The Journal of Clinical

Pharmacology
http://www.jclinpharm.org

Clinical Development of an Everolimus Pediatric Formulation: Relative Bioavailability, Food Effect, and
Steady-State Pharmacokinetics
John M. Kovarik, Adele Noe, Stephane Berthier, Louis McMahon, Wayne K. Langholff, Alan S. Marion, Peter Friedrich
Hoyer, Robert Ettenger and Christiane Rordorf
J. Clin. Pharmacol. 2003; 43; 141
DOI: 10.1177/0091270002239822

The online version of this article can be found at:

http://www.jclinpharm.org/cgi/content/abstract/43/2/141

Published by:

http://www.sagepublications.com

On behalf of:
American College of Clinical Pharmacology

Additional services and information for The Journal of Clinical Pharmacology can be found at:

Email Alerts: http://www.jclinpharm.org/cgi/alerts

Subscriptions: http://www.jclinpharm.org/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.com/journalsPermissions.nav

Downloaded from http://www.jclinpharm.org by Luciana Oliveira on April 21, 2009

KOVARIK ET AL OF EVEROLIMUS PEDIATRIC FORMULATION
ARTICLE
DEVELOPMENT
PEDIATRICS
Clinical Development of an Everolimus Pediatric
Formulation: Relative Bioavailability, Food
Effect, and Steady-State Pharmacokinetics
John M. Kovarik, PhD, FCP, Adele Noe, PhD, Stephane Berthier, PharmD,
Louis McMahon, PhD, Wayne K. Langholff, PhD, Alan S. Marion, MD, PhD,
Peter Friedrich Hoyer, MD, Robert Ettenger, MD, and Christiane Rordorf, MD
The immunosuppressant everolimus used in organ trans-
plantation is formulated as a conventional tablet for adults
and a dispersible tablet that can be administered in water for
pediatric use. As part of the pediatric clinical development
program, the relative bioavailability and food effect for the
dispersible tablet were evaluated in healthy adult subjects as
a prelude to characterizing the steady-state pharmaco-
kinetics in pediatric kidney allograft recipients. In a random-
ized, open-label, three-way crossover study, 24 healthy adults
received single 1.5-mg oral doses of everolimus as (1) six 0.25-
mg dispersible tablets in water, (2) two 0.75-mg conventional
tablets, and (3) six 0.25-mg dispersible tablets in water after a
high-fat breakfast. Cmax and AUC were evaluated by standard
bioequivalence testing to determine relative bioavailability
and to quantify the effect of food. In a multicenter open-label
efficacy/safety trial, pediatric renal allograft recipients re-
ceived 0.8 mg/m2 (maximum 1.5 mg) bid everolimus as
dispersible tablets in water. Serial trough concentrations over
the first week and a steady-state pharmacokinetic profile on
day 7 posttransplant were collected in 19 patients ranging
from ages 2 to 16 years old. The bioavailability of everolimus
C hildren who receive an organ allograft face a life-
time on immunosuppressive therapy. Conse-
quently, this patient population is particularly likely to
From Novartis Pharmaceuticals, Basel, Switzerland, and East Hanover,
New Jersey (Dr. Kovarik, Dr. Noe, Dr. Berthier, Dr. McMahon, Dr. Langholff,
Dr. Rordorf); MDS Pharma Services, Lincoln, Nebraska (Dr. Marion); De-
partment of Pediatric Nephrology, Universitätsklinik Essen, Essen, Ger-
many (Dr. Hoyer); and Mattel Children’s Hospital at UCLA, Division of Pe-
diatric Nephrology, Los Angeles (Dr. Ettenger). Submitted for publication
September 29, 2002; revised version accepted November 19, 2002. Ad-
dress for reprints: John M. Kovarik, Novartis Pharma AG, Building WSJ
27.4093, 4002 Basel, Switzerland.
DOI: 10.1177/0091270002239822
J Clin Pharmacol 2003;43:141-147
from the dispersible tablet was 10% lower relative to the con-
ventional tablet, with a ratio (90% confidence interval) of
0.90 (0.76-1.07). After a high-fat meal, tmax was delayed by a
median 2.5 hours, and Cmax was reduced by 50%. Overall ab-
sorption, however, was not affected by food inasmuch as the
fed/fasting AUC ratio was 0.99 (0.83-1.17). In pediatric pa-
tients, steady state was reached between days 3 and 5. The
corresponding steady-state parameters were as follows: Cmin,
4.4 ± 1.7 ng/ml; Cmax, 13.6 ± 4.2 ng/ml; and AUC, 87 ± 27
ng•h/ml. Steady-state concentration-time profiles in pediat-
ric transplant patients receiving the dispersible tablet were
comparable to those of adult patients receiving the conven-
tional tablet when both were dosed to yield similar trough
concentrations. If a pediatric patient is converted from the
everolimus dispersible tablet to the conventional tablet, this
should be based on a 1:1 milligram switch with subsequent
therapeutic drug monitoring to further individualize the dose
as needed. The dispersible tablet formulation should be
taken consistently either with or without food to minimize
fluctuations in exposure over time.
Journal of Clinical Pharmacology, 2003;43:141-147
©2003 the American College of Clinical Pharmacology
benefit from an expansion of their therapeutic options.
Everolimus (Certican, Novartis Pharmaceuticals) is a
cell proliferation inhibitor in development for
immunosuppression after solid organ transplantation.
It is intended to be used in combination with
cyclosporine and corticosteroids. In two international
trials in adult kidney transplantation, everolimus was
equivalent in efficacy to the comparator myco-
phenolate mofetil.1,2 In an international trial in adult
heart transplantation, everolimus was superior in effi-
cacy to the comparator azathioprine.3
In parallel with the development of everolimus in
adult organ transplantation, a pediatric development
141
 KOVARIK ET AL
program was initiated in renal transplantation. The
everolimus pediatric program was designed in accor-
dance with the guidelines set forth in the International
Conference on Harmonization’s Guidance for Industry
E11 on clinical investigations in pediatric populations4
and the Food and Drug Administration’s Draft Guid-
ance for Industry on pediatric pharmacokinetic stud-
ies.5 The pediatric program components included (1)
developing a pediatric oral dosage form, (2) determin-
ing the relative bioavailability of everolimus from the
pediatric formulation compared with the conventional
tablet, (3) quantifying the influence of a high-fat meal
on absorption from the pediatric formulation to pro-
vide guidance to prescribers and patients on adminis-
tration with respect to meals, (4) characterizing the
single-dose pharmacokinetics of the formulation in
maintenance pediatric renal transplant patients to de-
rive a dose regimen for clinical use, and (5) performing
a multicenter clinical trial in de novo pediatric renal
transplant patients to document safety, efficacy, and
longitudinal steady-state pharmacokinetics.
For patients who cannot swallow tablets, such as
children, everolimus is formulated as a dispersible tab-
let in dose strengths of 0.1 and 0.25 mg. These tablets
are placed in a small amount of water in an oral syringe,
on a spoon, or in a plastic cup; the tablets are allowed to
disperse, and the contents are administered to the pa-
tient. Before proceeding to studies with this formula-
tion in pediatric transplant patients, a relative
bioavailability link to the conventional adult tablet
needed to be established to extrapolate safety and ex-
posure data from adult studies with the conventional
tablet and thereby design appropriate pediatric studies
with the dispersible tablet. Reported herein is a clinical
pharmacology study in healthy adults addressing the
relative bioavailability and food effect of the
dispersible tablet (the second and third components of
the development program). Of the two clinical studies
in pediatric transplant patients, the single-dose
pharmacokinetic study (the fourth component) has
been summarized elsewhere.6 Pertinent pharmaco-
kinetic aspects of the multicenter trial (the fifth compo-
nent) are presented here to demonstrate some of the
biopharmaceutical performance characteristics of the
dispersible tablet in children compared with the con-
ventional tablet in adults.
MATERIALS AND METHODS
Study Designs
The study in healthy subjects was a randomized, open-
