PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
For publications based on this study, see associated bibliography.
PROPRIETARY DRUG NAME/INN: Zithromax®/Azithromycin
THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI
PROTOCOL NO.: A0661113
PROTOCOL TITLE: An Open-Label Study of the Pharmacokinetics, Safety, Tolerability, and
Clinical Response of a 60 mg/kg Single Oral Dose of an Experimental Azithromycin Dihydrate
Microspheres Sustained-Release Formulation in Pediatric Subjects
Study Center(s): Two centers in the United States
Study Initiation and Completion Dates: 24 June 2003 to 28 August 2003
Phase of Development: Phase 1
Study Objective(s):
01000005427352 \ 1.1 \ Approved \ 06-Dec-2005 13:55
Primary objective: To evaluate the pharmacokinetics in the empty stomach and fed states, of a
single 60 mg/kg oral dose of azithromycin dihydrate microspheres sustained-release formulation
(ASR) in pediatric subjects with non-life-threatening respiratory tract infections or with
uncomplicated skin or soft tissue infections for which azithromycin, alone or in combination,
could be beneficial.
Secondary objectives: To evaluate the safety, tolerability, and clinical response of ASR in this
population.
METHODS
Study Design: This was an open-label, non-randomized, single-dose pharmacokinetic study in
pediatric subjects with non-life-threatening respiratory tract infections or uncomplicated skin and
soft-tissue infections. Each subject received a single oral dose of ASR. Blood samples were
collected for evaluation of azithromycin pharmacokinetics at 0 hours (just prior to dosing), and
1.5, 3, 6, 12-24, 48-72, 96, and 144-168 hours post-dose. Safety and tolerability were assessed
throughout the study, and efficacy was evaluated on Day 7-8 post-dose. Excluding the screening
period, total participation in the study for each subject was approximately 8 days. Six subjects (8
subjects for Group VII) were enrolled into each of the following age groups:
• Group I: 3 months to 18 months, dosed on empty stomach
• Group II: >18 months to 36 months, dosed on empty stomach
• Group III: >36 months to 48 months, dosed on empty stomach
• Group IV: >48 months to 8 years, dosed on empty stomach
CLINICAL STUDY SYNOPSIS
• Group V: >8 years to 12 years, dosed on empty stomach
• Group VI: >12 years to 16 years, dosed on empty stomach
• Group VII: 18 months to 8 years, dosed following a high-fat meal
•
Each subject in Groups I through VI received a single oral dose of ASR 60 mg/kg (total dose not
to exceed 2g) on an empty stomach (“fasted”, at least 1 hour before or 2 hours after a meal.) At
1 study site, an additional cohort of 8 subjects (Group VII), ages 18 months to 8 years
(inclusive), was dosed with ASR 60 mg/kg within 5 minutes of consuming an age-appropriate,
high-fat breakfast (“fed”). The investigator assigned subjects to be dosed on an empty stomach
or under fed conditions based on subject (and/or parent) preference until the fed cohort was
filled. Thereafter, subjects only had the option of receiving the study drug on an empty stomach.
Serial blood samples were collected through Days 7-8 post-dose for evaluation of azithromycin
pharmacokinetics.
Number of Patients (planned and analyzed): Thirty-six subjects were planned for enrollment
in this study. Another 8 subjects were added in protocol Amendment 1 to bring the total number
of planned patients to 44. Forty-four (44) subjects were assigned to treatment (6 in Groups I –VI
and 8 in Group VII).
01000005427352 \ 1.1 \ Approved \ 06-Dec-2005 13:55
Diagnosis and Main Criteria for Inclusion: Subjects screened for this study were males and
females between 3 months and 16 years of age, inclusive, with non-life-threatening respiratory
tract infections or with uncomplicated skin or soft tissue infections for which azithromycin, alone
or in combination with other appropriate treatment, could be beneficial. Subjects were inpatients
or outpatients.
Study Treatment: Azithromycin dihydrate microspheres sustained-release formulation was
administered orally as a single, 60-mg/kg dose in the form of a slurry on Day 1. Subjects who
weighed 28 kg or less were dosed from 1 bottle using the provided Pediatric Constitution and
Dosing Instructions. Subjects weighing 29-33 kg were dosed using 2 bottles of ASR using the
provided Pediatric Constitution and Dosing Instructions. All subjects >33kg were dosed from
1 bottle using the provided Adult Constitution and Dosing Instructions. Medical and/or
paramedical personnel directly observed each subject for 2 hours after study drug administration.
