The absence of an effect of food on the bioavailability ...

Journal of Antimicrobial Chemotherapy (1996) 37, Suppl. C, 37-44

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

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). 03O5-7453/96/37CO37 + 08 $12.00/0

37 © 1996 The British Society for Antimicrobial Chemotherapy

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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.

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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 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

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


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.

Food and azithromycin bloavailability

39

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


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 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^,.

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G. Foulds et al.

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),


10

41

Food and azithromycin bioavailability 0.5 i-

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


10

250 mg tablet

40 g/L suspension

sachet

I

II

III

1000

500

500

Dosage (mg) 12 12 28 28 12 12

No. of subjects

•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.

Formulation

Study fasted fed" fasted fed" fasted fed"

Alimentary status 0.336 0.412 0.294 0.474 0.749 1.052

mean 88-145% — 134-194% — 116-185%

CL'

C , (mg/L)

mean 96% — 113% — 112%

Mean AUC (mg.h/L) 2.4941 2.4041 3.19" 3.6072 6.49" 7.3772

82-113% — 103-124% — 99-127%

Relative bioavailability11

Table. Pharmacokinetics of azithromycin when administered as different formulations to volunteers after an overnight fast or after a standard high-fat breakfast


fi.

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.

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.

References


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