label, three-way crossover trial enrolling 27 healthy
142 • J Clin Pharmacol 2003;43:141-147
men and women. The mean age was 28 ± 8 years (range:
19-42 years), and the mean weight was 75.8 ± 12.1 kg
(range: 53.1-97.6 kg). They received three 1.5-mg oral
doses of everolimus in a randomized sequence as fol-
lows: six 0.25-mg dispersible tablets in water under
fasting conditions (treatment A), two 0.75-mg conven-
tional tablets under fasting conditions (treatment B),
and six 0.25-mg dispersible tablets in water after a high-
fat breakfast (treatment C). In each of the three study pe-
riods, subjects remained at the clinical center for 48
hours after each treatment and returned on days 4 and 5
for pharmacokinetic blood draws. Consecutive treat-
ments were separated by a 14-day washout. An end-of-
study clinical evaluation was performed 7 days after re-
ceiving the last dose.
The patient pharmacokinetic data were collected
as part of an international, 1-year, open-label safety/
efficacy trial in 19 pediatric de novo kidney allograft re-
cipients. The 9 boys and 10 girls were 9.9 ± 4.4 years of
age and categorized as 1 infant (1.9 years), 10 children
(3.4-10.3 years), and 8 adolescents (12.9-16.7 years).
They weighed 32.7 ± 19.7 kg (range: 10.7-76.8 kg) with
body surface areas (BSAs) of 1.06 ± 0.43 m2 (range: 0.49-
1.92 m2). Everolimus was begun on the day of trans-
plantation at 0.8 mg/m2 (maximum 1.5 mg) twice daily
in addition to cyclosporine microemulsion (Neoral,
Novartis) and corticosteroids, with the optional use of a
CD25 monoclonal antibody. Cyclosporine was initi-
ated at 6 to 12 mg/kg/day in two divided doses and sub-
sequently individualized to yield morning predose
trough levels of 200 to 350 ng/ml in month 1 and 100 to
300 ng/ml thereafter. Oral prednisone or equivalent
was dosed according to local practice through at least
month 6 posttransplant and a minimum dose of 0.1 mg/
kg/day.
Both study protocols were reviewed by investiga-
tional review boards at the participating study centers.
The healthy subject study was conducted at MDS
Pharma Services (Lincoln, NE). The patient study was
conducted at 14 clinical centers in Belgium, Brazil,
France, Germany, Spain, the United Kingdom, and the
United States. The healthy subjects gave written con-
sent for participation in the relative bioavailability,
food effect study. The patients gave informed assent,
and their parents or legal guardians gave written con-
sent for participation in the clinical trial.
Drug Administration and Assessments
The healthy subjects reported to the study center the
evening before each treatment period and received a
standard dinner. After a 10-hour overnight fast, they re-
ceived the scheduled treatment. For treatment A, the
 DEVELOPMENT OF EVEROLIMUS PEDIATRIC FORMULATION
everolimus dispersible tablets (Certican, Novartis)
were placed in a 20-ml oral syringe, and 15 ml water
was added. The tablets were dispersed by gentle shak-
ing of the syringe for about 90 seconds, and the con-
tents were administered directly into the subject’s
mouth. The residue at the syringe tip was retracted into
the syringe with an additional 5 ml of water and the
contents administered orally. Thereafter, the subject
drank 200 ml water. For treatment B, the everolimus
conventional tablets (Certican, Novartis) were swal-
lowed with 200 ml water. For treatment C, subjects re-
ceived a standardized, high-fat breakfast with 250 car-
bohydrate calories, 600 fat calories, and 150 protein
calories. The everolimus dispersible tablets were pre-
pared as described for treatment A and administered
within 5 minutes after completing the breakfast.
Scheduled, standardized meals were served beginning
4 hours postdose in all three treatment arms.
To characterize the single-dose pharmacokinetics of
everolimus, 2-ml venous blood samples were collected
into EDTA-coated collection tubes predose and 0.5, 1,
1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours
postdose. Samples were transferred to polypropylene
