![[Feedback]](/icons/banner/feedbackACT.gif)
![[For Subscribers]](/icons/banner/subscriberACT.gif)
![[Archive]](/icons/banner/archiveACT.gif)
![[Search]](/icons/banner/searchACT.gif)
![[Contents]](/icons/banner/tocACT.gif)
Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, January 2001, p. 150-157, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.150-157.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Oral Acyclovir in Neonates and
in Infants: a Population Analysis
M.
Tod,1,*
F.
Lokiec,2
R.
Bidault,3
F.
De
Bony,3
O.
Petitjean,1
Y.
Aujard,4 and
the
Acyclovir Pediatric French Group
Pharmacie and Centre de Recherche en
Pathologie Infectieuse et Tropicale, Hopital Avicenne, Bobigny
93009,1 Service de Pharmacologie,
Centre René Huguenin, Saint
Cloud,2 Glaxo-Wellcome,
Marly-le-Roi,3 and
Néonatalogie, Hôpital Robert Debré,
Paris,4 France
Received 18 November 1999/Returned for modification 4 July
2000/Accepted 26 September 2000
 |
ABSTRACT |
Acyclovir is approved for the treatment of herpes simplex virus
(HSV) and varicella-zoster virus (VZV) infections in children by the
intravenous and oral routes. However, its use by the oral route in
children younger than 2 years of age is limited due to a lack of
pharmacokinetic data. The objectives of the present study were to
determine the typical pharmacokinetics of an oral suspension of
acyclovir given to children younger than 2 years of age and the
interindividual variabilities in the values of the pharmacokinetic
parameters in order to support the proposed dosing regimen (24 mg/kg of
body weight three times a day for patients younger than 1 month of
age or four times a day otherwise). Children younger than age 2 years
with HSV or VZV infections were enrolled in a multicenter study.
Children were treated for at least 5 days with an acyclovir oral
suspension. Plasma samples were obtained at steady state, before
acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir
administration. Acyclovir concentrations were measured by
radioimmunoassay. The data were analyzed by a population approach. Data
for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related
to the estimated glomerular filtration rate, body surface area, and
serum creatinine level. The volume of distribution was related to body
weight. The elimination half-life decreased sharply during the first
month after birth, from 10 to 15 h to 2.5 h. Bioavailability
was 0.12. The interindividual variability was less pronounced when the
parameters were normalized with respect to body weight. Hence, dosage
adjustment by body weight is recommended for this population.
Simulations showed that the length of time that acyclovir remains above
the 50% inhibitory concentration during a 24-h period was more than
12 h for HSV but not for VZV. The proposed dosing regimen seems
adequate for the treatment of HSV infections, while for the treatment
of VZV infections, a twofold increase in the dose seems necessary for children older than age 3 months.
| |
INTRODUCTION |
Acyclovir is currently used for the
prevention and treatment of herpes simplex virus (HSV) and
varicella-zoster virus (VZV) infections (7). It is
available at different dosages in the form of tablets, oral suspensions
(containing 200, 400, or 800 mg in 10 ml), and injectable solutions.
About 20 clinical studies have documented the use of acyclovir in
children (for a review, see reference 24). Most
frequently, acyclovir has been administered intravenously. Hintz et al.
(8) recommended 10 mg/kg of body weight every 8 h
(q8h) for neonates, while Blum et al. (2) recommended 250 mg/m2 (for HSV infections) and 500 mg/m2 (for
HSV encephalitis and VZV infections) q8h in children between 3 months
and 12 years of age. Owing to the ease of its administration and dosage
adjustment, the oral suspension is also used in children. The
recommended dosage in neonates is 100 mg four times a day (q.i.d.) (HSV
infections) and 200 mg q.i.d. (for VZV infections). In the latter case,
it is also possible to give 20 mg/kg q.i.d., provided that the
total daily dose is less than 800 mg. Oral acyclovir is also
effective for the prevention of cutaneous recurrences after HSV type 2 (HSV-2) disease of the skin, eyes, and mouth in neonates at a dose of
300 mg/m2 q8h (10). Despite the large amount
of clinical experience, these dosage recommendations were substantiated
with limited pharmacokinetic data obtained with neonates after oral
administration (10, 16, 21). These preliminary data showed
that the kinetics of acyclovir in neonates were probably strongly
modified compared to those in adults, as expected, but acyclovir
bioavailability and the interindividual variability of its
pharmacokinetics could not be well characterized. As a consequence,
doubt remained regarding the optimal dosing schedule for acyclovir
given orally to neonates. One reason for this lack of pharmacokinetic
data was ethical and practical, since it is difficult to draw many
samples from neonates in a short period. Therefore, a population study
of the kinetics of oral acyclovir in neonates, based on a sparse
sampling design, was undertaken. The data were analyzed by a nonlinear
mixed-effect modeling approach (19) in order to estimate
the typical values of the pharmacokinetic parameters and their
interindividual variabilities and to find the biological or demographic
indices related to their variation. Ultimately, simulation techniques
were used to give some support to the optimal dosing regimen for this population.
| |
MATERIALS AND METHODS |
Oral formulation study.
