AIDS RESEARCH AND HUMAN RETROVIRUSESVolume 16, Number 5, 2000, pp. 415–421Mary Ann Liebert, Inc.

Effect of Food and Pharmacokinetic Variability on DidanosineSystemic Exposure in HIV-Infected Children

ROBERT C. STEVENS,1,2 JOHN H. RODMAN,1,2 FLORENCE H. YONG,3 VINCENT CAREY,3,4

CATHERINE A. KNUPP,5 LISA M. FRENKEL6 and the PEDIATRIC AIDS CLINICAL TRIALS GROUP PROTOCOL 144 STUDY TEAM

ABSTRACT

The effect of food on didanosine bioavailabilit y and interpatient pharmacokinetic variability was examinedin children infected with human immunodeficiency virus type 1 (HIV-1). Didanosine pharmacokinetics weredetermined during fasting and fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clini-cal Trials Group Protocol 144 randomized to receive didanosine at 50 mg/m2 or 150 mg/m2 orally every 12hr. Pharmacokinetic parameters from patients in the low (n 5 39) and high (n 5 38) dosing groups were notsignificantly different, but intersubject variability was substantial. The fraction absorbed was higher whilefasting than with food (0.27 6 0.13 versus 0.19 6 0.09, p , 0.0001); the zero order absorption rate was faster(0.48 6 0.31 versus 0.76 6 0.72 hr, p 5 0.003); and the plasma half-life was shorter (0.93 6 0.43 versus 1.39 60.65 hr, p , 0.0001). The lower fraction absorbed with food was offset by the absorption rate becoming ratelimiting for elimination, resulting in similar areas under the concentration–time curves (normalized to 100mg/m2) when fasted (853.9 6 465.8 m g/liter ? hr) versus fed (796.3 6 367.5 m g/liter ? hr). Oral clearances duringfasting (152.5 6 81.7 liters/hr/m2) and fed states (163.6 6 99.3 liters/hr/m2) were similar, but these values inchildren are substantially higher than previously reported for adults. The systemic exposure (i.e., AUC) of di-danosine was highly variable in children but similar in the presence and absence of food. Administration ofdidanosine with food in children may be permissible if total systemic exposure rather than maximum plasmaconcentration is sufficient for antiretroviral activity. The higher oral clearance and substantial pharmacoki-netic variability suggest the need to reexamine current didanosine dose recommendations for HIV-infectedchildren.

415

INTRODUCTION

D IDANO SINE IS A NUCLEO SIDE A NALO G with an established rolefor treatment of human immunodefici ency virus (HIV) in

children, 1,2 with a palatable oral formulation and safety profilethat have led to extensive use for pediatric patients. Guidelinesrecommend combination therapy for all infants, children, andadolescents who are treated with antiretroviral agents, and di-danosine is well established as one of several nucleoside analogs

appropriate for combination regimens.3 Dosage regimens of an-tiretroviral drugs for children are commonly based on adultdoses adjusted for body surface area with limited clinical orpharmacokineti c pediatric studies. Previous studies of didano-sine in children have demonstrated substantial interpatient phar-macokinetic variability, 4–6 and there is evidence this variabil-ity may be relevant to treatment outcome.4

Didanosine absorption is incomplete, ranging from 14 to52%,4,7–9 and is a contributing factor for variability in plasma

1Department of Pharmaceutica l Sciences, St. Jude Children’s Hospital, Memphis, Tennessee 38015.2Department of Clinical Pharmacy and Center for Pediatric Pharmacokine tics and Therapeutics, University of Tennessee, Memphis, Tennessee

38163.3Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts 02115.4Channing Laboratory, Harvard Medical School, Boston, Massachusetts 02115.5Department of Metabolism and Pharmacokinet ics, Bristol-Myers Squibb Company, Pharmaceutica l Research Institute, Princeton, New Jer-

sey 08543.6Departments of Pediatrics and Laboratory Medicine, University of Washington, Seattle, Washington 98105.

concentrations. Food was found to reduce significantly thebioavailability of didanosine in adults. In asymptomatic HIV-infected adults, the area under the plasma concentration– timecurve (AUC) for didanosine was reduced by approximately 50%in the presence of food compared with fasting conditions. 10,11

To increase absorption and decrease variability, didanosine isformulated or given with antacids under fasting conditions.