tubes and frozen at –20°C. Safety assessments included
physical examinations, electrocardiograms, vital signs
measurements (blood pressure, pulse rate, tempera-
ture), laboratory evaluations (biochemistry, hematol-
ogy, urinalysis), and adverse event monitoring at base-
line (the day before each treatment period), at multiple
times during the treatments, and at study completion.
The assessments during treatment consisted of routine
laboratory parameters predose and at 24 and 96 hours
postdose and vital signs predose and at 2, 24, 48, 72,
and 96 hours postdose. Subjects were discharged from
the study center after the 48-hour safety and
pharmacokinetic blood draws. The study completion
evaluation was performed 7 days after the last
treatment.
In the pediatric clinical trial, everolimus dispersible
tablets (0.1- and 0.25-mg strengths) were placed in a 10-
ml oral syringe or spoon. The tablets were dispersed in
5 ml water over 90 seconds and administered to the
child. For administration by syringe, the residue at the
syringe tip was retracted with an additional 5 ml water
and the contents administered. After administration by
either route, the child drank an additional 10 to 100 ml
water. The dose could also be delivered via nasogastric
tube in the early days posttransplant, prepared in a sy-
ringe. Everolimus was given within 10 minutes after
the morning and evening cyclosporine dose, separated
by at least 1 hour before or after the nearest meal. Ve-
nous blood samples of 1.2 ml were obtained in EDTA-
PEDIATRICS
containing collection tubes before the morning
everolimus dose on days 3, 5, 6, and 7. Additional
blood samples were obtained on day 7 at 1, 2, 5, and 8
hours postdose for a steady-state profile. Blood sam-
ples were transferred to polypropylene tubes and
frozen at –20°C.
Bioanalytical Methods
Everolimus concentrations were determined in blood
by a validated liquid chromatography method. Briefly,
after addition of ammonium hydroxide, samples were
extracted with tert-butylmethylether. The organic ex-
tract was evaporated to dryness and reconstituted in
the chromatographic mobile phase. Samples were ana-
lyzed using liquid chromatography with atmospheric
pressure chemical ionization and mass spectrometry.
Assay performance was assessed on the basis of cali-
bration concentrations ranging from 0.26 to 51.4 ng/ml
and quality control concentrations ranging from 0.29 to
38.7 ng/ml determined in duplicate with patient sam-
ples. The lower limit of quantification was 0.26 ng/ml.
Pharmacokinetic and Statistical Evaluation
Conventional noncompartmental pharmacokinetic pa-
rameters were derived for single-dose everolimus, in-
cluding the peak blood concentration (Cmax), time to
reach the peak (tmax), area under the concentration-time
curve extrapolated to infinity (AUC), and half-life (t1/2)
by unweighted log-linear regression on the terminal
portion of the profile. For the multiple-dose profiles in
patients, parameters included the predose concentra-
tion (Cminss), tmax, Cmaxss, AUCτss, the average concentra-
tion over the dosing interval (Cavgss = AUCτss/12), the
percent swing (Swing = [Cmaxss – Cminss]/Cminss), and the
peak-trough fluctuation (PTF = [Cmaxss – Cminss]/Cavgss).7,8
To calculate the AUC over the full 12-hour dosing inter-
val, the measured concentrations at 5 and 8 hours in the
terminal phase were extrapolated by log-linear regres-
sion to yield the estimated 12-hour concentration.
The single-dose pharmacokinetic parameters were
compared among treatments in an ANOVA with se-
quence, subject within sequence, treatment, and pe-
riod as sources of variation on log-transformed data.
Relative bioavailability was quantified as the AUC ratio
of the dispersible tablet/conventional tablet with its
90% confidence interval (CI). The presence of a food ef-
fect was based on the Cmax and AUC parameter ratios
(fed/fasting) with 90% confidence intervals. If the ratio
and its confidence interval were within the bounds of
0.80 to 1.25, lack of a food effect was concluded for a
143