The study was designed as a
prospective French multicenter open study conducted in pediatric units.
The study was approved by the Ethics Committee of the Bichat-Claude
Bernard Hospital, Paris, France. Patients were enrolled if they were
younger than 2 years of age, were immunocompetent, presented with a
proven or suspected HSV or VZV infection, and their parents gave
written consent. The patients were treated for at least 5 days with an oral suspension (400 mg, 10 ml) of acyclovir administered per os.
Patients younger than 1 month of age received acyclovir at 24 mg/kg of
body weight q8h. Patients aged between 1 month and 2 years received
acyclovir at 24 mg/kg of body weight q.i.d. according to a schedule of
treatment at 0, 4, 8, 12, and 24 h. These dosages were based on
the limited pharmacokinetic data available (16, 21): about
25 mg/kg per dose was expected to be adequate. The value of 24 mg/kg
was retained because it corresponded to three graduations of the dosing syringe.
Venous blood samples were drawn after at least 30 h of treatment.
The sampling schedule depended on the status of the child. For
hospitalized children, blood samples were drawn before dosing and at 2, 3, 5, and 8 h after dosing. For ambulatory children, a sample was
obtained 4 h after dosing. Dosing history and sampling times were
recorded precisely by a nurse for inpatients, while theoretical times
were recorded for outpatients. The accuracies and consistencies of the
records were further assessed for all patients by a pharmacist. All
plasma samples were stored and kept frozen (
20°C) until analysis.
Acyclovir levels were measured by radioimmunoassay at the Laboratory of
Pharmacology, René Huguenin Center, St. Cloud, France. The limit
of quantification of the assay (determined as the lowest concentration
with a variability of less than 15%) was 0.01 µM, and the
variability (coefficient of variation [CV]) was less than 12% over
the entire calibration range.
Intravenous treatment study.
Data from a previous
multicenter study with 18 immunocompromised pediatric patients (S. Liao, M. R. Blum, D. A. Page, and P. De Miranda, Acyclovir
(Zovirax) multiple-dose pharmacokinetic analyses in pediatric patients
with herpes virus infections, internal document, Glaxo Wellcome Co.)
treated with intravenous acyclovir for a HSV, VZV, or cytomegalovirus
infection were also considered in order to improve the population model
building. Patients received acyclovir by a 1-h intravenous infusion at
250 or 500 mg/m2 q8h for 5 days. Blood samples were taken
before each infusion, at the end of each infusion, and at 0.5, 1, 2, 4, 8, 16, and 24 h after the end of the last infusion. Acyclovir
levels were measured by the same radioimmunoassay used in the study
with the oral formulation.
Database.
The following items were recorded: time of each
event, acyclovir dose (in micromoles), acyclovir concentration (in
micromolar), body weight (BW; in kilograms), height (H; in
centimeters), sex, postnatal age (PNA) and postconceptional age (PCA),
body surface area (BSA; in square meters), serum creatinine level
(SCR; in micromolar), blood urea nitrogen level (in
millimolar), and intake of antacids.
Acyclovir doses were calculated by taking into account the exact titer
of each lot and the exact volume of oral suspension administered.
Acyclovir concentrations below the limit of quantification were
recorded as half the lower limit of quantification (i.e., 0.005 µM).
This event never occurred more than once in each patient. All measured
values of the demographic and biological indices were recorded in the
database at the corresponding time of measurement. Ages (PCA and PNA)
were expressed in months by using the following rules: 1 year = 12 months and 1 month = 30 days = 4.33 weeks, so that 1 year = 52 weeks. BSA was calculated according to the formula
BSA = 0.02667 · H0.38217 · BW0.53937, i.e., the formula of Gehan and Georges for
children younger than age 5 years (5). SCR and
the BUN level at each time were calculated by linear interpolation
between known values. Other missing values were estimated as follows.
H, which had not been measured for seven patients, was recorded as the
ideal height according to sex (6). SCR, which
had not been measured for eight patients, was recorded as the mean
value according to gestational age and PNA (18). For all
patients older than age 3 months, PCA was calculated as PNA + 9.
With the exception of BUN levels and intake of antacids, the same items
were recorded for the intravenous treatment study. Only the data from
the last administration were considered in the analysis.
Pharmacokinetic modeling.
Since the infrequent sampling
schedule did not enable individual pharmacokinetic parameters to be
estimated by usual methods for most patients, a population
pharmacokinetic method based on a nonlinear mixed-effect modeling
approach was used (19). Two levels of variability (intra-
and interindividual) were considered. The details are described in the
Appendix.
