Journal of Antimicrobial Chemotherapy (1996) 37, Suppl.

C, 37-44

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The absence of an effect of food on the bioavailability of azithromycin
administered as tablets, sachet or suspension

G. Foulds', D. R. Luke', R. Teng', S. A. Willavize', H. Friedman' and W. J. Curatolo*

'Drug Metabolism;*Pharmaceutical Research and Development; 'Clinical Pharmacology;

''Clinical Research; and'Biometrics Departments, Central Research Division, Pfizer Inc.,
Grown, CT 06340, USA

Present product labelling indicates that azithromycin capsules should not be taken
with food. However, three recent studies demonstrated that food does not
significantly decrease the bioavailabilities of three new formulations of azithromycin
(250 mg tablets, 1000 mg sachet, 500 mg paediatric suspension). With a 500 mg
dosage, the mean relative bioavailability of azithromycin following ingestion of a
standard high-fat breakfast was 96% when administered as two 250 mg tablets and
113% when administered as a suspension. The mean relative bioavailability of a
1000 mg sachet was 112%. The absolute bioavailability of the sachet formulation,
relative to a 1 h iv infusion of 1000 mg, was 44%. Thus, azithromycin tablets,
suspension and sachet may be given without regard to meals, further enhancing the
convenience of once-daily, short-duration dosing regimens.

Introduction
Azithromycin is an azalide antibacterial agent (Retsema et ah, 1987; Bright et al., 1988)
with a long half-life (Foulds, Shepard & Johnson, 1990; Gardner & Ronfeld, 1992),
thereby enabling once-daily dosing regimens (Foulds & Johnson, 1993). Its
bioavailability in humans is approximately 37% (Foulds et al., 1990; Gardner &
Ronfeld, 1992). In the USA, two-dose regimens have been approved. A regimen of
500 mg on thefirstday followed by 250 mg/day for 4 additional days has been approved
as treatment of patients with community-acquired pneumonia caused by Streptococcus
pneumoniae or Haemophilus influenzae, streptococcal pharyngitis/tonsillitis and
uncomplicated skin and skin structure infections. In some countries, the same total
amount of drug (1500 mg) is administered as one 500 mg dose daily for only 3 days.
These regimens are currently administered orally in 250 mg capsules; a 250 mg tablet
formulation is under development. A second regimen which has been approved in the
USA for the treatment of patients with non-gonococcal urethritis or cervicitis caused
by Chlamydia trachomatis consists of a single, oral 1 g dose. This regimen can be
administered as capsules, tablets or as a 1 g sachet formulation. Additionally, a powder
for oral suspension has been approved for use in children.
Based on a study with a research capsule formulation of azithromycin, the present
labelling for azithromycin capsules reads "ZITHROMAX (azithromycin) should be
given at least 1 hour before or 2 hours after a meal" (Physicians Desk Reference, 1995).
37
03O5-7453/96/37CO37 + 08 $12.00/0 © 1996 The British Society for Antimicrobial Chemotherapy
38 G. FouMs et at.

We now report studies of the effects of a standard high-fat breakfast, containing at least
50 g of fat, on the bioavailabilities of azithromycin from the tablet, suspension and

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sachet formulations. These studies indicate that a reduction in the bioavailability of
azithromycin is avoided if these formulations are not given with food.

Subjects and methods

Three studies are reported. All protocols were reviewed and approved by Institutional
Review Boards. Study I was a two-period, two-treatment, randomized, crossover design
in which 12 subjects were given 500 mg of azithromycin in two 250 mg tablets following
an overnight (12 h) fast and a standard high-fat breakfast. Study II was a two-period,
two-treatment, randomized, crossover design in which 28 subjects were each given
500 mg of azithromycin in a paediatric cherry-banana-flavoured suspension (40 g/L)
following an overnight fast and a standard high-fat breakfast. Study III was a
three-treatment, three-period, crossover design in which 12 subjects were given 1 g of
azithromycin by iv infusion, as the oral sachet formulation following an overnight fast
and the sachet following the standard high-fat breakfast. Before entry into the studies,
all subjects read and signed consent forms. All of the subjects in these studies were
healthy male volunteers. For Study I, the mean age was 26.4 years (range 21-36) and
the mean weight was 75.8 kg (range 54.9-90.7). For Study II, the mean age was 26.7
years (range 18-45) and the mean weight 74.6 kg (range 60.6-90.8). For Study III, the
mean age was 27.6 years (range 18-42) and the mean weight 74.5 kg (range 62.6-86.2).
All subjects were non- or ex-smokers and light or non-users of alcohol.
The standard high-fat breakfast consisted of two eggs fried in one tablespoon of
butter, two strips of bacon, 170 g of hashbrown potatoes, two pieces of toast with two
teaspoons of butter and two pats of jelly (no jelly in Study II) and 227 m of whole milk,
ingested within a 20 min period. This meal contained at least 50 g of fat. Azithromycin
was taken immediately following completion of the meal. Fasted and non-fasted
volunteers were allowed a standard meal 4 h following the doses. All tablet doses were
administered with 240 mL of water. Azithromycin powder for oral suspension was
supplied in a 150 cm3 polyethylene bottle. Sterile water (48 mL) for injection was added
to each bottle which was then vigorously shaken to provide a suspension containing
40 g/L azithromycin activity; aliquots (12.5 mL) were administered orally. The
suspension was administered with 240 mL of water in the fasted state and with 50 mL
of water following the high-fat breakfast. For administration of the sachet dosing form,
the contents of each 1 g packet of azithromycin were emptied into a cup containing
60 mL of water. The mixture was then stirred to dissolve the powder. Following
ingestion of this solution, an additional volume of 180 mL of water (one 60 mL rinse
of the cup plus 120 mL) was administered.
Following each dosing regimen, blood was obtained at up to 96 h after dosing in
Study I and up to 120 h in Studies II and III. Serum samples were stored at — 70°C
until assayed for azithromycin by HPLC with electrochemical detection (Shepard et al.,
1991) at BAS Analytics, West Lafayette, IN, USA. The lower limit of quantification
was 0.010 mg/L. Samples with concentrations above the upper limit of the standard
curves (1.01 or 1.21 mg/L) were diluted to bring the concentrations within the range of
the standard curves. The validities of the standard curves were assessed by assaying
quality control samples, run in duplicate at each of three concentrations during the
assays of samples from the studies. The mean values of the assayed quality control
 Food and azithromycin bloavailability 39