Table I Relative Bioavailability and Food Effect
Dispersible
Tablet Tablet
Parameter Fasting Fasting
tmax (h) 1.0 (0.5-2.0) 1.0 (0.5-1.5)
Cmax (ng/ml) 12.3 ± 4.8 9.3 ± 3.3
AUC (ng•h/ml) 99 ± 28 92 ± 37
t1/2 (h) 41.0 ± 11.2 39.1 ± 11.7
Values are mean ± standard deviation except for tmax, which is median
(range). tmax, time to reach peak exposure; Cmax, peak exposure; AUC, area
under the curve; t1/2, half-life.
9 ss
given parameter. In the patient study, serial C val-
ues were assessed by ANOVA, with patient and visit as
sources of variation; lack of a visit effect was consid-
ered evidence for attainment of steady state. An un-
paired t-test was used to compare steady-state parame-
ters between pediatric and adult patients from the
phase 3 trials in renal transplantation (data on file,
Novartis). Data are presented as mean ± standard devia-
tion unless otherwise stated.
RESULTS
Single-Dose Study: Subject Disposition
and Clinical Observations
Of the 27 subjects enrolled, 24 completed the study.
One subject discontinued due to pharyngolaryngeal
pain that the investigator did not consider treatment re-
lated; 1 subject discontinued due to urticaria, which
was suspected by the investigator as treatment related;
and 1 subject withdrew consent to participate. Over the
full course of the study, 17 subjects reported 65 adverse
events, mostly of mild intensity. These consisted pri-
marily of headache, rhinorrhea and cold-related symp-
toms, general body aches, and tiredness. There were no
clinically relevant changes in vital signs, electrocardio-
grams, or laboratory parameters over the course of the
study.
Relative Bioavailability from
the Dispersible Tablet
Pharmacokinetic parameters from the conventional
tablet and the dispersible tablet under fasting condi-
tions are compared in Table I, and the corresponding
parameter ratios (dispersible tablet/tablet) are shown
in Figure 1. The peak concentration occurred at a me-
144 • J Clin Pharmacol 2003;43:141-147
KOVARIK ET AL
3.0
Dispersible 2.5
Tablet
Parameter ratio
Fed 2.0
3.0 (2.0-6.1) 1.5
4.6 ± 1.8
1.0
94 ± 39
37.7 ± 10.9 0.5
0.0
C max AUC
Figure 1. Individual Cmax and AUC ratios from the dispersible
tablet/conventional tablet (filled circles). Bars designate the geomet-
min ric mean, and dashed lines demarcate the equivalence boundaries of
0.8 to 1.25.
dian 1 hour postdose and was not different between
formulations (p = 0.12). The Cmax ratio was 0.76 (90%
CI, 0.64-0.91), indicating that the peak concentration
was 24% lower on average from the dispersible tablet
relative to the tablet. Interindividual variability in Cmax
was similar for both formulations: 39.0% for the tablet
versus 35.5% for the dispersible tablet.
Inspection of Figure 1 indicates that the AUC from
the dispersible tablet for half of the subjects (n = 13) was
within ±20% of that from the tablet. Of the remaining
11 subjects, 7 had a lower and 4 had a higher AUC from
the dispersible tablet. The overall average bioavail-
ability of everolimus from the dispersible tablet was
0.90 (0.76-1.07) relative to the tablet. There was a trend
toward higher interindividual variability in AUC from
the dispersible tablet, but this was not statistically sig-
nificant and appeared to be influenced by a single out-
lier value: 28.3% for the tablet versus 40.2% for the
dispersible tablet (p = 0.09). The half-life of everolimus
from both formulations was similar.
Food Effect on the Dispersible Tablet
Pharmacokinetic parameters after a fasting and fed ad-
ministration of the dispersible tablet are summarized
in Table I, and the mean concentration-time profiles are
compared in Figure 2. After a high-fat meal, tmax was de-
layed in all subjects; the median delay was 2.5 hours,
with a range of 1.0 to 5.6 hours (p = 0.001). Cmax was no-
tably decreased in the majority of subjects, on average,
by 50% in the presence of food; the Cmax ratio was 0.50
(0.42-0.59). Interindividual variability in Cmax was not
influenced by a high-fat meal: 35.5% for fasting admin-
 DEVELOPMENT OF EVEROLIMUS PEDIATRIC FORMULATION