The requirement for fasting before and after didanosine ad-ministration is particularly difficult for infants and children andis further complicated with regimens containing protease in-hibitors taken with meals to enhance bioavailability (e.g., nel-finavir, ritonavir, saquinavir). Didanosine absorption has notbeen rigorously evaluated in children when given with or with-out conventional meals or feeding. To evaluate the effect offood on didanosine bioavailability and determine the extent ofintersubject pharmacokinetic variability in HIV-infected chil-dren, didanosine plasm a concentrations were determined whilefasting and with an age-appropriate meal in two groups of chil-dren receiving different didanosine doses.

MATERIALS AND METHODS

Patients

A subset of children studied enrolled in the Pediatric AIDSClinical Trial Group protocol 144 (ACTG 144) were randomlyselected for pharmacokinetic studies to evaluate the effect offood on didanosine bioavailability. ACTG 144 was a random -ized, comparative trial of two doses of didanosine monother-apy taken orally for a minimum of 48 weeks by children aged3 months to 18 years with symptomatic HIV infection who wererefractory or intolerant of zidovudine. The protocol was ap-proved by the institutional review board at each study site, andwritten informed consent was given by the child’s parent or le-gal guardian.

Children were excluded from participation if they met anyof the following conditions: prior didanosine therapy; con-comitant use of zidovudine; use of immunomodulating agentswithin 2 weeks of entry or any experim ental therapy within 7days of entry; pregnancy; seizures that were not well controlledby concurrent anticonvulsant agents; symptom atic pancreatitis;peripheral neuropathy; unable to be maintained on an oral fooddiet; active malignancy requiring concomitant chemotherapy;and the following abnormal baseline laboratory findings: biliru-bin $ 3 times upper limit of normal, serum creatinine $ 2.0mg/dl, absolute neutrophil count # 500 cells/mm3, hemoglobin# 7.0 g/dl, platelet count # 50,000/mm 3, and pancreatic amy-lase $ 2 times the upper limit of normal.

Study design

Didanosine was supplied by Bristol-M yers Squibb (Prince-ton, NJ) as 2- and 4-g bottles of pediatric powder for oral so-lution. After reconstitution, the oral solution was prepared bymixing the appropriate volum e of didanosine solution with thevolume of antacid (Maalox TC, Extra Strength Maalox Plus, orMylanta Double Strength Liquid) needed to achieve a final dis-pensing concentration of 2.5 mg of didanosine per milliliter forthe 50-mg/m2 dose and 7.5 mg of didanosine per milliliter forthe 150-mg/ m2 dose.

Patients were randomized to receive didanosine at 50 or 150mg/m2 orally every 12 hr. During the first week of study, thepharmacokinetic s of didanosine were determined for each childon two separate clinic visits. The first pharmacokinetic evalu-ation occurred when the child had received no food for 2 hr be-fore and 1 hr after drug administration. The second evaluationwas after the child received an age-appropriate morning meal10 min before drug administration. Didanosine administrationwas supervised by study personnel in the clinic during bothevaluation periods.

Blood samples (1 ml) were collected at predose and 0.25,0.5, 1, 1.5, 2, 3, and 4 hr after didanosine dosing. Blood sam-ples were centrifuged and plasma was stored at 2 20°C untilassayed. Plasma concentrations of didanosine were determinedby a validated radioimmuno assay performed by the Bristol-Myers Squibb Pharmaceutical Research Institute. The lowerlimit of quantification was 5 ng/ml. The coefficient of variationwas less than 10% above 25 ng/ml and less than 15% from 5to 25 ng/ml.