Numerous previous pharmacokinetic studies have shown that acyclovir
disposition is adequately described by a one-compartment (oral route)
or a two-compartment (intravenous route) open model with first-order
rate constants (2, 11, 14). Therefore, only these
pharmacokinetic models were considered. The basic parameters were the
elimination clearance (CL), volume of distribution (V), and the
absorption rate constant (ka) for the
one-compartment model. Additional parameters for the two-compartment
model were V of the central compartment
(Vc), V of the peripheral compartment (Vp), and the distribution clearance
(CLd; which describes the rate of diffusion
between the two compartments). Bioavailability (more precisely, the
fraction of the dose that reached the systemic circulation) was denoted
as F. These models enabled the computation of the acyclovir
concentration at any time for any given dosing regimen
(23). Elaboration of the covariate model was based on the
following rationale. Acyclovir is primarily eliminated by the renal
route, by glomerular filtration and tubular secretion (11). Because of knowledge of the evolution of renal
function after birth, acyclovir clearance was expected to exhibit a
linear or hyperbolic relationship with age and especially with PCA. The inverse SCR was also expected to be correlated with
acyclovir clearance. Finally, a measure of body volume (such as H, BW,
or BSA) was expected to be a third covariate of acyclovir clearance, although it is highly correlated with age. The V of
acyclovir corresponds to total body water (14).
Therefore, V was expected to be correlated with a measure of
body volume, but BW is usually the better covariate in this respect
(9). The absorption rate constant was not expected to vary
with any of the demographic or biological indices. By contrast,
F was found in one study (3) to be saturable
and dose dependent for doses between 100 and 600 mg. This phenomenon
could be related to the poor solubility of acyclovir or to a
carrier-mediated active absorption. Therefore, appropriate covariate
models relating F to dose and/or age were also considered.
Model building.
The population model was built step by step.
At each step, a specific assumption was tested (e.g., one-compartment
versus two-compartment model). The main criterion of decision was the likelihood ratio test (25). The level of significance was
0.05. Secondary criteria were the aspects of the various residual plots and the values of the random-effects variances. Possible correlations between the demographic or biological indices and the pharmacokinetic parameters were explored by the three-step approach (12,
13).
Assessment of goodness of fit.
The final population model
was considered adequate when several criteria were met: (i) adequate
fit of each individual concentration-versus-time curve compared to the
experimental data, (ii) linear pattern of observed versus predicted
acyclovir concentrations, (iii) absence of trend in the weighted
residuals-versus-time plot, and (iv) an approximately normal
distribution of the weighted residuals. For the last three criteria,
concentrations were calculated by reference to the typical parameters
[i.e. f(
j,
tij), where f is the function describing
the pharmacokinetic model, 
j is
the typical value for a individual pharmacokinetic parameters, and
tij is the time of i-th sample in
j-th individual].
Simulations.
The final population model was used to generate
acyclovir concentration-versus-time curves for 500 fictitious
individuals by simulation for several age ranges. Each "individual"
had a different set of pharmacokinetic parameters, which were sampled from the distribution of values for the pharmacokinetic parameters defined by the population model. The 5th, 50th (median), and 95th percentiles of the acyclovir concentration were then calculated for
several "sampling" times from the 500 individual values. Likewise, the times that the concentration remained above 2.5 and 5 µM were calculated for each individual, and the percentiles of these
distributions were calculated.
Programs.
Fitting of the population model and individual
Bayesian estimations were made by using the NONMEM IV software
(1). The first-order method was used for model building.
Once the final model was found, the parameters were estimated by the
first-order conditional estimation method, taking into account the
-
interaction. Analysis of covariate models, statistical tests,
and relevant graphs were computed by using SPSS for Windows (release
6.1; SPSS France, Boulogne, France). Simulations were performed with
our POPSIM software (22).
| |
RESULTS |
Patients.
A total of 90 patients was enrolled in the study.
However, data for six patients were not included in the pharmacokinetic database because the dosing and/or sampling times had not been recorded
and the data for five patients were discarded from the per-protocol
analysis because they were older than 2 years of age. Therefore, data
for 79 patients could be considered for the main analysis of the
disposition of acyclovir in neonates and infants after oral
administration. The data for these 79 patients were combined with those
for the 5 patients older than age 2 years treated per os and with those
for the 18 pediatric patients treated intravenously for the global
analysis (n = 102) of acyclovir disposition. The
demographic data are summarized in Table
1.
Acyclovir doses and levels.
In the oral formulation study
(n = 79), the median (range) of the actual dose of
acyclovir was 164 mg (43 to 292 mg), corresponding to 24.1 mg/kg (21.7 to 32.6 mg/kg) or 446 mg/m2 (280 to 574 mg/m2).