Pharmacokinetic data from subjects who vomited within 2 hours following dosing with ASR
were analyzed separately. The time of vomiting in relationship to the dose of ASR and the
approximate volume of emesis were recorded in the CRF. A subject who vomited within
5 minutes of ASR administration received alternative therapy. Azithromycin was not
re-administered to any subject who vomited.
Subjects in the fed cohort received ASR within 5 minutes of consuming an age-appropriate,
high-fat breakfast. All other subjects received ASR on an empty stomach (at least 1 hour before
or 2 hours after a meal). Administration of aluminum- or magnesium-containing antacids was
prohibited within 2 hours before and 4 hours after study drug dosing.
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CLINICAL STUDY SYNOPSIS
Efficacy Evaluations: Clinical response was assessed on Days 7-8 post-dose or when subject
discontinued from the study, and were classified by the investigator as “cure” or “failure.”
Pharmacokinetics: Blood samples were collected for evaluation of azithromycin
pharmacokinetics at 0 hours (just prior to dosing), and 1.5, 3, 6, 12-24, 48-72, 96, and
144-168 hours post-dose. The pharmacokinetic endpoints of the study were maximum observed
serum concentrations (Cmax), Tmax (defined as the time of the first occurrence of Cmax), area under
the serum concentration-time curve (AUC) from time 0 to the time of the last quantifiable
concentration [AUC(0-Tlast)] and, when data permitted, from time 0 to 24 hours post-dose
[AUC(0-24)], from time 0 to 72 hours post-dose [AUC(0-72)] and from time 0 to 96 hours post-
dose [AUC(0-96)], the terminal phase half-life (t½), and the AUC extrapolated to infinity
[AUC(0-inf)]. Actual sample collection times were used for pharmacokinetic parameter
estimation as well as in the plotting of individual concentrations over time. In general, when
sample collection windows (e.g., 24-48 hours) were specified, samples were collected close to
the earliest or the latest nominal time point.
Safety Evaluations: All subjects were evaluated for safety, which was assessed by clinical
observation, spontaneous AE reporting, limited physical examinations, body temperature
measurements, and clinical laboratory evaluations. In addition, subjects were queried regarding
adverse events (AEs) at 1.5, 3, 6, 12-24, 48-72, 96, and 144-168 hours following dosing.
Statistical Methods: All pharmacokinetic parameters were summarized and tabulated using
01000005427352 \ 1.1 \ Approved \ 06-Dec-2005 13:55
descriptive statistics (N, Mean, Geometric Mean [AUC and Cmax], Standard Deviation, CV%
[coefficient of variation], Minimum, and Maximum). Mean and individual azithromycin
concentrations were plotted and tabulated by time.
RESULTS
Subject Disposition and Demography: Forty-four (44) pediatric subjects (27 males, 17
females) received treatment with azithromycin. All subjects entered the study with non-life-
threatening respiratory tract infections (n=38) or uncomplicated skin or soft tissue infections
(n=6). One subject in Group VII (fed) was discontinued from the study after vomiting
immediately after dosing.
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CLINICAL STUDY SYNOPSIS
Table S1 Subject Disposition
Disposition Number of Subjectsa
Group I - Group II Group III Group IV Group V - Group VI Group VII
Empty - Empty - Empty - Empty Empty - Empty - Fed
Stomach Stomach Stomach Stomach Stomach Stomach
Total Assigned to Study Treatment
44
Total Treated 6 6 6 6 6 6 8
Completed 6 6 6 6 6 6 7
Discontinued 0 0 0 0 0 0 1
Assessed for Pharmacokinetics 6 6 6 6 6 6 7
Assessed for Adverse Events 6 6 6 6 6 6 8
Assessed for Laboratory 6 6 6 6 6 6 7
Evaluations
a
All subjects were treated with a single 60 mg/kg dose of azithromycin dihydrate-coated microspheres
sustained release formulation (ASR)
Empty stomach = dosed with ASR at least 1 hour before or 2 hours after a meal
Fed = dosed with ASR within 5 minutes of consuming an age-appropriate high-fat breakfast
Group I– empty stomach = ages 3-18 months Group V– empty stomach = ages >8-12 years
Group II– empty stomach = ages >18-36 months Group VI– empty stomach = ages >12-16 years
Group III– empty stomach = ages >36-48 Group VII– Fed = ages 18 months-8 years
months (inclusive)
Group IV– empty stomach = ages >48 months-8
years
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Efficacy Results: For all subjects, the clinical signs and symptoms were considered to have
either resolved or had improved such that no additional therapy was necessary and the final
assessment was considered to be “cure”.
