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Antimicrobial Agents and Chemotherapy, March 1999, p. 609-615, Vol. 43, No. 3
Department of Infectious Diseases, St. Jude
Children's Research Hospital, Memphis, Tennessee
38105-27941; Glaxo Wellcome Inc.,
Research Triangle Park, North Carolina 277092;
Department of Pediatrics, Baylor College of Medicine and
Texas Children's Hospital, Houston, Texas
770303; and Department of
Pediatrics, Children's Memorial Hospital, Chicago, Illinois
606144
Received 1 July 1998/Returned for modification 26 October
1998/Accepted 26 December 1998
Abacavir (formerly 1592U89) is a potent 2'-deoxyguanosine analog
reverse transcriptase inhibitor that has been demonstrated to have a
favorable safety profile in initial clinical trials with adults with
human immunodeficiency virus (HIV) type 1 infection. A phase I study
was conducted to evaluate the pharmacokinetics and safety of abacavir
following the administration of two single oral doses (4 and 8 mg/kg of
body weight) to 22 HIV-infected children ages 3 months to 13 years.
Plasma was collected for analysis at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of each dose. Plasma
abacavir concentrations were determined by high-performance liquid
chromatography, and data were analyzed by noncompartmental methods.
Abacavir was well tolerated by all subjects. The single
abacavir-related adverse event was rash, which occurred in 2 of 22 subjects. After administration of the oral solution, abacavir was
rapidly absorbed, with the time to the peak concentration in plasma
occurring within 1.5 h postdosing. Pharmacokinetic parameter
estimates were comparable among the different age groups for each dose
level. The mean maximum concentration in plasma
(Cmax) and the mean area under the curve from
time zero to infinity (AUC0- The predominant mode of pediatric
human immunodeficiency virus (HIV) type 1 (HIV-1) infection is by the
vertical transmission of HIV-1 from infected mothers to their infants
(18). The Centers for Disease Control and Prevention (CDC)
has estimated that 6,000 to 7,000 children have been born annually to
HIV-1-infected women since 1978 (10, 19). The rapid
evaluation of novel antiretroviral therapies alone and in combination
with more established therapies with pediatric populations is therefore critical.
Currently, five antiretroviral agents are approved for use in children.
Four of the agents are nucleoside analogs that act as competitive
inhibitors or chain terminators of the reverse transcriptase enzyme of
HIV-1 and include zidovudine, stavudine, and didanosine. The remaining
agent, ritonavir, is an inhibitor of HIV-1 protease. Several of the
currently available antiretroviral therapies have a limited duration of
efficacy due to toxicities or the emergence of viral resistance.
The potent and selective anti-HIV activity of abacavir (formerly
1592U89),
( (This work was presented in part at the 3rd Conference on Retroviruses
and Opportunistic Infections, Alexandria, Va., 1996 [14].)
Study population.
Subjects between the ages of 3 months and
13 years and with HIV infection were eligible for the study. The study
was approved by the institutional review board of each participating
institution. Written informed consent was obtained from each child's
parent or legal guardian. Subjects were eligible for the study if they had HIV infection defined as positive results on two separate determinations (excluding a determination with cord blood) by one or
more HIV detection tests (HIV culture, HIV PCR, or HIV p24 antigen) and
met the criteria for an AIDS diagnosis based on the 1994 CDC AIDS
surveillance case definition (5). Subjects who were 18 months of age or older were also eligible for the study if they tested
positive for antibody to HIV-1.
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Safety and Single-Dose Pharmacokinetics of Abacavir (1592U89) in
Human Immunodeficiency Virus Type 1-Infected Children
ABSTRACT
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Abstract
Introduction
Materials and methods
Results
Discussion
References
) increased by 16 and 45%
more than predicted, respectively, as the abacavir dose was doubled from 4 to 8 mg/kg (Cmax increased from 1.69 to
3.94 µg/ml, and AUC0- increased from 2.82 to 8.09 µg · h/ml). Abacavir was rapidly eliminated, with a mean
elimination half-life of 0.98 to 1.13 h. The mean apparent
clearance from plasma decreased from 27.35 to 18.88 ml/min/kg as the
dose increased. Neither body surface area nor creatinine clearance were
correlated with pharmacokinetic estimates at either dose. The extent of
exposure to abacavir appears to be slightly lower in children than in
adults, with the comparable unit doses being based on body weight. In
conclusion, this study showed that abacavir is safe and well tolerated
in children when it is administered as a single oral dose of 4 or 8 mg/kg.