Table II Steady-State Pharmacokinetics

10
10 in Renal Transplant Patients
8
8
Concentration (ng/ml)

6 Pediatric Patients Adult Patients

4 Parameter Dispersible Tablet Tablet p-Value
6
2
0
Number 19 116 —
4
0 2 4 6 Dose 0.8 mg/m2 bid 0.75 mg bid —
Cminss (ng/ml) 4.4 ± 1.7 4.6 ± 2.1 0.97
2
tmax (h) 1 (1-5) 2 (1-5) 0.93
Cmaxss (ng/ml) 13.6 ± 4.2 11.0 ± 4.5 0.02
0
AUCτss (ng•h/ml) 87 ± 27 76 ± 31 0.08
0 12 24 36 48 60 72
Cavgss (ng/ml) 7.2 ± 2.2 6.3 ± 2.6 0.08
Time (h)
Swing (%) 242 ± 159 158 ± 94 0.14
PTF (%) 132 ± 64 117 ± 49 0.44
Figure 2. Mean concentration-time profiles from the dispersible
tablet under fasting conditions (open squares) and after a high-fat Values are mean ± standard deviation except tmax, which is median (range).
Cmin, predose trough concentration; tmax, time to reach peak; Cmax, peak
meal (filled squares). Bars represent the 95% confidence interval. concentration; AUC, area under the concentration curve; PTF, peak-trough
The inset compares the initial portion of the profiles to 6 hours fluctuation.
postdose.

Everolimus was well tolerated by pediatric patients

istration versus 39.1% after a high-fat meal. There was
no overall food effect on the extent of absorption, with
an AUC ratio of 0.99 (0.83-1.17). Nonetheless, inspec-
tion of the individual fed/fasting AUC ratios indicated
that occasionally a notable food effect occurred. Spe-
cifically, 1 subject had a 145% increase and another
had an 88% decrease in AUC after a high-fat meal.
Interindividual variability in AUC was not influenced
by food: 40.2% for fasting administration versus 41.5%
after a high-fat meal. Elimination half-lives were simi-
lar under both administration conditions.
Dosing and Administration
in Pediatric Patients
Everolimus doses averaged 0.9 ± 0.3 mg twice daily,
with individual doses ranging from 0.4 to 1.5 mg twice
daily. This complied with the protocol-specified dos-
ing inasmuch as the average BSA-adjusted dose was
0.81 ± 0.03 mg/m2 bid, ranging from 0.77 to 0.88 mg/m2
bid. The small deviations from 0.8 mg/m2 in individual
cases were due to rounding the calculated dose to the
available tablet strengths. In the first few postsurgical
days, 4 patients received the dose via nasogastric tube
and all others orally. The preferred device for oral ad-
ministration was the syringe used for 15 patients; only
4 patients used a spoon. When the pharmacokinetic
profile was obtained on day 7, a single patient was re-
ceiving everolimus via nasogastric tube. The pharma-
cokinetic parameters of this 1-year-old girl (tmax, 1 h;
Cmaxss, 15.2 ng/ml; AUCτss, 71 ng•h/ml) were similar to
those from the rest of the population (see Table II).
over the year-long study. Full clinical results will be re-
ported elsewhere.
Steady-State Pharmacokinetics
in Pediatric Patients
Mean serial trough blood concentrations on day 3 aver-
aged 3.6 ± 1.7 ng/ml, which was 84% of the subsequent
steady-state level. Steady state itself was reached be-
tween the day 3 and 5 visits, with concentrations on
day 5 averaging 4.3 ± 1.8 ng/ml. These levels were
maintained at subsequent visits, with values of 4.2 ± 2.1
ng/ml on day 6 and 4.4 ± 1.7 ng/ml (predose) and 4.3 ±
2.4 ng/ml (12 h postdose) on day 7. Attainment of
steady state was supported by lack of a visit effect on
Cminss from days 5 through 7 (p = 0.93).
Table II and Figure 3 compare the steady-state
pharmacokinetics in pediatric patients receiving the
dispersible tablet with those of adults receiving 0.75
mg twice daily with the conventional tablet, which was
a safe and effective regimen in the international pivotal
trials.1,2 At doses yielding similar trough concentra-
tions, tmax and AUCτss were not different between the
groups; however, Cmaxss was significantly higher in pe-
diatric patients by an average 19%. The profile shapes,
as indicated by percent swing and percent peak-trough
fluctuation, were comparable. When AUC was plotted
against age in the pediatric group, the slope of 2.3 ng•h/
ml per year was not different from zero (p = 0.11), indi-
cating that there was no age-related trends in exposure
when pediatric patients were dosed on a BSA-adjusted
basis.