In the intravenous study (n = 18), the actual doses
ranged from 83 to 500 mg/m2. A total of 212 samples were
analyzed in the main study (1 to 5 samples per subject), while 131 samples (7 or 8 samples per subject) were considered for the
intravenous study. There were 351 samples in the global analysis
(n = 102). Figures 1A and
B show the data for the oral and intravenous studies, respectively.
View larger version (13K):
[in this window]
[in a new window]
|
FIG. 1.
Distribution of acyclovir concentrations after oral
administration to 79 children (A) and after intravenous administration
to 18 pediatric patients (B).
|
|
Model building for oral disposition.
The main models and
hypotheses tested are described in Table
2. The two-compartment model was not
superior to the one-compartment model. Therefore, the one-compartment
model was used to describe oral data. The typical value of the apparent
clearance of acyclovir (
/F) was found to
be related to the estimated glomerular filtration rate (G
R),
BSA, and SCR, /F = 
1 · GR · (BSA/1.73)
(40/SCR), where GR = (7.2 × PCA
3)/(23 + PCA3) (1, 2, and
3 are defined below), while the interindividual variability of /F was expressed as
CLj/F = (/F)
· exp(CLj)
The GFR was estimated as a function of PCA. With this relationship, GFR
tends to a maximal value in adults, in whom it reaches 7.2 liters/h/1.73 m2, i.e., 120 ml/min/1.73 m2. The
parameter 2 is the PCA at which GFR reaches half its
maximal value. The parameter 3 is a sigmoidicity
coefficient, which is proportional to the steepness of the sigmoid
curve at PCA equal to 2. The coefficient (BSA/1.73)
transforms the estimated GFR into liters per hour. The last term
(40/SCR) takes into account the deviation of a given
individual from the median SCR for this population to
correct the estimated clearance. Finally, 1 is a scaling
factor which accounts for the unknown F and for the fact
that acyclovir clearance is higher than GFR owing to the tubular
secretion of acyclovir.
The typical value of the apparent volume of distribution
(
/F), was related only to BW:
/F = 4(BW/6.9), where 6.9 is the typical value of BW for this population. None of the demographic or biological indices was found to be related to the typical value of
ka: 
= 5 and kaj =
exp(kaj).
Allowing for covariance between the values did not improve the fit;
therefore, covariances were fixed to zero. The values of the parameters
of the final model, based on the data for 79 patients, are summarized
in Table 3. The interindividual CVs of
the CL and V of acyclovir after having taken into account
the covariates were 49 and 57%, respectively. The variability of
ka was estimated to be near zero. This should
not be interpreted as reflecting the absence of interindividual
variability in ka but, rather, as the inability
to estimate the variability owing to the small amount of information on
the absorption phase because of the sparse amount of data as a result
of the sampling schedule.
View this table:
[in this window]
[in a new window]
|
TABLE 3.
Values of population pharmacokinetic parameters for
acyclovir from data for patients younger than age 2 years receiving
the drug by the oral routea
|
|
A graph of the predicted concentrations versus the observed
concentrations is presented in Fig. 2. No
systematic deviation from the line of y equal to
x is observed. The plot of the weighted residuals of the
concentrations versus time (data not shown) showed no systematic
deviation from the line of y equal to 0. Other validation scatterplots did not reveal any particular trend (data not shown), so
that the population model fit the data reasonably well. Individual curves based on post hoc estimates were also adequate.
View larger version (14K):
[in this window]
[in a new window]
|
FIG. 2.
Scatterplot of predicted versus observed acyclovir
concentrations for data for administration by the oral route. Predicted
concentrations were calculated by using the population model, the
covariates for each patient, and the patient's dosing history.
|
|
According to the definition of the residual error model, the residual
variabilities of the acyclovir concentrations, expressed as a CV, were
61% at 0.3 µM, 35% at 3 µM, and 20% at 30 µM.
The distribution of individual pharmacokinetic parameters for acyclovir
(more precisely, of the post hoc estimates) is summarized in Table
4. The dispersion of the individual
values was very large, even after normalization with respect to BW or
BSA.
View this table:
[in this window]
[in a new window]
|
TABLE 4.
Median and 5th to 95th percentiles of individual
pharmacokinetic parameters (post hoc estimates) for acyclovir after
oral administration
|
|
Figure 3 illustrates the variation of
typical values for pharmacokinetic parameters for acyclovir as a
function of age; the steep variation in the elimination half-life
(t1/2) in the first month of life as well as the
large value for premature infants is clearly visible. The concomitant
variations of BSA and BW are also represented, after scaling for the
sake of clarity.
View larger version (20K):
[in this window]
[in a new window]
|
FIG. 3.