INTRODUCTION
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, a nucleoside analog, has recently been described (7, 9, 11-14,
21, 22) and is summarized in the accompanying report of a
single-dose study with adults (16). The pharmacokinetics of
escalating single oral doses of abacavir in adults have been evaluated
for the companion report (16). Abacavir is rapidly and well
absorbed over the range of doses studied (100 to 1,200 mg), with the
time to the peak concentration in plasma occurring at 1 to 1.7 h
postdosing. All doses resulted in plasma abacavir concentrations that
exceeded the mean 50% inhibitory concentration (IC50) of
abacavir for clinical HIV isolates in vitro. Abacavir was well
tolerated, with no treatment-limiting toxicities reported. On the basis
of the favorable data, this single-dose phase I study (Glaxo Wellcome
protocol CNAA1001) was initiated with children to examine the
pharmacokinetics and safety of abacavir.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and methods
Results
Discussion
References
Study design. To ensure an adequate distribution for pharmacokinetic analysis of both doses, at least six subjects were enrolled in each of the following cohorts, by age: 3 to 5 months, 6 to 23 months, 2 to 5 years, and 6 to 13 years. Subjects received single oral doses of 4 mg of abacavir solution per kg of body weight, followed by a second single dose of 8 mg/kg after at least a 14-day washout period. Those in the older-age cohorts received both doses of abacavir and completed the study before the youngest-age cohort (3 to 5 months) was enrolled. The doses selected for use in the current study were based on results from an escalating, single-oral-dose study of abacavir with HIV-infected adults (16). To ensure comparable exposures to abacavir, doses of 4 and 8 mg/kg (approximately equivalent to unit doses of 300 and 600 mg for adults, respectively) were evaluated and predicted to produce total drug concentrations in plasma greater than the mean in vitro IC50 of abacavir for clinical isolates of HIV-1 for approximately 3.5 to 4.5 h.
Abacavir was supplied as the lyophilized succinate salt containing 300 mg of free base equivalent and was reconstituted with 50 ml of sterile distilled water to a concentration of 6 mg/ml. The drug was administered via a 10-ml Exacta-Med Dispenser, provided by Glaxo Wellcome Inc., for volumes of less than 10 ml. The same dispenser was used to measure aliquots, which were combined in a dosing cup for dosing volumes of greater than 10 ml. Each dose was followed immediately by a minimum amount of water, given as follows: 1 oz (for subjects ages 3 to 5 months), 2 oz (for subjects ages 6 to 23 months), and 3 oz (for subjects ages 2 to 13 years). Within 7 days of administration of the first dose, the subjects underwent a screening evaluation, including a medical history, physical examination, and measurement of clinical and laboratory parameters. All drugs were discontinued at least 48 h before dosing with abacavir and were not reinstituted until 24 h after the administration of each dose. The subjects fasted for at least 2 h before dosing and for 1 h after dosing. The subjects returned to the study site at least 14 days later to begin the next dosing period. At 10 to 14 days after completion of the last dosing period, subjects returned for a follow-up examination similar to that used for the screening evaluation.Clinical and laboratory monitoring. The safety and tolerability of abacavir were evaluated on the basis of adverse experience reports, measurements of vital signs and clinical laboratory test values, and the results of physical examinations. In each dosing period, the severity (mild, moderate, or severe), duration, and potential relationship to abacavir (unrelated or possibly, probably, or almost certainly related, according to the investigator) of any adverse events were recorded. Medical histories were obtained and complete physical examinations were performed at all visits. Vital sign determinations (sitting blood pressure and sitting pulse), electrocardiogram (ECG) studies, routine hematologic studies, serum chemistry studies, and urinalysis (dipstick for protein and blood) were performed at screening, at 48 h postdosing in each dosing period, and at each follow-up visit (10 to 14 days postdosing).
Blood sampling and analytical methods.
Blood samples (1.5 ml
each) were collected by venipuncture and placed in a powdered
EDTA-containing pediatric tube immediately before dosing and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 5.0, and 8.0 h postdosing. Blood samples
were kept at 4°C upon collection and were centrifuged within 1 h
of collection to separate the plasma, which was stored at 40°C
until it was analyzed. The stability of abacavir in plasma samples has
been validated at 40°C for 11 months, which covered the period from
the time of sample collection to the time of analysis of the plasma samples.
Pharmacokinetic analysis.