Data analysis

A one-compartme nt model with zero-order absorption inputand a lag time was fit to the didanosine plasma concentrationsfor each patient’s study. Pharmacokinetic parameters estimatedwere elimination rate constant (Kel), apparent volume of distri-bution (V), zero-order absorption rate constant (Ka,zero), lagtime, and fraction absorbed (F). First-order absorption was alsoexamined, in a subset of patients zero-order absorption was su-perior as determined by comparative sums of squares, while inthe remainder of subjects there was no difference between zero-or first-order inputs. Half-life (T1/2) was calculated as 0.693/Kel.Oral clearance (CLoral) was determined from the product of Kel

and V/F. Area under the plasm a concentration– time curve(AUC) was calculated as dose/CLoral. The parameters were es-timated by maximum likelihood estimation (ADAPT II12) witha Bayesian prior consistent with previously published data.13

The prior assumed the parameters were independently distrib-uted with mean (CV%) values as follows: Kel 5 0.5 hr 2 1 (30%),V 5 43 liters/m2 (25%); lag time 5 0.2 hr (100%); Ka,zero 50.5 mg/hr (30%); F 5 25% (50%). The use of a prior allowedestimation of both F and V. Fraction absorbed was essentiallyconstrained to a value within the ranges defined by the Bayesianprior. Parameters were also estimated by maximum likelihoodestimation without a Bayesian prior but with F fixed at a nom-inal value and there were no discernible differences in estimatesfor Kel, Ka,zero , lag time, or AUC.

Baseline characteristics were compared between the two dos-ing groups using the Pearson x 2 test for categorical variablesand a two-sam ple t test in the analysis of variance or Wilcoxonrank-sum test for continuous variables. Raw weight measure-ments were converted to the age- and sex-corrected z scores(weight-for-age z score) by using the CDC/WHO internationalgrowth standards based on the National Center for Health Sta-tistics and Fels Longitudinal Study reference databases. 14 Apaired-comparis ons t test was used to examine differences inthe pharmacokineti c param eters between the fasted and fed con-ditions. The AUC for the two dosing groups was normalized toa dose of 100 mg/m2 (AUC100) for comparison. The Shapiro–Wilk test was used to test for normality of the distribution of

STEVENS ET AL.416

the AUC100. All reported p values are two sided. The assignedlevel of significance was p , 0.05.

RESULTS

There were 106 patients enrolled in the pharmacokineticstudy (n 5 52 in the 50-mg/m2 group and n 5 54 in the 150-mg/m2 group). Thirteen subjects in the low-dose group and 16patients in the high-dose group were not evaluable. Reasons forthe exclusions were as follows: unable to complete both phar-macokinetic evaluations (n 5 11); less than three blood sam-ples available to reliably estimate the pharmacokinetic para-meters (n 5 14); and no documentation of the fast or fedcondition (n 5 4). The demographic characteristics for the 77patients evaluable for pharmacokinetic analysis are summarizedin Table 1. Patients were evenly matched between the two dos-ing groups except for race/ethnicity.

The median values for V, Kel, Ka,zero , F, and AUC while fast-ing for the 50-mg/m2 versus 150-mg/ m2 dosing groups were37.0 versus 39.4 liters/m2, 0.92 versus 0.82 hr 2 1, 0.40 versus0.42 mg/hr, 0.28 versus 0.22, and 392.0 versus 1065.8 m g/liter? hr, respectively. Likewise, the median values for V, Kel, Ka,zero ,F, and AUC during fed conditions for the 50-mg/m2 versus 150-mg/m2 dosing groups were 40.8 versus 41.4 liters/m2, 0.62 ver-sus 0.60 hr 2 1, 0.57 versus 0.50 mg/hr, 0.19 versus 0.17, and402.8 versus 1162.4 m g/liter ? hr, respectively. A lag time wasrequired for only 12 subjects studied while fasting and 9 sub-jects studied while fed. There were no significant differences(p values range from 0.08 to 0.86 in each comparison) for anypharmacokinetic parameter estimates between the 50-mg/m2

and 150-mg/m2 dosing groups. The param eters listed in Table

2 represent data from both dosing groups collectively. The AUCvalues listed in Table 2 were normalized to 100 mg/m2

(AUC100). Didanosine AUC100 was not significantly differentbetween the fasted and fed evaluations (p 5 0.22). The median(CV%) AUC100 was 758.3 m g/liter ? hr (55%) and 776.6 m g/liter? hr (46%), respectively, indicating that systemic exposure wassimilar between the two conditions.