samples deviated from standard concentrations of 0.050, 0.200 and 0.499 mg/L by
— 1.4%, 0.2% and —1.1% respectively for seven assay runs for samples from Study
I; coefficients of variation were 3.5%, 1.3% and 3.2% respectively. The mean assay

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concentrations of the quality control samples for Study II deviated from standard
concentrations of 0.050, 0.200 and 0.501 mg/L by 1.9%, 2.4% and 5.0% respectively
for 17 assay runs; coefficients of variation were 3.8%, 4.6% and 5.6%, respectively. The
mean assayed concentrations for the quality control samples for Study III deviated from
standard concentrations of 0.050, 0.200 and 0.499 mg/L by - 1 . 9 % , 0.2% and - 1 . 8 %
respectively for 13 assay runs; coefficients of variation were 5.6%, 4.9% and 5.4%,
respectively.
The maximum observed serum concentrations ( C ^ ) were determined by inspection
of the data. T^ was defined as the time of the first occurrence of Cm«. Areas under
the serum concentration versus time curves (AUC) were calculated by the linear
trapezoidal method. The interval between the immediate predose period and 48 h after
was chosen for the calculation of the AUC following administration of the tablets
because all subjects had quantifiable concentrations of azithromycin in the blood after
all treatment regimens at 48 h, but not at later times. Following administration of the
suspension and the sachet, the interval between the immediate predose period and 72 h
after was chosen for calculation of the AUC because 72 h was the last time for which
samples from almost all subjects following all treatment regimens contained measurable
concentrations of azithromycin. Truncation of AUCs at 48 or 72 h has been shown to
provide reliable estimates for bioavailability calculations for azithromycin (Gardner &
Ronfeld, 1992). Terminal phase rate constants were not calculated because the duration
of concentrations above the lower limit of quantification of the assay, during the
terminal phase of the serum concentration curves, was too short, relative to the known
terminal half-life of azithromycin (approximately 3 days), to permit the calculation
(Foulds et al., 1990; Gardner & Ronfeld, 1992). Geometric mean values of C™ and
AUC are reported. Relative bioavailability was calculated as AUC(fed)/AUC(fasted)
and is reported as a percentage. Mean relative bioavailability was calculated from the
geometric mean values of the AUC. In Study III, absolute bioavailability was calculated
as AUC(oral)/AUC(iv). AUCs following high-fat breakfasts were compared with those
following the overnight fast by means of an ANOVA of the natural-log transform of
the AUCs. Following verification that there were no sequence or period effects,
treatment effects were examined. Ninety percent confidence limits on the ratio of
AUC(fed)/AUC(fasted) are reported as percentages. Similar calculations were
performed for C^,.

Results
Mean azithromycin concentrations during the interval 0.5-4 h after dosing were
increased by administration of the suspension or sachet immediately following the
standard high-fat meal (Figures 1 and 2). However, mean concentrations after 6 h
following dosing were unaffected by meals (Figures 1 and 2). Concentrations following
administration of the tablets were similar at all times after the high-fat breakfast and
the overnight fast (Figure 1). For the three dosing formulations, the mean AUCs were
similar following the overnight fast and following the high-fat breakfasts, with mean
bioavailabilities of 96%, 113% and 112% for Studies I, II, and III, relative to the
40 G. Foulds et al.

