caa a22 4500 445312343 CHVBK 20180317142634.0 cr unu---uuuuu 170323e20110701xx s 000 0 eng 10.1007/s11095-011-0386-9 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0386-9 Effects of Food on a Gastrically Degraded Drug: Azithromycin Fast-Dissolving Gelatin Capsules and HPMC Capsules [Elektronische Daten] [William Curatolo, Ping Liu, Barbara Johnson, Angela Hausberger, Ernest Quan, Thomas Vendola, Neha Vatsaraj, George Foulds, John Vincent, Richa Chandra] ABSTRACT: Purpose: Commercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with "superdisintegrants” to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect. Methods: Healthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules. Result: When the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®. Conclusion: Interaction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin bioavailability in the fed state is largely (and probably entirely) due to gastric degradation to DCA. Capsules can provide a useful and elegant dosage form for almost all drugs, but may result in a negative food effect for drugs as acid-labile as azithromycin. Springer Science+Business Media, LLC, 2011 azithromycin nationallicence capsules nationallicence des-cladinose-azithromycin nationallicence food effect nationallicence HPMC capsules nationallicence Curatolo William Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut Liu Ping Clinical Pharmacology, Specialty Care, Pfizer Inc., 06320, New London, Connecticut, USA aut Johnson Barbara Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut Hausberger Angela Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut Quan Ernest Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut Vendola Thomas Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut Vatsaraj Neha Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut Foulds George Clinical Pharmacology, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut Vincent John Clinical Sciences, Primary Care, Pfizer, Inc., 10017, New York, New York, USA aut Chandra Richa Clinical Development, Emerging Markets, Pfizer Inc., 06320, New London, Connecticut, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1531-1539 0724-8741 28:7<1531 2011 28 11095 https://doi.org/10.1007/s11095-011-0386-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0386-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Curatolo William Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Liu Ping Clinical Pharmacology, Specialty Care, Pfizer Inc., 06320, New London, Connecticut, USA aut NATIONALLICENCE 700 1- Johnson Barbara Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Hausberger Angela Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Quan Ernest Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Vendola Thomas Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Vatsaraj Neha Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Foulds George Clinical Pharmacology, Pfizer Global R&D, 06340, Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Vincent John Clinical Sciences, Primary Care, Pfizer, Inc., 10017, New York, New York, USA aut NATIONALLICENCE 700 1- Chandra Richa Clinical Development, Emerging Markets, Pfizer Inc., 06320, New London, Connecticut, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1531-1539 0724-8741 28:7<1531 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer