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Mechanistic Study of the Azithromycin Dosage-Form-Dependent Food Effect

Pharmaceutical Research volume 27, pages 1361–1366 (2010)Cite this article

ABSTRACT

Purpose

Azithromycin capsules are known to exhibit a negative food effect, manifest as a decrease in azithromycin bioavailability in the fed state. Azithromycin tablets are known to be bioequivalent to capsules in the fasted state, but do not exhibit a food effect. In the present study, the involvement of gastric degradation of azithromycin to des-cladinose azithromycin (DCA) has been investigated as a possible mechanism for the observed capsule food effect.

Methods

Healthy volunteers were dosed with azithromycin tablets and capsules, fasted and fed, in a four-way randomized crossover study. Serum levels of DCA were measured as a function of time post-dose. Natural log-transformed PK parameters were statistically analyzed using an ANOVA model appropriate for the study design.

Results

When capsules were dosed to fed subjects, the systemic AUC for DCA was 243% of the value observed after fasted-state dosing, and the DCA Cmax was 270% of the value observed after fasted-state dosing. When azithromycin tablets were dosed in the fasted and fed states, there was no significant difference in systemic DCA.

Conclusion

Gastric degradation of azithromycin to DCA is the likely mechanism for the observed negative food effect observed for azithromycin capsules. This effect is not observed for tablets. These observations suggest that azithromycin capsules exhibit slow and/or delayed disintegration in the fed stomach, resulting in extended gastric residence and degradation of a portion of the gastrically retained azithromycin.

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ACKNOWLEDGEMENTS

We gratefully acknowledge the excellent contributions of Mr. Scott Hessong of BAS Analytics and Ms. Theresa Morse of the Clinical Pharmacology Department, Pfizer Global R&D. We also gratefully acknowledge the excellent contribution of Dr. Glen Aspeloff and colleagues at Ohio State University, who carried out the dosing and sample collections. We thank Dr. Barbara A. Johnson of Pfizer Global R&D for helpful discussions about azithromycin in vitro dissolution. We gratefully recognize Dr. Hylar Friedman of Pfizer Clinical Pharmacology for his enthusiastic support of mechanistic studies.

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Affiliations

  1. Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, MS-4124, Groton, Connecticut, 06340, USA

    William Curatolo

  2. Retired, Clinical Pharmacology Department, Pfizer Global R&D, Groton, Connecticut, 06340, USA

    George Foulds

  3. Research Statistics, PharmaTherapeutics, Pfizer Global R&D, Groton, Connecticut, 06340, USA

    Robert LaBadie

Authors
  1. William Curatolo
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  2. George Foulds
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  3. Robert LaBadie
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Correspondence to William Curatolo.

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Curatolo, W., Foulds, G. & LaBadie, R. Mechanistic Study of the Azithromycin Dosage-Form-Dependent Food Effect. Pharm Res 27, 1361–1366 (2010). https://doi.org/10.1007/s11095-010-0126-6

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  • DOI: https://doi.org/10.1007/s11095-010-0126-6

KEY WORDS

  • azithromycin
  • capsule disintegration
  • des-cladinose azithromycin
  • food effect