Pharmacokinetics: Mean serum azithromycin exposures were comparable across different age
groups in pediatric subjects aged 3 months to 16 years following a 60 mg/kg single oral dose
(maximum of 2g) of ASR. Food, emesis, and sex appeared to have no apparent effect on the
exposure to ASR in pediatric subjects, given limited data. However, there was a considerable
inter-subject variability of systemic azithromycin exposure in these pediatric subjects.
The mean serum azithromycin concentration vs. time profiles following administration of ASR
on an empty stomach or under fasted conditions in different age groups are shown in Figure S1.
Azithromycin exposure was comparable across the different age groups, and the mean absorption
profiles in these age groups were slightly different, possibly due to variability in the absorption
of a 60-mg/kg dose (maximum of 2g). Among all pharmacokinetic (PK) profiles, the mean PK
profiles of Group I (3-18 months) and Group VII (fed, 18 months to 8 years) were at the lower
end, while the mean PK profile of Group II (18 – 36 months) was at the upper end.
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CLINICAL STUDY SYNOPSIS
Figure S1 Mean Serum Azithromycin Concentration Versus Time Profiles Following
Administration of a Single 60 mg/kg Oral Dose of Azithromycin SR on an
Empty Stomach Across Six Different Age Groups (n=6 per Group) and in Fed
Conditions (n=7) in Pediatric Subjects
3mon-18mon
10000
18mon-36mon
36mon-48mon
48mon-8y
8y-12y
Mean Azithromycin Concentration (ng/mL)
1000 12y-16y
fed 18mon-8y
100
10
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1
0 24 48 72 96 120 144
Nominal Time (hr)
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CLINICAL STUDY SYNOPSIS
A summary of the PK parameters is provided in Table S2. Azithromycin exposure [AUC(0-96),
AUC(0-inf), and Cmax] was comparable in pediatric subjects aged 3 months to 16 years given
large inter-individual variability. Group II (18 to 36 months) had relatively high mean AUC
driven by 2 subjects with very high exposure. In Group VII, the mean AUC appeared to be
slightly lower than that in the empty stomach, while the mean Cmax was comparable to that in the
empty stomach.
The mean t½ in the younger age groups (up to 48 months) was slightly shorter (~40 hours) than
that of the oldest 2 groups (46-52 hours, 8-16 years old). The median Tmax was 3 hours for all
pediatric subjects, regardless of fed condition or empty stomach.
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CLINICAL STUDY SYNOPSIS
Table S2 Mean (SD) Azithromycin Pharmacokinetic Parameters Following
Administration of a Single 60 mg/kg (Maximum 2 g) Oral Dose of ASR to
Pediatric Subjects Aged 3 Months to 16 Years
Pharmacokinetic Parameters
Treatment Group Cmax AUC(0-Tlast) AUC(0-96) AUC(0-inf) t½ Tmaxa
(ng/mL) (ng•h/mL) (ng•h/mL) (ng•h/mL) (h) (h)
736 11300 11700 14100 40.2 3
Group I (n=6) (200) (2690) (2040) (2160) (2.16) (3-3)
[n=4] [n=3] [n=3]
1880 33800 31600 37300 38.6 3
Group II (n=6) (501) (11800) (10700) (12900) (4.22) (3-3)
[n=5] [n=5]
1230 21400 20200 22400 38.7 3
Group III (n=6) (415) (5650) (5240) (5960) (1.98) (3-6)
1130 21100 19900 22200 42.1 3
Group IV (n=6) (344) (6610) (6260) (6890) (2.37) (3-6)
1650 27900 25700 30100 46.3 3
Group V (n=6) (375) (9890) (8930) (10700) (2.96) (3-6)
983 19400 17700 21300 52.1 3
Group VI (n=6) (345) (8350) (7530) (9370) (5.72) (3-6)
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Groups I – VI 3
1270 22500 21700 25200 43.4
(All Subjects With (3-6)
(525) (10300) (9250) (10700) (6.03)
Empty Stomach;
[n=34] [n=32] [n=32]
n=36)
1410 12300 12600 18900 42.2 3
Group VII (n=7) (616) (5560) (4790) (3570) (3.94) (1.5-3.1)
[n=6] [n=3] [n=3]
All subjects were treated with a single 60 mg/kg dose of azithromycin dihydrate-coated microspheres
sustained release formulation (ASR)
Empty stomach = dosed with ASR at least 1 hour before or 2 hours after a meal
Fed = dosed with ASR within 5 minutes of consuming an age appropriate high fat breakfast
Group I – empty stomach = ages 3-18 months Group V – empty stomach = ages >8-12 years
Group II – empty stomach = ages >18-36 months Group VI – empty stomach = ages >12-16 years
Group VII – Fed = ages 18 months-8 years
Group III – empty stomach = ages >36-48 months
(inclusive)
Group IV – empty stomach = ages >48 months-8
years
a
Median (range) presented for Tmax
Individual AUC(0-Tlast) and Cmax values were distributed randomly among pediatric subjects
aged 3 months to 16 years with relatively large variability. No clear trend was observed.
Safety Results: No deaths or serious AEs were reported in this study. One subject in the fed
cohort discontinued due to an adverse event (vomiting). A total of 27 AEs were reported, of
which 17 were considered related to study medication. All AEs were mild in severity. The
majority of the AEs were related to the GI system, occurred within 3 hours of dosing, and
resolved spontaneously.
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CLINICAL STUDY SYNOPSIS
Among subjects who were dosed on an empty stomach (6 subjects in each age group), AEs were
reported for 4 subjects in Group I, 2 subjects in Group II, 1 subject in Group III, 2 subjects in
Group IV, 4 subjects in Group V, and 1 subject in Group VI. Among the 8 subjects dosed under
fed conditions (Group VII), 6 subjects had AEs. The most frequently reported AEs were related
to the GI system: diarrhea (7 subjects: 3 in Group I, 1 in Group II, and 3 in Group VII) and
abdominal pain (4 subjects: 1 in Group V, 1 in Group VI, and 2 in Group VII). Six of the
7 subjects who experienced diarrhea were receiving concomitant treatment with other
protocol-allowed antibiotics (4 received amoxicillin, 1 received amoxicillin/clavulanic acid,
1 received cephalexin).
Vomiting was reported by 3 subjects in Group VII only. One subject vomited approximately
11 minutes post-dose and was discontinued from the study; 2 subjects vomited between 1 to
2 hours post-dose and remained in the study: These subjects had received concomitant antibiotic
treatment (2 received amoxicillin and 1 received cefadroxil). Rash was reported in 2 subjects in
Group V (unrelated eczema in 1 subject and unrelated heat rash in 1 subject). Other AEs
(accidental injury, fever, nausea, increased cough, and respiratory tract infection) were reported
by 1 subject each in either treatment group.
No clinically significant laboratory test abnormalities were observed following dosing with
azithromycin, and no abnormal liver function test results were reported at any time during the
study.
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CONCLUSION(S):
In pediatric subjects with non-life-threatening respiratory tract or uncomplicated skin or soft
tissue infections, serum azithromycin exposure was comparable across all age groups (aged
3 months to 16 years) following a single oral dose of 60 mg/kg (maximum of 2 g) of ASR, given
relatively high inter-subject variability. The exposure achieved at this dose was comparable to
that of 2g ASR administered to adults. The results also suggest that food has a minimal effect on
azithromycin exposure in pediatric patients, however, other factors (e.g., small sample size) may
account for the lack of food effect in this study. ASR was well tolerated by all age groups when
dosed on an empty stomach or following a meal, and all subjects were considered cured at the
final assessment.
Based on a report completed on: 22 March 2004
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