Variations in the typical values of pharmacokinetic
parameters for acyclovir as a function of age.
|
|
Model building for intravenous disposition.
The
two-compartment model was found to be much more adequate than the
one-compartment model for description of the acyclovir disposition
after intravenous dosing (difference in objective function values
[DOFVs], 125). Relating the typical value of CL to GR, BSA,
and SCR and that of Vc to BW by
relationships similar to those used in the oral disposition population
model increased further the adequacy of the model (DOFV, 133). Finally,
typical values of CLd and
Vp were modeled as being proportional to BW,
which yielded a DOFV of 20. With this final model, the adequacy of the
fit to the data was very good. The various scatterplots revealed no
systematic deviation (data not shown). The distribution of the
individual pharmacokinetic parameters (post hoc estimates) for
acyclovir is summarized in Table 5.
View this table:
[in this window]
[in a new window]
|
TABLE 5.
Median and range of individual pharmacokinetic parameters
(post hoc estimates) for acyclovir after intravenous administration
|
|
Analysis of acyclovir F.
The data for the 102 patients
were combined in order to estimate the acyclovir F. A
one-compartment model and a two-compartment model were first compared.
In these two models, the typical values of the parameters were related
to the covariates in the same way that they were in the final oral and
intravenous models, respectively. The two-compartment model was found
to be more adequate than the one-compartment model (DOFV, 231). The
point estimate and standard error of F were 0.118 and 0.026, respectively, while the interindividual variability of F was
16%. Individual estimates of F were plotted against the
dose and the covariates to examine possible relationships. Specific
models relating F to dose and age were then tested, but these relationships were not found to be significant.
Simulation of acyclovir kinetics.
The final population model
describing the kinetics of acyclovir after oral administration (Table
4 was used to generate the acyclovir
concentration profile for 500 fictitious individuals by simulation in
order to visualize the evolution of the typical acyclovir concentration
profile as a function of age. Figure 4A shows the median concentration-versus-time curves at steady state after
the administration of 24 mg/kg q8h to neonates (PNA, 0 to 1 months) of
various gestational ages (7, 8, or 9 months). Figure 4B shows the
corresponding curves after administration of 24 mg/kg according to a
schedule of 0, 4, 8, 12, and 24 h to children with various PNA
ranges: 1 to 3, 3 to 12, and 12 to 24 months. The lengths of time that
the acyclovir concentrations remain above 2.5 and 5 µM at steady
state, according to several dosing schedules, are reported in Table 6.
View this table:
[in this window]
[in a new window]
|
TABLE 6.
Daily AUC and length of time that acyclovir concentration
remains above 2.5 and 5 µM at steady state in a 24-h interval,
calculated by simulation with data for 500 fictitious individuals
|
|
View larger version (18K):
[in this window]
[in a new window]
|
FIG. 4.
Simulation of the median acyclovir
concentration-versus-time curve at steady state from 500 fictitious
individuals after oral administration of 24 mg/kg q8h to children ages
0 to 1 month (A) or after administration q.i.d. at 0, 4, 8, 12, and
24 h to children ages 1 to 24 months (B).
|
|
| |
DISCUSSION |
The pharmacokinetics of acyclovir administered by the oral route
were well described, as in earlier studies with adults, by a
one-compartment model with first-order absorption and elimination. Therefore, only four parameters were needed to characterize the disposition of acyclovir, namely CL, V,
ka, and F. The population approach
based on a mixed-effects modeling approach enabled the estimation of
the typical values of these parameters and their interindividual
variabilities; it also enabled correlation of some of the demographic
and biological indices to variations in these parameters. A possible
limitation of our approach is that data for the intravenous route were
mainly from older children, whereas data for the oral route were mainly
from younger children. Hence, the estimation of F is
reliable only if the variation of CL with age is appropriately
described by the covariate model. In this respect, the absence of any
trend in the scatterplot of CL (actually
CLj) versus age is reassuring.
The F of acyclovir administered as an oral suspension was
about 12%. This value is in the range of F values estimated
for adults (20% for the 200-mg dose, 12% for the 800-mg dose) for various pharmaceutical forms (tablets, solution, etc.) (11, 24). From a practical point of view, it implies that for a given dosing regimen, mean acyclovir concentrations are about eight times
lower after oral administration than after intravenous administration to the same patients, so that doses administered by the oral route must
be about eight times higher than those administered by the intravenous
route to ensure the same exposure. This relationship may not hold for
higher dosages, since the F of acyclovir decreases as the
dose increases owing to saturation of the absorption.
The interindividual variability in the pharmacokinetic parameters for
acyclovir in the pediatric population studied in the present
investigation was found to be very large, but it depends on the way in
which the variability is expressed. The "crude" variability is
reflected by the dispersion of the individual values for the parameters
when they are expressed in their "natural" units, i.e., liters per
hour for CL and liters for V; the ratios between the 95th
and the 5th percentiles are about 55 and 6.7 for CL and V,
respectively (Table 4). If the individual parameters are normalized to
BW or BSA, the same ratio is reduced to 16 for CL in liters per hour
per kilogram and 2.3 for V in liters per kilogram but only
to 27 for CL in liters per hour per square meter and 3.1 for
V in liters per square meter. Hence, the values of the
parameters normalized with respect to BW are less variable than those
normalized with respect to BSA. Comparison of these ratios for CL and
V also shows that the interindividual variability of CL is
much larger than that of V, probably because V is
mainly related to body size, while CL is related to body size as well as to maturity and to all the factors that influence the renal handling
of acyclovir. The population model shows how several covariates are
quantitatively related to CL and V: CL was found to be
related to PCA, BSA, and SCR, while V was
related to BW. The deviation of the values of the individual parameters
from the typical value (calculated according to the covariate model and
the values from the covariate model for that individual) represents the
residual (unexplained) variability of the parameters once the
contribution of the covariates (PCA, BSA, SCR, BW) has been taken into account. As described in the Results section, these residual
variabilities correspond to CVs of 49 and 57% for CL and V,
respectively. Hence, about half of the interindividual variability in
CL and V remains unexplained, so that the uncertainty about
predicted acyclovir concentrations in a given individual for a given
dosing schedule remains large. However, it is possible to obtain a
confidence interval of the acyclovir concentration profile by several
techniques, e.g., by Monte-Carlo simulation.
We examined the acyclovir concentration profile by simulation for
different age ranges. It was found that prematurity had a profound
influence on the kinetics of acyclovir since within the first three PCA
ranges (7 to 8, 8 to 9, and 9 to 10 months), an increase of one age
range led to a twofold decrease in the acyclovir concentration. The
question arises whether the dosing regimen used in the study is
adequate or whether a new dosing regimen must be proposed. The efficacy
of acyclovir is dependent on the daily dose, the number of doses per
day, and the 50% inhibitory concentration (IC50) for the
viral strain. For example, the proportions of 1,050 patients free of
genital HSV recurrence after 1 year of treatment with valaciclovir at
250, 500, or 1,000 mg once daily were 22, 40, and 48%, respectively,
while the mean daily areas under the concentration-time curve (AUCs)
for acyclovir were 22.0, 45.8, and 80.4 µM · h, respectively
(15). In the same study, 50% of the patients treated with
valaciclor at 250 mg twice daily (mean daily AUC for acyclovir, 55.1 µM · h) were free of recurrence after 1 year of treatment;
i.e., 250 mg twice daily had the same efficacy as 1,000 mg once daily,
despite a lower daily AUC. This finding and other results
(4) support the assumption that the length of time that
the acyclovir concentration remains above a given threshold (the
IC50) is also an important criterion for efficacy. It has
been suggested that maximal efficacy is reached when the length of time
that the acyclovir concentration remains above the IC50 is
greater than 12 h in each 24-h period of treatment (17,
20). For VZV infections, a higher acyclovir AUC is required because the IC50 for VZV isolates is higher. It has been
shown that the time to healing in 994 adult patients is related to the daily AUC for acyclovir after oral administration of acyclovir or
valaciclovir (S. Weller and M. R. Blum, Population
pharmacokinetics of acyclovir after administration of valaciclovir or
oral acyclovir to patients for the treatment of herpes zoster, internal
document, Glaxo Wellcome Co.). The mean daily AUCs for acyclovir at the doses approved for the treatment of herpes zoster in adults are 107 µM · h (acyclovir at 800 mg five times per day) and 253 µM · h (valaciclovir at 1,000 mg q8h), respectively, with the
latter treatment having a greater efficacy. On the basis of these
considerations and the results of our simulations for thresholds of 2.5 and 5 µM, which correspond to a worst-case IC50 for HSV
strains and a bad-case IC50 for VZV strains (Table 6),
respectively, the proposed dosing regimen (24 mg/kg q8h for patients
younger than 1 month of age or q.i.d. otherwise) seems to be
appropriate for the treatment of HSV-1 and HSV-2 infections in children
up to age 2 years. For VZV infections, a twofold increase in the dose (i.e., 48 mg/kg according to a schedule of treatment at 0, 4, 8, 12, and 24 h) seems to be necessary in order to ensure maximal efficacy in children older than age 3 months. These suggestions should
serve as starting point for the design of clinical efficacy studies.
| |
APPENDIX |
The population pharmacokinetic method based on a nonlinear
mixed-effects modeling approach is as follows. Two levels of
variability were considered. The first level of variability, i.e.,
residual (intraindividual) variability, accounted for the deviation of the observed acyclovir concentration at time i in individual
j (Cij) from the predicted
concentration (
ij) according to the equations Cij = ij + ij · ijb and
ij = f(Pj,
tij), where ij is a random
variable with a normal distribution with zero mean and variance
2, and b is a parameter of the residual error
model. 2 and b are parameters to be
estimated. The predicted concentration is given by the pharmacokinetic
model f( · ) for a given set (vector) of individual
pharmacokinetic parameters Pj. This error model assumes that residual errors are uncorrelated and that the residual error variance increases as a function of concentration, a pattern which is very common in pharmacokinetics.