Despite similar AUC100 values in the fasting and fed states,there was a demonstrable effect of food on the estimate for frac-tion absorbed (Fig. 1) and for the absorption rate in the absenceand presence of food. The fraction absorbed was significantlylower in the presence of food (0.19 versus 0.27, p , 0.0001).Table 3 lists the median (CV%) didanosine plasma concentra-tions at the seven time points when samples were collected.Compared with the fed condition, concentrations during thefasting state were higher in the first hour and lower during thelast 2 hr of sampling for both dosing groups (Fig. 2 and Table3). The Cm ax and AUC values increased proportionately be-tween the 50- and 150-mg/m2 dosing groups.

The similar AUC100 values, despite a lower estimate for frac-tion absorbed with food, are explained by a correspondingchange in the rate of absorption. Ka,zero increased from a meanof 0.48 to 0.76 mg/hr with food and Tm ax was significantly de-layed. The apparent plasma elimination half-life was also in-creased from 0.93 to 1.39 hr with food. Thus the reduced frac-tion absorbed from 0.27 to 0.19 was offset by the absorptionrate becoming rate limiting for elimination, resulting in the sim-ilar AUCs in the presence and absence of food. The higher co-efficient of variation for Ka,zero with food (95%) versus fasting(65%) is consistent with more variable absorption in the fedstate.

The overall systemic exposure, as reflected by the AUC, was

ddI PHARMACOKINETICS AND FOOD: EFFECT IN CHILDREN 417

TABLE 1. CHA RA CT ERIST IC S OF TH E 77 HIV-INFECT ED CH ILD REN a

50-mg/m 2 dose group 150-mg/m 2 dose group(n 5 39) (n 5 38) p Value

Age, years 6.1 6 3.5 7.0 6 4.1 0.29b

(3.3, 8.4) (4.3, 10.2)Male sex, n (%) 17 (43.6%) 23 (60.5%) 0.14c

Weight, kg 18.8 6 9.6 20.6 6 9.3 0.25d

(12.1, 22.1) (13.9, 26.8)Weight-for-age z-score 2 1.2 6 1.3 2 1.3 6 1.3 0.81e

( 2 2.1, 2 0.3) ( 2 2.0, 2 0.7)Race/ethnicity, n (%)

White, non-hispanic 7 (17.9%) 16 (42.1%) 0.02f

Black, non-hispanic 17 (43.6%) 7 (18.4%)Hispanic 14 (35.9%) 14 (36.8%)Other 1 (2.6%) 1 (2.6% )

CD4 1 T cell count, cells/mm3 321.4 6 344.0 271.5 6 376.2 0.16d

(29.0, 559.5) (10.5, 391)CD4 1 T cells, % 15.0 6 13.1 12.4 6 12.5 0.40d

(3.0, 22.0) (3.0, 21.0)

aData represent means 6 SD and values in parentheses represent the 25th and 75th percentiles, respectively, unless otherwisenoted.

bANOVA.cPearson x 2.dWilcoxon rank-sum test.et test.fPearson x 2 (“other” category omitted).

similarly variable in the presence or absence of food. The co-efficient of variation for AUC100 while fasting was 55% witha 10-fold range (242.9–2587.1 m g/liter ? hr) and 46% with foodwith a 9-fold range (192.8–1814.9 m g/liter ? hr). The mediannormalized AUC10 0 for fasted and fed states were similar(fasted, 758.3 m g/liter ? hr; fed 776.6 m g/liter ? hr) but were notnormally distributed (p , 0.0001 and p 5 0.03, respectively).Figure 3 shows the overall variability in didanosine AUC (n 577) after oral administration of 50 mg/m2 and 150 mg/m2 forboth fasting and fed conditions.

DISCUSSION

The somewhat surprising result from this study is that, de-spite differences in the time course of didanosine plasma con-centrations in the presence and absence of concurrent food, sys-temic exposure as reflected by AUC is not different. Didanosineelimination half-life is short in adults, and as shown in thisstudy, even shorter in children. The effect of food was to pro-long absorption time, which then became rate limiting for elim-ination of didanosine from plasma as well as reducing the fraction absorbed. This resulted in lower maximum plasma con-centrations but higher concentrations between 2 and 4 hr (Table3, Fig. 2), yielding a similar AUC with food as that found whenchildren were fasting.