PEDIATRICS 145
 KOVARIK ET AL
16
14
Concentration (ng/ml)
12
10
8
6 which Cmax was reduced by 60% and AUC reduced by
4 16%.10 While the average food effect on AUC for both
2 formulations was generally modest, there were a few
0 subjects who displayed a notable food effect, with up to
0 2 4 6 8 10 12
Time (h)
Figure 3. Mean steady-state concentration-time profiles in pediat-
ric renal transplant patients receiving the dispersible tablet (filled
circles) and adult patients receiving the conventional tablet (open
circles) at doses yielding similar trough blood concentrations. Bars
represent 95% confidence intervals.
DISCUSSION
Everolimus is formulated as a conventional tablet for
use in the general organ transplant population. For pa-
tients unable to swallow tablets—such as children, the
elderly, or adults in the immediate postoperative pe-
riod—a dispersible tablet was developed. This tablet
disintegrates in water in an oral syringe, on a spoon, or
in a plastic cup and is then administered by mouth. The
two studies described herein were components of a pe-
diatric clinical development program for everolimus in
renal transplantation using this formulation.
The relative bioavailability study was an essential
first clinical study with the dispersible tablet in order
to link the safety and exposure data generated in adult
trials using the conventional tablet to appropriate dos-
ing for a single-dose pharmacokinetic study in pediat-
ric maintenance renal transplant patients.6 It also pro-
vided useful information for converting between
formulations during patient care. Specifically, the
crossover evaluation in healthy adults demonstrated
that the bioavailability of everolimus from the
dispersible tablet was 10% lower relative to the con-
ventional tablet, and the Cmax was 24% lower. This im-
plies that when a child or adolescent, for example,
switches from the dispersible tablet to the conventional
tablet, the switch should be on a 1:1 milligram basis.
When the new regimen reaches steady state (after 4-5
days), therapeutic drug monitoring should be per-
formed to further individualize the dose as necessary.
The food effect part of the healthy subject study pro-
vided guidelines for administering the dispersible tab-
let with respect to meals. A high-fat meal slowed the
146 • J Clin Pharmacol 2003;43:141-147
absorption of everolimus from the dispersible tablet, as
evidenced by a median 2.5-hour delay in tmax and an av-
erage 50% decrease in the peak concentration. None-
theless, the overall extent of absorption (AUC) was not
affected, on average. Similar results were found for the
conventional tablet in a previous development study in
twofold changes in AUC after a high-fat meal. Based on
the individual responses to food, it would appear pru-
dent to administer the dispersible tablet to an individ-
ual patient on a consistent basis either with or without
food to avoid unnecessary fluctuations in exposure
over time. This conforms to the recommendation for
the conventional tablet.10
Pharmacokinetic evaluations in the context of the
international pediatric clinical trial demonstrated that
steady state was reached on or before day 5, as is also
the case in adult patients11 and consistent with the fact
that pediatric and adult patients have similar elimina-
tion half-lives.6 The steady-state concentration-time
profiles indicated that exposure, which is safe and ef-
fective in adults receiving the conventional tablet,1,2,12
can be achieved in pediatric patients with the
dispersible tablet. When dosed to yield comparable
trough levels, the shape of the profiles was generally
similar between formulations and age groups, with the
exception that Cmaxss was 19% higher in pediatric pa-
tients. The extent to which biopharmaceutical charac-
teristics of the two formulations or physiologic differ-
ences in the patient populations may have contributed
to this cannot be definitively answered from these data.
Based on the results from the formulation crossover in
healthy adults, a lower Cmaxss from the dispersible tablet
would be anticipated when Cminss is similar between
formulations. The higher Cmaxss actually measured sug-
gests that age-related differences in distribution vol-