The pharmacokinetic parameters for
abacavir were determined by noncompartmental methods with the WinNonlin
Noncompartmental Analysis Program (Scientific Consulting, Inc., Cary,
N.C.). The peak concentration in plasma (Cmax)
and the time to Cmax
(Tmax) were obtained from direct inspection of
the plasma concentration-time profile. Estimates for the apparent
terminal elimination half-life (t1/2
) were
calculated as ln(2)/
z, where
z is the terminal elimination rate constant
and is a first-order rate constant determined from the negative of the
slope of the linear regression line of the apparent terminal linear
portion of the log concentration-versus-time curve. The WinNonlin
program selected at least three points for inclusion in the linear
regression. These points were visually inspected, with no changes made
to the selected points. The area under the curve from time zero to time
t (AUC0-t), where t is
the last time point with a measurable concentration of abacavir, was
calculated by the linear trapezoidal method. The AUC from time zero to
infinity (AUC0-) was then determined as
AUC0-t + Clast/z, where
Clast is the last measurable concentration. The
apparent clearance from plasma (CL/F) was calculated as the
dose divided by AUC0- and was then normalized to body
weight. The apparent volume of distribution (V/F) was
calculated as the dose divided by the product of
z and AUC0-. Creatinine
clearance was obtained as the product of 0.55 and the ratio of the
subject's height to serum creatinine value (20). Body
surface area was calculated as the product of 9.8 and (body
weight)0.67 (8).
Statistical analysis.
Differences between treatments with
respect to Cmax, AUC0-,
t1/2, z,
CL/F, and V/F values were assessed by analysis of
variance with PROC MIXED (or mixed effects linear models) from SAS
(version 6.09). The model included age category as the fixed effect and
subjects as the random effect. Analyses were performed for both
log-transformed and untransformed data. Descriptive statistics,
including geometric least-squares means and their 95% confidence
intervals (CIs), were calculated for each treatment. Dose
proportionality was determined by calculating the ratios of the
geometric least-squares mean for the 8-mg/kg dose to the geometric
least-squares mean for the 4-mg/kg dose and the resultant 90% CI of
each parameter of interest. The 90% CI of the geometric least-squares
ratios was used because this dose-proportionality comparison is
essentially a bioequivalence comparison between the 4- and 8-mg/kg
treatments in which the 90% CI is the standard for bioequivalence
comparisons. Treatments were considered dose proportional if the
resultant 90% CI for the ratios of the least-squares means of
AUC0- and Cmax contained 2.0. Treatments were considered similar if the 90% CIs for the ratios of
the least-squares means of t1/2, z, CL/F, and V/F
contained 1.0. Nonparametric methods were used to compute the 95% CI
for the untransformed median Tmax values for
each treatment. A 90% CI for the median Tmax
difference between treatments was calculated, and the Wilcoxon signed
rank test was used to compare differences between treatments. The
Spearman test was used to determine the correlation between each
log-transformed parameter (Cmax,
AUC0-, and z) and each
demographic variable (age, weight, creatinine clearance, and body
surface area). A stepwise procedure with PROC REG from SAS was used to select demographic variables that can be good predictors of the pharmacokinetic parameters.
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RESULTS |
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Abstract
Introduction
Materials and methods
Results
Discussion
References
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Subject demographics and accountability.
Twenty-two subjects
were actually enrolled in this study (Table
1). Three subjects were enrolled in the
youngest-age cohort (3 to 5 months). Subjects in all cohorts except the
cohort of subjects ages 6 to 23 months received both doses of abacavir. In the cohort of subjects ages 6 to 23 months, five subjects received both doses of abacavir, one subject received the 4-mg/kg dose, and
another subject received the 8-mg/kg dose.
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Safety evaluation. Abacavir was well tolerated. There were no withdrawals due to adverse events. Two subjects experienced four adverse events while receiving the 4-mg/kg dose, and three subjects experienced four adverse events while receiving the 8-mg/kg dose. None of the adverse events were serious, and all were considered mild or moderate in intensity. Three subjects each experienced a single event of rash, and for two subjects (ages 5 and 13 years), the rash was attributed to the 8-mg/kg dose of abacavir. The rash resolved within 24 h after administration of diphenhydramine hydrochloride. For the third subject, the rash was diagnosed as candidiasis and was treated with topical antifungal agents.
