ABSTRACT
Azithromycin is a unique antibiotic due to its serum half-life of 69 h. This half-life is long enough to permit administration of an entire course of therapy in a single dose, if the gastrointestinal (GI) side effects of such a high dose can be minimized. A series of exploratory clinical pharmacology studies were carried out to understand the site-specific absorption and toleration constraints involved in delivering a 2 g oral single-dose regimen. These studies demonstrated that (a) GI side effects were locally mediated in the GI tract, (b) the duodenum was more sensitive than the ileocecal region, and (c) colonic absorption was limited. A novel controlled release suspension dosage form was designed to meet these constraints, and was shown to deliver the desired systemic dose with acceptable toleration. This dosage form, Zmax®, is an oral powder-for-constitution which possesses two major features: (a) 200 μm controlled release microspheres which release the drug as they transit down the small intestine, and (b) alkalizing agents which raise the pH of the gastric milieu for ∼20 min to minimize gastric release of the drug (which has high solubility at low pH), in order to minimize exposure of the drug to the sensitive duodenal region. The ability to provide a high single dose of azithromycin results in “front-loading” the mononuclear and polymorphonuclear leukocytes which concentrate the drug and carry it to sites of infection. This provides high drug concentrations early on at infection sites, when the bacterial burden is greatest, potentially improving efficacy and potentially overcoming resistant bacterial strains. Finally, this revolutionary single dose formulation gives 100% compliance, which maximizes the likelihood of therapeutic success.
Similar content being viewed by others
REFERENCES
Retsema J, Girard A, Schelkly W, Manousos M, Anderson M, Bright G, et al. Spectrum and mode of action of azithromycin (CP-62, 993), a new 15-membered-ring macrolide with improved potency against Gram-negative organisms. Antimicrob Agents Chemother. 1987;31:1939–47.
Neu H. Clinical microbiology of azithromycin. Am J Med. 1991;91(Suppl 3A):12S–8S.
Gardner M, Ronfeld R. Interpretation and characterization of the pharmacokinetics of azithromycin in man. In “Program and Abstracts of the Eighth Mediterranean Congress of Chemotherapy 1992”; Athens, Greece; Abstract 407, p. 302.
Luke D, Foulds G, Cohen S, Levy B. Safety, toleration, and pharmacokinetics of intravenous azithromycin. Antimicrob Agents Chemother. 1996;40:2577–81.
Foulds G, Shepard R, Johnson R. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother. 1990;25(Suppl A):73–82.
Gladue R, Bright G, Isaacson R, Newborg M. In vitro and in vivo uptake of azithromycin (CP-62, 993) by phagocytic cells: possible mechanism of delivery and release at site of infection. Antimicrob Agents Chemother. 1989;33:277–82.
Shentag J, Ballow C. Tissue-directed pharmacokinetics. Am J Med. 1991;91(Suppl 3A):5S–11S.
McDonald P, Pruul H. Phagocytic uptake and transport of azithromycin. Eur J Clin Microbiol Infect Dis. 1991;10:828–33.
Girard A, Cimochowski C, Faiella J. Correlation of increased azithromycin concentrations with phagocyte infiltration into sites of localized infection. J Antimicrob Chemother. 1996;37(Suppl C):9–19.
Foulds G, Johnson R. Selection of dose regimens of azithromycin. J Antimicrob Chemother. 1993;31(Suppl E):39–50.
Curatolo W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm Sci Tech Today. 1998;1:387–93.
Hagen T, Lo JB, Thombre A, Herbig S, Appel L, Crew M, et al. Azithromycin dosage forms with reduced side effects. US Patent 6,984,403B2. European Patent EP-1537859B1. European Patent Application published 2005.
Yuhas L, Fuerst J, Timpano J, Fiese E. pKa values of CP-62,993, azithromycin, assigned using 1H-NMR spectroscopy. The AAPS Journal 2003;5(S1), Abstract 001468. Available from http://www.AAPSJ.org/.
Fiese EF, Steffen S. Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother. 1990;25(Suppl A):39–47.
Foulds G, Curatolo W. Unpublished.
Foulds G, Connolly A, Fortner J, Fletcher A. Separation of presystemic and post-absorptive influences on the bioavailability of azithromycin in cynomolgous monkeys. In: Zinner SH, editor. Expanding Indications for the new Macrolides, Azalides, and Spectrogramins. New York: Marcel Dekker Inc; 1997. p. 460–3.
Foulds G, Shepard R, Allen R, Ferraina R, Fletcher A. Transintestinal elimination of azithromycin in dogs. 5th European Congress of Clinical Microbiology and Infectious Diseases, Oslo, Norway. Sept. 9–11, 1991; Abstract 220.
