclovir. American Journal of Medicine 73 (Supp!.): 197-201 (Jul 1982c). Laskin, O.L.; Longstreth, J.A.; Whelton, A.; Rocco, L.; Lietman, P.S.; Krasny, H.C. and Keeney, R.E.: Acyclovir kinetics in end-stage renal disease. Clinical Pharmacology and Therapeutics 31: 594-60 I (1 982d). Laskin. O.L.; Saral, R.; Burns, W.H.; Angulopulus, CM. and Lietman, P.S.: Acyclovir concentrations and tolerance during repetitive administration for 18 days. American Journal of Medicine 73 (Supp!.): 221-224 (Jul 1982e). Mar. E.-e. and Huang, E-S.: Comparative study of herpes group virus-induced DNA polymerases. Intervirology 12: 73-83 (1979). McGuffin. R.W.; Shiota, F.M. and Meyers, J.D.: Lack of toxicity of acyclovir to granulocyte progenitor cells in vitro. Antimicrobial Agents and Chemotherapy 18: 471-473 (1980). Meyers, J.D.; Wade, J.e.; Mitchell, CD.; Saral, R.; Lietman, P.S.; Durack. D.T.; Levin, M.J.; Segreti, A.C. and Balfour, H.H.:
200
Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. American Journal of Medicine 73 (Supp!.): 229-235 (Jul 1982). Miller, W.H. and Miller, R.L.: Phosphorylation of acyclovir (acycloguanosine) monophosphate by GMP kinase. Journal of Biological Chemistry 255: 7204-7207 (1980). Mitchell, C.D.; Bean, R; Gentry, S.R.; Groth, K.F.; Boen, J.R. and Balfour, H.H.: Acyclovir treatment for mucocutaneous herpes simplex infections in immunocompromised patients. Lancet 2: 1389-1392 (1981). Moore, D.F.; Taylor, S.C and Bryson, Y.J.: Virus inhibition assay for measurement of acyclovir levels in human plasma and urine. Antimicrobial Agents and Chemotherapy 20: 787-792 (1981). Pagano, J.S. and Datta, A.K.: Perspectives on interactions ofacyc10vir with Ebstein-Barr and other herpes viruses. American Journal of Medicine 73 (Supp!.): 18-26 (Jul 1982). Park, N.; Paven-Langston, D.; Mclean, S.L. and Albert, D.: Therapy of experimental herpes simplex encephalitis with acyclovir in mice. Antimicrobial Agents and Chemotherapy 15: 775-779 (1979). Perera. P.A.J. and Morrison, J.M.: Evidence for the induction of a new deoxycytidine kinase in ceUs infected with herpes virus. Biochemistry Journal 117: 21 p-22p (1970). Quinn. R.P.; de Miranda, P.; Gerald, L. and Good, S.S.: A sensitive radioimmunoassay for the antiviral agent BW248U 9(2-hydroxyethoxymethyl)guanine. Analytical Biochemistry 98: 319-328 (1979). Saral. R.; Burns, W.H.; Laskin, O.L.; Santos, G.W. and Lietman, P.S.: Acyclovir prophylaxis of herpes simplex vif4s infections: A trial in bone marrow transplant recipients. New England Journal of Medicine 305: 63-67 (1981). Schaeffer, H.J.: Acyclovir chemistry and spectrum of activity. American Journal of Medicine 73 (Suppl.): 4-6 (Jul 1982). Schaeffer, H.J.; Beauchamp, 1..; de Miranda, P.; Elion, G.B.; Bauer, D.J. and Collins, P.: 9-(2-hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 272: 583585 (1978). Skubitz, K.M.; Quinn, R.P. and Lietman, P.S.: Rapid acyclovir radioimmunoassay, using charcoal adsorption. Antimicrobial Agents and Chemotherapy 21: 352-354 (1982). Soike. K.F. and Gerone, P.J.: Acyclovir in the treatment ofSimian VariceUa virus infection of the African green monkey. American Journal of Medicine 73 (SuppL): 112-117 (JuI1982). Spector, S.A.; Connor, J.D.; Hintz, M.; Quinn, R.P.; Blum, M.R. and Keeney, R.E.: Single-
Clinical Pharmacokinetics of Acyclovir
SI. Claire, M.H.; Furman, P.A.; Lubbers, e.M. and Elion, G.B.: Inhibition of cellular alpha and virally induced deoxyribonucleic acid polymerases by the triphosphate of acyclovir. Antimicrobial Agents and Chemotherapy 18: 741-745 (1980). Straus, S.E.; Smith, HA.; Brickman, e.; de Miranda, P.; McLaren. e. and Keeney, R.E.: Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients. Annals of Internal Medicine 96: 270-277 (1982). Thouless, M.E. and Skinner, G.R.B.: Differences in the properties of thymidine kinase produced in cells infected with type I or type 2 herpes virus. Journal of General Virology 12: 195-197 (1971).
Van der Meer, J.W.M. and Versteeg, J.: Acyclovir in severe herpes virus infections. American Journal of Medicine 73 (Supp!.): 271-274 (Jul 1982). Vall Dyke, R.B.; Connor, J.D.; Wyborny, e.; Hintz, M. and Keeney, R.E.: Pharmacokinetics of orally administered acyclovir in patients with herpes progenitalis. American Journal of Medicine 73 (Supp!.): 172-175, (Jul I 982a). Van Dyke, R.B.; Straube, R.; Large, K.; Hintz, M.; Spector, S. and Connor, J.D.: Pharmacokinetics of increased dose oral acyclovir. Twenty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, Miama, Abstract 414 (1982b). Wade, J.e.; Hintz, M.; McGuffin, R.W.; Springmeyer, S.e.; Connor. J.D. and Meyers, J.D.: Treatment of cytomegalovirus
201
pneumonia with high-dose acyclovir. American Journal of Medicine 73 (Supp!.): 249-256 (Jul I 982a). Wade, J.e.; Newton, S.; Flournoy, N. and Meyers, J.D.: Oral acyclovir prophylaxis of herpes simplex infections after marrow transplant. Twenty-second lnterscience Conference on Antimicrobial Agents and Chemotherapy, Miama, Abstract 184, (1982b). Whitley, R.J.; Barton, N.; Collins, E.; Whelchel, J. and Diethelm, A.G.: Mucocutaneous herpes simplex virus infections in immunocompromised patients: A model for evaluation of topical antiviral agents. American Journal of Medicine 73 (Supp!.): 236-240 (Jul I 982a). Whitley, R.J.: Blum, M.R.; Barton, N. and de Miranda, P.: Pharmacokinetics of acyclovir in humans following intravenous administration. A model for the development of parenteral antivirals. American Journal of Medicine 73 (Supp!.): 165171 (Jul 1982b). Yeager, A.S.: Use of acyclovir in premature and term neonates. American Journal of Medicine 73 (Supp!.): 205-209 (Jul 1982).
Author's address: Dr Oscar L. Laskin, Division of Clinical Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021 (USA).