No clinically significant changes in hematologic findings, clinical chemistry findings, vital signs, physical examination findings, or urinalysis parameters attributable to abacavir were noted during the study. Hematologic changes were noted in several subjects: three subjects (4 mg/kg) and two subjects (8 mg/kg) had decreased hemoglobin levels (grade 2), one subject (4 mg/kg) had a decreased neutrophil count (grade 3) which returned to normal at follow-up, and one subject (8 mg/kg) also had a decreased neutrophil count (grade 2). Clinical chemistry changes were noted in two subjects. One subject had elevated alkaline phosphatase and aspartate aminotransferase (grade 1) values after taking the 4-mg/kg dose, but the values had decreased at subsequent follow-up visits. Another subject with elevated baseline alkaline phosphatase values had normal values after taking the 4-mg/kg dose but had elevated values again after taking the 8-mg/kg dose.Pharmacokinetic evaluation. The mean plasma abacavir concentration-versus-time profiles by age category for the 4- and 8-mg/kg doses are presented in Fig. 1A. Following oral administration, abacavir was rapidly absorbed, with measurable concentrations in plasma recorded at the first postdose sampling time (30 min). Mean concentration-time curves were generally similar within each dose group, with a single peak value observed at 0.5 or 1 h. The median plasma abacavir concentration with respect to the in vitro IC50 for clinical HIV-1 isolates (0.07 µg/ml) is also presented in Fig. 1B. For the 4-mg/kg dose, the median plasma abacavir concentration was greater than 0.07 µg/ml from 0.5 h (first measurable concentration in plasma) to 3.0 h (last measurable concentration in plasma), or for a duration of at least 2.5 h. For the 8-mg/kg dose, the median plasma abacavir concentration was greater than 0.07 µg/ml from 0.5 h (first measurable concentration in plasma) to 5.0 h (last measurable concentration in plasma), or for a duration of at least 4.5 h.
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, Cmax, and
t1/2, but CL/F values were lower.
Both AUC0- and Cmax values
clearly increased with dose, but the trends for the other parameters
were much less distinct.
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and Cmax
values did not include the value 2, indicating that the
pharmacokinetics of abacavir were not strictly proportional to the dose
(Table 3). A twofold increase in dose
from 4 to 8 mg/kg resulted in a 2.90-fold increase in
AUC0-, and the AUC0- value obtained with the 8-mg/kg dose (7.46 µg · h/ml) exceeded the expected
AUC0- value obtained from the 4-mg/kg dose (2.57 × 2 = 5.14 µg · h/ml) by 45%. Similarly, a twofold
increase in dose from 4 to 8 mg/kg resulted in a 2.33-fold increase in
Cmax, and the Cmax value
obtained with the 8-mg/kg dose (3.68 µg/ml) exceeded the expected
Cmax value obtained from the 4-mg/kg dose
(1.58 × 2 = 3.16 µg/ml) by 16%. For
Tmax, t1/2,
CL/F, and z, the values were
significantly different between treatments since their 90% CIs did not
include 1.0. Of the untransformed parameters, neither
Cmax nor AUC0- was dose
proportional, and the other parameters were significantly different
between treatments.
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Regression modeling.
No significant correlations (P > 0.05) between the demographic parameters and
Cmax, AUC0-, or
z, with or without data for subject 17, were
detected for either dose. Stepwise regression analysis did not generate
consistent associations between the demographic variables and the
pharmacokinetic parameters, with or without data for subject 17, for
each dose level.
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DISCUSSION |
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Abstract
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Materials and methods
Results
Discussion
References
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This is the first study to evaluate the safety and
pharmacokinetics of abacavir in HIV-infected children. The results
indicate that abacavir is rapidly absorbed following the
administration of single oral doses of 4 and 8 mg/kg. The
pharmacokinetics of abacavir are not strictly dose proportional
in the population studied, as indicated by the greater than predicted
increases in Cmax (16%) and
AUC0- (45%) observed when the administered dose was
doubled from 4 to 8 mg/kg. Our study did not identify a strongly
predictable relationship between measures of growth and development and
the pharmacokinetic estimates of abacavir by stepwise regression analysis.
Abacavir was well tolerated by HIV-infected children. A rash attributed to abacavir occurred in 2 of 22 children who received the 8-mg/kg dose. The favorable safety profile of abacavir is well supported by preclinical toxicology studies with animals (7, 12, 13) and by an initial dose-escalation study with adults (16).
One child (subject 17) clearly presented values for all pharmacokinetic
parameters that were very different from those for the other children
in the study population. At the time of screening, this 6-month-old
patient received a waiver of the exception criteria because she weighed
less than 5 kg. Because abacavir is eliminated primarily by metabolism
rather than by renal filtration, one possible reason for this
subject's results may be unusually underdeveloped metabolic pathways
resulting in elevated AUC0- and Cmax values or prolonged
t1/2 values.