The effect of food on didanosine in children differs fromwhat has been reported previously in adults. In two well-con-trolled although small (8 and 10 subjects, respectively) inves-tigations in adults, there was an approximately 50% reductionin bioavailability as determined by AUC and Cm ax when di-danosine was taken with meals10,11 but there was no reportedeffect on the absorption or elimination rate. In addition to pos-sible age-related differences between adults and children thatmay explain differing pharmacokineti c parameters, there werealso differences in the study design. The children in our inves-tigation received their normal diet rather than the standardizedmeal used to assess food effect in the adult trials. Differencesamong the various didanosine formulations may also have in-fluenced the net effect of food on absorption.

A practical question pertaining to didanosine therapy for chil-dren is whether administration during fasting conditions or atleast 30 min before a meal is necessary. Adult data suggestedthe substantially lower fraction absorbed required such a con-straint.10,11 In particular, for infants and young children, such

STEVENS ET AL.418

TABLE 2. DIDANO SINE PHA RM ACOKINETIC PA RA M ETER ESTIM A TES a

Fasted Fed p Value

AUC100 ( m g/liter � hr)b 853.9 6 465.8 796.3 6 367.5 0.22(566.1, 1064.6) (486.4, 1012.1)

CLoral (liters/ hr/m2) 152.5 6 81.7 163.6 6 99.3 0.26(93.9, 176.7) (98.8, 205.6)

V (liters/m 2) 39.0 6 5.4 43.3 6 8.6 , 0.0001(35.8, 41.3) (38.4, 45.7)

Kel (hr 2 1) 0.84 6 0.25 0.60 6 0.23 , 0.0001(0.69, 1.01) (0.40, 0.80)

T1/2 (hr) 0.93 6 0.43 1.39 6 0.65 , 0.0001(0.69, 1.01) (0.87, 1.73)

Ka,zero (mg/hr) 0.48 6 0.31 0.76 6 0.72 0.003(0.30, 0.50) (0.38, 0.72)

F 0.27 6 0.13 0.19 6 0.09 , 0.0001(0.17, 0.34) (0.12, 0.25)

Tm ax (hr) 0.52 6 0.36 0.79 6 0.74 0.005(0.31, 0.58) (0.38, 0.84)

Abbreviations: AUC, area under the plasma concentration– time curve; CLoral, oral clearance; V, apparent volume of distribu-tion; Kel, terminal elmination rate constant; T1/2, half-life; Ka,zero , zero-order absorption rate constant; F, absorption fraction; Tm ax,time to achieve maximum plasma concentration.

an 5 77 patients. Results represent means 6 SD, and represent data combined from both the 50 mg/m2 (n 5 39) and 150 mg/m2

(n 5 38) dosing groups. All 77 patients were evaluated during both the fasted and fed states. Values in parentheses represent the25th and 75th percentiles, respectively.

bAUC100 for both dosing groups was normalized to 100-mg/m2 dose.

FIG. 1. Histogram showing the frequency distribution for per-cent change in fraction absorbed (F) between the fasted versusfed states in 77 children with symptomatic HIV-infection (FFed

2 FFast/FFast ? 100). A negative value on the abscissa indicatesF was lower when taken with food compared with the fastedcondition.

a constraint can be impractical. These results indicate that if theAUC is an appropriate metric for comparing systemic exposurein the presence and absence of a routine diet, avoiding mealsmay be unnecessary. However, there are significant differencesin plasma concentration profiles in the presence and absence offood. Didanosine given with a regular meal results in lowermaximum but more sustained plasma concentrations over the4 hr after a dose is administered to children (Table 3, Fig. 2).The finding that didanosine concentrations 4 hr after adminis-tration with a meal are on average 40 to 75% higher may evensuggest an advantage to didanosine administration with food.These data do not provide insight as to which concentration–time profile (i.e., fasted versus fed) yields enhanced antiretro-viral activity, and thus cannot provide the basis for a definitivechange in recom mendations for didanosine administration withrespect to meals. However, the results clearly indicate that con-current food is not necessarily contraindicated in children.

These data suggest the pharmacokinetic s of didanosine inchildren differ substantially from those in adults. Results fromthis investigation along with data from other pediatric pharma-cokinetic studies 4–6 reveal that the mean AUC ranges from 446

to 860 m g/liter ? hr for children when normalized to 100 mg/m2

(AUC100). The mean half-life was 0.6 to 0.9 hr. On the basisof comparable doses under fasting conditions in adults, theAUC100 was 1880 to 2493 m g/liter ? hr and the half-life was1.4 to 1.6 hr.7,8,10,15 The higher oral clearance and shorter half-

ddI PHARMACOKINETICS AND FOOD: EFFECT IN CHILDREN 419

TA BLE 3. MED IAN (CV%) DIDA NOSIN E PLA SM A CO NCEN TR AT ION Sa

50-mg/m 2 dose group 150-mg/m 2 dose group(n 5 39) (n 5 38)

Time Percent change Percent change(hr) Fasted Fed from fasting Fasted Fed from fasting

0.25 165.4 (97) 94.8 (108) 2 43 441.0 (84) 183.1 (99) 2 580.5 284.2 (75) 143.3 (81) 2 50 566.0 (74) 354.8 (84) 2 371.0 192.9 (70) 167.1 (57) 2 13 404.9 (78) 360.8 (64) 2 111.5 104.0 (57) 112.4 (48) 8 319.5 (49) 341.8 (50) 72.0 61.0 (72) 84.8 (50) 39 199.8 (50) 239.8 (49) 203.0 25.6 (112) 40.2 (63) 57 99.5 (57) 123.2 (43) 244.0 12.2 (131) 20.0 (71) 64 45.5 (68) 65.2 (70) 43

aValues presented represent micrograms per liter.

FIG. 2. Median plasma concentration– time profiles underfasting (d ) and fed ( s ) states after administration of didano-sine oral solution at 50 mg/m2 (dashed lines) and 150 mg/m2

(solid lines). There were 39 and 38 HIV-infected children ineach dosing group, respectively.

FIG. 3. Variability in area under the plasma concentration–time curve for didanosine after oral administration didanosineat 50 mg/m2 (n 5 39) and 150 mg/m2 (n 5 38) during fast andfed conditions.

life result in a substantially lower systemic exposure for chil-dren. Indeed, the oral clearance determined in our study and byLambert et al.6 is 1.6- to 2.7-fold higher than has been reportedfor adults.16,17 The clinical relevance of these pharmacokineticdifferences remains to be determined.

Pediatric didanosin e dosing arose from limited pharm aco-kinetic data4 in children (median, 7.4 years of age) and fromextrapola tion of dose regim ens shown to be effective inadults. Adult doses of 5 mg/kg or 150 mg/m2 for didanosin ehave been suggested as effective without undue risk of toxi-city.18 The validity of extrapola ting pediatric doses fromthese adult doses based on body surface area rests on an as-sumption that systemic exposure will be similar. However,the findings of higher oral clearance along with a corre-sponding lower systemic exposure suggest that children mayrequire higher doses for similar antiretrov iral activity andclinical outcom es.

A possible relationshi p between systemic exposure andclinical end points has been suggested for children 4 andadults19 even though the antiviral activity for the nucleosideanalogs, including didanosine , requires intracellul ar sequen-tial phosphoryl ation of the parent compound to the active an-abolite. There is growing evidence for zidovudine that moni-toring and controlling systemic exposure is associated withincreased treatm ent efficacy, 20 and is also related to theamount of intracellula r active metabolite formed.21 It remainsto be shown that a similar relationshi p between systemic con-centrations , intracellula r metabolism, and antiviral activity canbe demonstra ted for didanosine but it is a highly plausible hypothesis.