Sugie M, Asakura E, Zhao Y, Torita S, Nadai M, Baba K, et al. Possible involvement of the drug transporters P glycoprotein and multidrug resistance-associated protein Mrp2 in disposition of azithromycin. Antimicrob Agents Chemother. 2004;48:809–14.
Bennett J, Horspool K. Unpublished, personal communication.
Amsden G, Nafziger A, Foulds G, Cabelus L. A study of the pharmacokinetics of azithromycin and nelfinavir when coadministered in healthy volunteers. J Clin Pharmacol. 2000;40:1522–7.
Luke D, Foulds G. Disposition of oral azithromycin in humans. Clin Pharmacol Ther. 1997;61:641–8.
Garey K, Peloquin C, Godo P, Nafziger A, Amsden G. Lack of effect of zafirlukast on the pharmacokinetics of azithromycin, clarithromycin, and 14-hydroxyclarithromycin in healthy volunteers. Antimicrob Agents Chemother. 1999;43:1152–5.
Hopkins S. Clinical toleration and safety of azithromycin. Amer J Med. 1991;91(suppl 3A):40S–5S.
Foulds G, Luke DR, Willavize SA, Curatolo W, Friedman H, Gardner MJ, et al. Effect of food and formulation on bioavailability of azithromycin. In: Zinner SH, editor. Expanding indications for the New Macrolides, Azalides, and Spectrogramins. New York: Marcel Dekker Inc; 1997. p. 469–73.
Curatolo W, Foulds G, Friedman H. Method of dosing azithromycin. U.S. Patent 5,605,899. European Patent EP-0679400B1. European Patent Application published 1995.
Foulds G, Luke DR, Teng R, Willavize SA, Friedman H, Curatolo W. The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chemother. 1996;37(Suppl C):37–44.
Curatolo W, Foulds G, LaBadie R. Mechanistic study of the azithromycin dosage form-dependent food effect. Pharm Res. 2010;27:1361–6.
Curatolo W, Liu P, Johnson BA, Hausberger A, Quan E, Vendola T, et al. Effects of food on a gastrically-degraded drug: Azithromycin fast-dissolving gelatin capsules and HPMC capsules. Pharm. Res. doi:10.1007/s11095-011-0386-9.
Curatolo W, Friedman H, Korsmeyer R, LeMott S. Controlled-release dosage forms of azithromycin. US Patent 6,068,859. European Patent EP-0758244B1. European Patent Application published 1997.
Curatolo W, Luke D, Foulds G, Friedman H. Site-specific absorption and toleration of azithromycin. Proc. Intl. Symp. Control. Rel. Bioactive Material 1996;23:57–58.
Luke D, Foulds G, Friedman H, Curatolo W, Scavone J. Clinical pharmacology of azithromycin given at various sites along the gastrointestinal tract in healthy subjects. In: Zinner SH, editor. Expanding indications for the New Macrolides, Azalides, and Streptogramins. New York: Marcel Dekker; 1997. p. 464–8.
Sutton S, Evans L, Fortner J, McCarthy J, Sweeney K. Dog colonoscopy model for predicting human colon absorption. Pharm Res. 2006;23:1554–63.
Luke D, Foulds G, Going P, Melnik G, Lawrence V. Rectal azithromycin in healthy subjects. In: Zinner SH, editor. Expanding indications for the New Macrolides, Azalides, and Streptogramins. New York: Marcel Dekker; 1997. p. 474–7.
Physicians’ Desk Reference, 56th Edition. Zithromax®. Medical Economics, Montvale, NJ, USA, publ. 2002; p.2739.
Lo JB, Appel L, Herbig S, McCray S, Thombre A. Formulation design and pharmaceutical development of a novel controlled release form of azithromycin for single-dose therapy. Drug Dev Ind Pharm. 2009;35:1522–9.
Appel L, Ray R, Newbold D, Friesen D, McCray S, West JB, et al. Azithromycin multiparticulate dosage forms by melt-congeal processes. US Patent Application 2005/0158391A1; published 2005.
Appel L, Ray R, Lyon D, West JB, McCray S, Crew M, et al. Multiparticulate crystalline drug compositions having controlled release profiles. US Patent Application 2005/0181062A1; published 2005.
Appel L, Crew M, Friesen D, Ray R. Method for making pharmaceutical microspheres. European Patent EP-1,691,787B1; published 2006.
Ray R, Appel L, Friesen D, Crew M, Newbold M. Controlled release dosage forms of azithromycin. US Patent Application 2005/0123615A1; published 2005.
Hunt J, MacDonald I. The influence of volume on gastric emptying. J Physiol. 1954;126:459–74.