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10
Time(h)
Figure 1. Mean serum concentrations of azithromycin following oral administration of 500 mg from the
tablet formulation (2 x 250 mg) or 1 g from the sachet formulation after an overnight fast (A, tablets, O,
sachet) and after a high-fat breakfast (A. tablets; 0 , sachet)

fasting state respectively (Table). Confidence limits on the relative bioavailabilities are
displayed in the Table.
Following the 1-h iv infusion of azithromycin in Study III, the mean concentration
immediately following the end of the infusion was 5.18 mg/L. The mean AUC was
10.76 mg.h/L. The mean absolute bioavailability of the oral 1000 mg sachet of
azithromycin was 44% following an overnight fast and 50% following the high-fat
breakfast.

Discussion
The absolute bioavailability of azithromycin delivered by the sachet formulation is
similar to or greather than the 37% reported following oral administration of 500 mg
in solution (Foulds et al., 1990). Following oral administration of 1000 mg from the
sachet, the mean Cmu (0.75 mg/L with a mean Tmv of 1.5 h) was similar to the values
reported following oral administration of 1000 mg taken as 250 mg capsules (0.82 mg/L
with a mean 7 ^ of 1.7 h) (Bergan et al., 1992).
The increase in the mean serum concentrations following administration of
azithromycin tablets or suspensions with a meal is of short duration, persisting for less
than 4 h. Thus, any influence on the incidence or severity of side-effects should be
minimal. The cause of the increased mean C™, following administration of these
formulations with food is unclear. Possible mechanisms include changes in the pH of
the intestinal contents, food-stimulated pancreatic exocrine secretion leading to changes
in pH or solubility (Go, Hoffman & Summerskill, 1970), accelerated emptying of the
stomach contents into the site(s) of absorption in the intestine (Edelbroek et al., 1993),
 Food and azithromycin bioavailability 41

0.5 i-

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10 20 30 40 50
Time (h)
Figure 2. Mean serum concentrations of azithromycin following oral administration of 500 mg in
suspension after an overnight fast (A) and after a high-fat breakfast (#).

food-induced increase in splanchnic blood flow, resulting in decreased first-pass

elimination by capacity-limited mechanisms, and food-induced increased absorption of
electrolytes and water in the jejunum and ileum (Anthone et al., 1992). The cause of
the difference in the effect of food on the bioavailability of azithromycin when taken
as capsules, relative to the lack of effect when taken as tablets or suspensions, is
unknown. Relevant mechanisms include differences in dissolution rates or in the
delivery rates of azithromycin to various sites within the gastrointestinal tract. However,
neither of these mechanisms explains why food should cause a marked decrease in
bioavailability following ingestion of capsules when bioavailability following ingestion
of other formulations is unaffected. A direct effect of the azithromycin within the
capsules on the capsule shells, causing incomplete dissolution, is unlikely, because
the absolute bioavailability of azithromycin from capsules is similar to that with the
other formulations.
The bioavailabilities of the macrolides are often affected by coadministration with
food. The bioavailability of erythromycin is generally decreased by food (Welling & Tse,
1982), whereas the bioavailability of its ethylsuccinate ester is increased (Coyne et al.,
1978). The bioavailability (AUCo-x) of clarithromycin 500 mg tablets was increased by
approximately 18% and (?„„ was increased by 52% when the tablets were administered
with food (Chu et al., 1992). Bioavailability was increased by 42% and C ^ was
increased by 28% when 7.5-mg/kg doses of the paediatric suspension of clarithromycin
were administered with food to paediatric patients. Thus, the increased C ^ observed
when azithromycin is administered with food is also observed with macrolide
antibiotics.
The bioavailabilities of azithromycin from 250 mg tablets, 500 mg suspensions and
1000 mg sachets were not significantly affected by administration immediately following
Table. Pharmacokinetics of azithromycin when administered as different formulations to volunteers after an overnight fast or after a standard
high-fat breakfast

C , (mg/L) Mean Relative bioavailability11

Dosage No. of Alimentary - AUC
Study Formulation (mg) subjects status mean CL' (mg.h/L) mean

I 250 mg tablet 500 12 fasted 0.336 2.4941

12 fed" 0.412 88-145% 2.4041 96% 82-113%
II 40 g/L suspension 500 28 fasted 0.294 — 3.19" — —
28 fed" 0.474 134-194% 3.6072 113% 103-124%
III sachet 1000 12 fasted 0.749 — 6.49" — — fi.
12 fed" 1.052 116-185% 7.3772 112% 99-127%

•Superscript indicates last time (h) for AUC calculations.

'AUC(fed)/AUC(fasted).
'Ninety percent confidence limits on the ratio of mean values.
"High-fat breakfast.

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 Food and azithromycin bioavailability 43

a high-fat breakfast. Thus, these tablet, sachet and suspension formulations of

azithromycin may be administered without regard to meals, increasing the convenience
of once-daily dosing regimens.

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Acknowledgements
The authors acknowledge the assistance of the following: Dr D. M. Hilligoss from
Central Research Division, Pfizer Inc., Groton, CT, USA; Dr B. Levy and the staff of
the Pharmacology Units of the National Medical Research Corporation, Hartford, CT,
USA; Dr T. Hunt and the staff of Pharmaco::LSR, Inc., Austin, TX, USA; and the
analytical services of Dr R. E. Shoup and the staff of BAS Analytics, West Lafayette,
IN, USA.

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