Two clinical trials of didanosine in children have employeddidanosine doses of 90 mg/m2 with zidovudine and 120 mg/m2

as monotherapy. 1,2 The conflicting results of these trials re-garding the relative efficacy of didanosine monotherapy versusdidanosine in combination with zidovudine may be explainedin part by the large interpatient variability in systemic exposureto didanosine. The empirical adjustment of doses from adultsto children without acknowledging substantial age-related dif-ferences and minimal pediatric pharmacokinetic data may re-sult in suboptimal didanosine therapy for younger children. Ourdata indicate that adult doses extrapolated to pediatric patientswill result in didanosine systemic exposures that are one-halfto two-thirds lower. Figure 3 highlights the magnitude of vari-ability of systemic exposure as a consequence of dose, food,and intersubject pharmacokinetic variability. Intersubject vari-ability in didanosine systemic exposure is substantial and is ofpotential importance in clinical trials and for managem ent ofindividual patients.

In summary, administration of didanosine with food in thecontext of a typical diet for children significantly reduces theextent of absorption but also prolongs absorption time, result-ing in similar AUCs. In addition, a higher oral clearance for di-danosine and substantially lower systemic exposures were ob-served in children as compared with that reported in adults.Given the substantial interpatient pharm acokinetic variability inthese children, measurement of didanosine plasma concentra-tions may be warranted in clinical investigations (e.g., exam-ining alternative dosing regimens such as once daily adminis-tration 6,22) and the treatment of HIV-1 infection.

ACKNOWLEDGMENTS

Support: This study was supported in part by the PediatricAIDS Clinical Trials Group of the National Institute of Allergyand Infectious Diseases; the Pediatric/Perinatal HIV ClinicalTrials Network of the National Institute of Child Health andHuman Development; the General Clinical Research CenterUnits funded by the National Center for Research Resources;SDAC/DMC Grant AI-41110; a Center of Excellence Grantfrom the State of Tennessee; and the American Lebanese Syr-ian Associated Charities.

Participating institutions: The following centers and princi-pal investigators participated in this study. Bellevue Hospital,William Borkowsky; Chicago Children’s Memorial Hospital,Ram Yogev; Children’s Hospital & Medical Center of Seattle,Lisa Frenkel; University of California, San Diego Medical Cen-ter, Stephen Spector; University of Puerto Rico, UniversityChildren’s Hospital AIDS Program, Irma Febo; Yale Univer-sity School of Medicine, Warren Andiman; Children’s MedicalCenter of Dallas, Janet Squires; Children’s Hospital of Philadel-phia, Stuart Starr; Boston Children’s Hospital, Kenneth McIn-tosh; Duke University, Ross McKinney; Schneider Children’sHospital, Vincent Bonagura; Metropolitan Hospital Center,Mahrukh Bamji, San Juan City Hospital, Eleanor Jimenez;Robert Wood Johnson University Hospital, Sunanda Gaur; Uni-versity of Alabama, Birmingham, Robert Pass; Columbus Chil-dren’s Hospital, Michael Brady; University of Rochester Med-ical Center, Francis Gigliotti; St. Joseph’s Hospital and MedicalCenter, Nancy Hutcheon; Long Beach Memorial Medical Cen-ter, Audra Deveikis; University of Maryland Medical Center,Peter Vink; the Columbia Presbyterian Medical Center, AnneGershon; University of Miami, Gwendolyn Scott; University ofCalifornia at San Francisco Medical Center, Diane Wara; Cor-nell University Medical Cetner, Joseph Cervia; University ofIllinois at Chicago, Ken Rich; State University of New YorkHealth Science Center at Syracuse, Coleen Cunningham; Chil-dren’s Hospital of Michigan, Duane Harrison; Howard Uni-versity Hospital, Sohail Rana; Bronx Lebanon Hospital Center,Andrew Wiznia; Children’s Hospital, Washington, D.C., JohnsSever; and Tulane University, Charity Hospital of New Orleans,Russell Van Dyke.

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Address reprint requests to:John H. Rodman

Department of Pharmaceutic al SciencesSt. Jude Children’s Research Hospital

332 North Lauderdale St.Memphis, Tennessee 38015-2794

E-mail: john.rodman@ stjude.org

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