Chandra R, Liu P, Breen J, Fisher J, Xie C, LaBadie R, et al. Clinical pharmacokinetics and gastrointestinal tolerability of a novel extended-release microsphere formulation of azithromycin. Clin Pharmacokinet. 2007;46:247–59.
D’Ignazio J, Camere M, Lewis D, Jorgenson D, Breen J. Novel, single-dose microsphere formulation of azithromycin versus 7-day levofloxacin therapy for treatment of mild to moderate community-acquired pneumonia in adults. Antimicrob Agents Chemother. 2005;49:4035–41.
Drehobl M, De Salvo M, Lewis D, Breen J. Single-dose azithromycin microspheres vs clarithromycin extended release for the treatment of community-acquired pneumonia in adults. Chest. 2005;128:2230–7.
Zervos M, Breen J, Jorgenson D, Goodrich J. Novel, single-dose microsphere formulation of azithromycin versus levofloxacin for the treatment of acute exacerbation of chronic bronchitis. Infect Dis Clin Pract. 2005;13:115–21.
Blasi F, Aliberti S, Tarsia P. Clinical applications of azithromycin microspheres in respiratory tract infections. Intl J Nanomed. 2007;2:551–9.
Harrison T, Keam S. Azithromycin extended release. A review of its use in the treatment of acute bacterial sinusitis and community-acquired pneumonia in the US. Drugs. 2007;67:773–92.
Liu P, Allaudeen H, Chandra R, Phillips K, Jungnik A, Breen J, et al. Comparative pharmacokinetics of azithromycin in serum and white blood cells of healthy subjects receiving a single-dose extended-release regimen versus a 3-day immediate-release regimen. Antimicrob Agents Chemother. 2007;51:103–9.
Girard D, Finegan S, Dunne M, Lame M. Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models. J Antimicrob Chemother. 2005;56:365–71.
Blumer J. Evolution of a new drug formulation: the rationale for high-dose, short-course therapy with azithromycin. Intl J Antimicrob Agents. 2005;26 Suppl 3:S143–7.
Greenberg R. Overview of patient compliance with medical dosing: a literature review. Clin Ther. 1984;6:592–9.
Bond W, Hussar D. Detection methods and strategies for improving medication compliance. Amer J Hosp Pharm. 1991;48:1978–88.
Sclar D, Tartaglione T, Fine M. Overview of issues related to medical compliance with implications for the outpatient management of infectious diseases. Infect Agents Dis. 1994;3:266–73.
Bergman A, Werner R. Failure of children to receive penicillin by mouth. New EnglJMed. 1963;268:1334–8.
Sutton S. The use of gastrointestinal intubation studies for controlled release development. Br J Clin Pharmacol. 2009;68:342–54.
Nellans H, Peterson A, Peeters T. Gastrointestinal side effects: clarithromycin superior to azithromycin in reduced smooth muscle contraction and binding. Abstracts of the 1991 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); Abstract 518; pg.185.
Bortolotti M, Annese V, Mari C, Lopilato C, Porrazzo G, Miglioli M. Dose-related stimulatory effect of clarithromycin on interdigestive gastroduodenal motility. Digestion. 2000;62:31–7.
Weber F, Richards R, McCallum R. Erythromycin: a motilin agonist and gastrointestinal prokinetic agent. Amer J Gastroenterol. 1993;88:485–90.
Feighner S, Tan C, McKee K, Palyha O, Hreniuk D, Pong S-S, et al. Receptor for motilin identified in the human gastrointestinal system. Science. 1999;284:2184–8.
Takeshita E, Matsuura B, Dong M, Miller L, Matsui H, Onji M. Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol. 2006;41:223–30.
ACKNOWLEDGMENTS
The assembly of this review was facilitated by many stimulating discussions with the authors of many of the publications quoted, in particular: Julian Lo, Timothy Hagen, Scott Herbig, Richard Korsmeyer, Steven LeMott, George Foulds, Ping Liu, Richa Chandra, David Luke, Hylar Friedman, Avinash Thombre, Michael Dunne, and Jeanne Breen of Pfizer; and Leah Appel, Joshua Shockey, David Lyon, Dwayne Friesen, Scott McCray, Rod Ray, and Marshall Crew of Bend Research Inc. I am indebted to Dwayne Friesen, Scott McCray, George Foulds, and Richard Korsmeyer for a critical reading of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Curatolo, W. Interdisciplinary Science and the Design of a Single-Dose Antibiotic Therapy. Pharm Res 28, 2059–2071 (2011). https://doi.org/10.1007/s11095-011-0382-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-011-0382-0