The second level of variability accounted for interindividual
variability. Individual pharmacokinetic parameters
Pj were assumed to arise from a multivariate
lognormal distribution whose typical value,
j (i.e., the median), depends on the set
(vector) of covariate values of individual j
(Xj) according to a covariate model
h( · ): j = h(P, Xj) and Pj = j
exp(j), where P is a set
(vector) of population parameters called fixed effects
(P = 1, 2, ...) and
j is a set (vector) of random effects with
normal distribution, zero mean, and 
variance-covariance matrix.
With this model, the distribution of the individual parameters in all
subjects having the same covariates Xj is skewed
to the right and negative values are avoided. The goal of the
population analysis was to determine the most adequate models for
f( · ) and h( · ) and to estimate
the parameters P, , 2, and b.
| |
ACKNOWLEDGMENT |
This work was supported in part by a grant from Glaxo-Wellcome.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Pharmacie,
Hôpital Avicenne, 125 route de Stalingrad, 93009 Bobigny, France.
Phone: 33 1 48 95 56 61. Fax: 33 1 48 95 56 59. E-mail:
michel.tod{at}avc.ap-hop-paris.fr.
The Acyclovir Pediatric French Group consists of Y. Aujard, C. Bouille, J. P. Carrière, G. Cheron, J. P. Dommergues, D. Floret, P. François, D. Gendrel, F. Guillot, H. Haas, P. Labrune, J. B. Lobut, E. Mallet, A. Mouzard, M. Odièvre, C. Olivier, P. Reinert, and F. de la Rocque.
| |
REFERENCES |
| 1.
|
Beal, S. L.,
A. Boeckman, and L. B. Sheiner.
1992.
NONMEM user's guides, version IV.
NONMEM Project Group, University of California, San Francisco.
|
| 2.
|
Blum, M. R.,
S. Liao, and P. De Miranda.
1982.
Overview of acyclovir pharmacokinetic disposition in adults and children.
Am. J. Med.
73(Suppl. 1A):186-192[CrossRef][Medline].
|
| 3.
|
Brigden, D.,
A. Fowle, and A. Rosling.
1980.
Acyclovir, a new antiherpetic drug: early experience in man with systemically administered drug, p. 53-62.
In
L. H. Collier, and J. Oxford (ed.), Developments in antiviral chemotherapy. Academic Press, London, United Kingdom.
|
| 4.
|
Bye, A.
1997.
A mechanistic approach to understanding the response to antiinfectives in the population approach: measuring and managing variability in response, concentration and dose, p. 105-113.
In
L. Aarons (ed.), European CommissionBrusells, Belgium.
|
| 5.
|
CIBA-GEIGY.
1981.
Geigy scientific tables, 8th ed.
, part 3, p. 329. CIBA-GEIGY, Basel, Switzerland.
|
| 6.
|
Dorosz, P.
1984.
Guide pratique des médicaments, 4th ed.
Maloine, Paris, France.
|
| 7.
|
Erlich, K. S.
1997.
Management of herpes simplex and varicella-zoster virus infections.
West. J. Med.
166:211-215[Medline].
|
| 8.
|
Hintz, M.,
J. D. Connor,
S. A. Spector,
M. R. Blum,
R. E. Keaney, and A. S. Yeager.
1982.
Neonatal acyclovir pharmacokinetics in patients with herpes virus infections.
Am. J. Med.
73(Suppl. 1A):210-214[CrossRef][Medline].
|
| 9.
|
Holford, N. H. G.
1996.
A size standard for pharmacokinetics.
Clin. Pharmacokinet.
30:329-332[Medline].
|
| 10.
|
Kimberlin, D.,
D. Powell,
W. Gruber,
P. Diaz,
A. Arvin,
M. Kumar,
R. Jacobs,
R. Van Dyke,
S. Burchett,
S. Soong,
A. Lakemen,
R. Whitley, and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.
1996.
Administration of oral acyclovir suppressive therapy after neonatal HSV disease limited to the skin, eyes and mouth: results of a phase I/II trial.
Pediatr. Infect. Dis. J.
15:247-254[CrossRef][Medline].
|
| 11.
|
Laskin, O. L.
1983.
Clinical pharmacokinetics of acyclovir.
Clin. Pharmacokinet.