ume, for example, would be a more likely explanation
for the observed differences in the early portion of the
concentration-time profile between populations. In
any case, the average Cmaxss in pediatric patients receiv-
ing the dispersible tablet was only modestly higher
than that in adults receiving the conventional tablet.
Furthermore, the range of individual Cmaxss values in
pediatric patients was 4.7 to 18.4 ng/ml, which fits
comfortably in the adult range of 2.2 to 24.6 ng/ml.
In sum, steady-state concentration-time profiles in
pediatric transplant patients receiving the dispersible
tablet were comparable to those of adult patients re-
ceiving the conventional tablet when both were dosed
to yield similar trough concentrations. If a pediatric pa-
 DEVELOPMENT OF EVEROLIMUS PEDIATRIC FORMULATION
tient is converted from the everolimus dispersible tab-
let to the conventional tablet, this should be based on a
1:1 milligram switch with subsequent therapeutic drug
monitoring to further individualize the dose as needed.
The dispersible tablet formulation should be taken
consistently either with or without food to minimize
fluctuations in exposure over time. The availability of a
dispersible tablet formulation should facilitate the use
of this drug in patients not able to take a conventional
tablet, such as children, the elderly, and patients with a
nasogastric or nasoduodenal tube.
REFERENCES
1. Vitko S, Margreiter R, Weimar W, Dantal J, Viljoen H, Cambon N,
et al: International, double-blind, parallel-group study of the safety
and efficacy of Certican versus mycophenolate mofetil in combina-
tion with Neoral and steroids [abstract]. Am J Transplant
2001;1(suppl. 1):474.
2. Kaplan B, Tedesco Silva H, Mendez R, Kahan B, Van Buren D,
Boger R: North/South American, double-blind, parallel-group study
of the safety and efficacy of Certican versus mycophenolate mofetil in
combination with Neoral and corticosteroids [abstract]. Am J Trans-
plant 2001;1(suppl. 1):475.
3. Valantine H, Eisen H, Dorent R, Mancini D, Vigano M, Starling R,
et al: Twelve-month results of a multicenter study comparing efficacy
and safety of everolimus to azathioprine in de novo cardiac trans-
plant recipients [abstract]. Am J Transplant 2002;2(suppl. 3):247.
4. International Conference on Harmonization: Guidance for Indus-
try E11: Clinical Investigations of Medicinal Products in Pediatric
Populations. Rockville, MD: Food and Drug Administration, 2000.
PEDIATRICS
5. Food and Drug Administration: Draft Guidance for Industry: Gen-
eral Considerations for Pediatric Pharmacokinetic Studies for Drugs
and Biological Products. Rockville, MD: Food and Drug Administra-
tion, 1998.
6. Webb N, Mahan J, Vandamme-Lombaerts R, Lemire J, Ettenger R,
Hoyer PF, et al: Pharmacokinetics and tolerability of RAD001 in pedi-
atric stable renal transplant patients [abstract]. Pediatr Transplant
2000;4(suppl. 2):123.
7. Food and Drug Administration: Draft Guidance for Industry:
Bioavailability and Bioequivalence Studies for Orally Administered
Drug Products—General Considerations. Rockville, MD: Food and
Drug Administration, 2002.
8. Sauter R, Steinijans VW, Diletti E, Boehm A, Schulz HU: Presenta-
tion of results from bioequivalence studies. Int J Clin Pharmacol Ther
Toxicol 1992;30(suppl. 1):S7-S30.
9. Schuirmann DJ: Comparison of the two one-sided tests procedure
and the power approach for assessing the bioequivalence of average
bioavailability. J Pharmacokinet Biopharm 1987;15:657-680.
10. Kovarik JM, Hartmann S, Figueiredo J, Rordorf C, Golor G, Lison A,
et al: Effect of food on everolimus absorption: quantification in
healthy subjects and a confirmatory screening in patients with renal
transplants. Pharmacother 2002;22:154-159.
11. Kahan BD, Wong RL, Carter C, Katz SH, von Fellenberg J,
van Buren CT, et al: Phase I study of a 4-week course of RAD in quies-
cent cyclosporine-prednisone-treated renal transplant patients.
Transplantation 1999;68:1100-1106.
12. Kovarik JM, Kaplan B, Tedesco Silva H, Kahan BD, Dantal J, Vitko S,
et al: Exposure-response relationships for everolimus in de novo kid-
ney transplantation: defining a therapeutic range. Transplantation
2002;73:920-925.
147