A comparison of the pharmacokinetic results obtained in the present
study with those reported previously for adults (16) on a
milligram-per-kilogram dose basis yield a number of observations. By
using a mean body weight of 70 kg, comparable doses of abacavir in
HIV-infected adults who received the 300- and 600-mg doses were
approximately 4 and 8 mg/kg, respectively. At these doses, the
least-squares mean values of AUC0- were approximately 45 to 48% lower in children than in adults (2.57 or 7.46 versus 4.93 or 13.5 µg · h/ml), indicating lower bioavailability in
children. The least-squares mean values of Cmax
were approximately 15 to 34% lower in children than in adults (1.58 or
3.68 versus 2.39 or 4.36 µg/ml). The median
Tmax occurred over the range of 0.5 to 1.5 h following the administration of abacavir as an oral solution formulation. These times are very similar to the
Tmax range noted for adults (1.0 to 1.7 h)
following the administration of abacavir as a tablet formulation,
suggesting that absorption rates may be comparable between children and
adults. The least-squares mean value of t1/2
was approximately 21 to 33% shorter for children than for adults (0.93 or 1.11 versus 1.17 or 1.66 h), which represents an actual
difference of 44 min between the lowest and highest values. The lower
AUC0- and the shorter t1/2 were consistent with the more rapid apparent clearance from children than from adults (25.62 or 17.84 versus 12.55 or 10.14 ml/min/kg). These results suggest that children may need a higher dose of abacavir
than adults on a milligram-per-kilogram basis in order to achieve the
same exposure.
The differences in pharmacokinetics of abacavir between children and adults are consistent with the results reported in previous studies in which the pharmacokinetics of other reverse transcriptase inhibitors were evaluated in children with HIV infection. Balis et al. (3) reported that with the exception of oral bioavailability the pharmacokinetics of didanosine in children appeared to be comparable to those in adults. Oral bioavailability, however, was significantly lower in children (35 versus 19%) (3). Chadwick et al. (6) reported that the concentrations of zalcitabine in plasma were lower and that the t1/2 was shorter in children than in adults given comparable doses. Kline et al. (15) indicated that higher doses (on a milligram-per-kilogram basis) of stavudine than those administered to adults (0.5 or 1 mg/kg/day) were needed to achieve equivalent drug exposure in children (1 or 2 mg/kg/day) (15). Similarly, Lewis et al. (17) reported that consistently lower concentrations of lamivudine in serum were recorded in children compared with those that were recorded in adults, suggesting the need for the administration of higher doses to children to achieve doses equivalent to those achieved in adults. In addition, the t1/2 in serum tended to be shorter in children than in adults (1.7 versus 2.5 h). Studies have shown that the pharmacokinetics of zidovudine in children older than several months of age are similar to those in adults (1, 2). However, different pharmacokinetics have been reported in infants under 2 weeks of age, including a longer t1/2 in serum, greater bioavailability, and a lower rate of clearance (4).
The median plasma abacavir concentration exceeded the IC50 noted in studies of clinical isolates from zidovudine-naive patients with <300 CD4+ cells/mm3 for at least 2.5 and 4.5 h for the 4- and 8-mg/kg doses, respectively. These times are consistent with those obtained from a dose-ranging study of abacavir with adults (3.5 and 4.5 h for the 300- and 600-mg doses, respectively) (16).
Because of the small number of patients enrolled in this study, no strongly predictive associations between demographic and pharmacokinetic parameters were noted. A large study that uses the population approach to data analysis is warranted to further evaluate the demographic parameters that are predictors of abacavir pharmacokinetics.
In summary, the results of this study confirm the desirable pharmacokinetic properties and the favorable safety profile of abacavir for use in the treatment of HIV-infected children. Studies are under way to evaluate the clinical efficacy of the 8-mg/kg dose of abacavir for the treatment of HIV-1 infection in pediatric patients. Use of this dose is supported by the pharmacokinetic observations in the present study.
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ACKNOWLEDGMENTS |
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This work was supported by a grant from Glaxo Wellcome Inc.
We gratefully acknowledge the assistance of the following study nurses at the indicated sites: Nana Howlett and Micki Roy of St. Jude Children's Research Hospital, Nancy R. Calles of Baylor College of Medicine, and Deborah Fonken of Children's Memorial Hospital. We also thank Laurene Wang for critical review of the manuscript, Michael J. O'Mara for performing the bioanalytical studies, and Laurel Adams for study monitoring.
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FOOTNOTES |
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* Corresponding author. Mailing address: Worldwide Clinical Pharmacology, Glaxo Wellcome Inc., Five Moore Drive, Research Triangle Park, NC 27709. Phone: (919) 483-1102. Fax: (919) 483-6380. E-mail: JAM36914{at}glaxowellcome.com.
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Abstract
Introduction
Materials and methods
Results
Discussion
References
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