8:187-201[Medline].
|
| 12.
|
Maitre, P. O.,
M. Buhrer,
D. Thomson, and D. R. Stansky.
1991.
A three step approach combining Bayesian regression and NONMEM population analysis: application to midazolam.
J. Pharmacokinet. Biopharm.
19:377-384[CrossRef][Medline].
|
| 13.
|
Mandema, J. W.,
D. Verotta, and L. B. Sheiner.
1992.
Building population pharmacokinetic-pharmacodynamic models: models for covariate effects.
J. Pharmacokinet. Biopharm.
20:511-528[CrossRef][Medline].
|
| 14.
|
Morse, G. D.,
M. J. Shelton, and A. M. O'Donnell.
1993.
Comparative pharmacokinetics of antiviral nucleoside analogues.
Clin. Pharmacokinet.
24:101-123[Medline].
|
| 15.
|
Reitano, M,
S. Tyring,
W. Lang,
C. Thoming,
A. M. Worm,
S. Borelli,
L. O. Chambers,
J. M. Robinson,
L. Corey, and the International Valaciclovir HSV Study Group.
1998.
Valaciclovir for the suppression of recurrent genital HSV infection: a large-scale dose range-finding study.
J. Infect. Dis.
178:603-610[Medline].
|
| 16.
|
Rudd, C.,
E. D. Rivadeneira, and L. T. Gutman.
1994.
Dosing considerations for oral acyclovir following neonatal herpes disease.
Acta Pediatr.
83:1237-1243[Medline].
|
| 17.
|
Saiag, P.,
D. Praindhui,
C. Chastang, and the Genival Study Group.
1999.
A double-blind randomized study for assessing the equivalence of valaciclovir 1000 mg once daily versus 500 mg twice daily in the early treatment of recurrent genital herpes.
J. Antimicrob. Chemother.
44:525-531[Abstract/Free Full Text].
|
| 18.
|
Schwartz, G. J.,
L. P. Brion, and A. Spitzer.
1987.
The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents.
Pediatr. Clin. N. Am.
34:571-590[Medline].
|
| 19.
|
Sheiner, L. B., and T. M. Ludden.
1992.
Population pharmacokinetics/dynamics.
Annu. Rev. Pharmacol. Toxicol.
32:185-209[Medline].
|
| 20.
|
Spruance, S. L.,
S. K. Tyring,
B. De Gregoris,
C. Miller,
K. Beutner, and the Valaciclor HSV Study Group.
1996.
A large scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis.
Arch. Intern. Med.
156:1729-1735[Abstract].
|
| 21.
|
Sullender, W. M.,
A. M. Arvin,
P. S. Diaz,
J. D. Connor,
R. Straube,
W. Dankner,
M. J. Levin,
S. Weller,
M. R. Blum, and S. Chapman.
1987.
Pharmacokinetics of acyclovir suspension in infants and children.
Antimicrob. Agents Chemother.
31:1722-1726[Abstract/Free Full Text].
|
| 22.
|
Tod, M.,
C. Padoin,
C. Minozzi,
J. Cougnard, and O. Petitjean.
1996.
Population pharmacokinetic study of isepamicin with intensive care unit patients.
Antimicrob. Agents Chemother.
40:983-987[Abstract].
|
| 23.
|
Wagner, J. G.
1993.
Pharmacokinetics for the pharmaceutical scientist.
Technomic Publishing Co, Lancaster, Pa.
|
| 24.
|
Wagstaff, A. J.,
D. Faulds, and K. L. Goa.
1994.
Acyclovir: a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy.
Drugs
47:153-205[Medline].
|
| 25.
|
White, D. B.,
C. A. Walawander,
D. Y. Liu, and T. H. Grasela.
1992.
Evaluation of hypothesis testing for comparing two populations using NONMEM analysis.
J. Pharmacokinet. Biopharm.
20:295-313[CrossRef][Medline].
|
Antimicrobial Agents and Chemotherapy, January 2001, p. 150-157, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.150-157.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Anand, K. J. S., Anderson, B. J., Holford, N. H. G., Hall, R. W., Young, T., Shephard, B., Desai, N. S., Barton, B. A., for the NEOPAIN Trial Investigators Group,
(2008). Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth
0: aen248v2-10
[Abstract]
[Full Text]
-
Garre, B., Shebany, K., Gryspeerdt, A., Baert, K., van der Meulen, K., Nauwynck, H., Deprez, P., De Backer, P., Croubels, S.
(2007). Pharmacokinetics of Acyclovir after Intravenous Infusion of Acyclovir and after Oral Administration of Acyclovir and Its Prodrug Valacyclovir in Healthy Adult Horses. Antimicrob. Agents Chemother.
51: 4308-4314
[Abstract]
[Full Text]
Top
Abstract
Introduction
