Interdisciplinary Science and the Design of a Single-Dose Antibiotic Therapy
- 197 Downloads
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.
KEY WORDSantibiotic compliance azithromycin controlled release leukocyte targeting microspheres single dose therapy
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.
- 3.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.Google Scholar
- 12.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.Google Scholar
- 13.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/.
- 15.Foulds G, Curatolo W. Unpublished.Google Scholar
- 16.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.Google Scholar
- 17.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.Google Scholar
- 19.Bennett J, Horspool K. Unpublished, personal communication.Google Scholar
- 24.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.Google Scholar
- 25.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.Google Scholar
- 28.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.
- 29.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.Google Scholar
- 30.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.Google Scholar
- 31.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.Google Scholar
- 33.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.Google Scholar
- 34.Physicians’ Desk Reference, 56th Edition. Zithromax®. Medical Economics, Montvale, NJ, USA, publ. 2002; p.2739.Google Scholar
- 36.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.Google Scholar
- 37.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.Google Scholar
- 38.Appel L, Crew M, Friesen D, Ray R. Method for making pharmaceutical microspheres. European Patent EP-1,691,787B1; published 2006.Google Scholar
- 39.Ray R, Appel L, Friesen D, Crew M, Newbold M. Controlled release dosage forms of azithromycin. US Patent Application 2005/0123615A1; published 2005.Google Scholar
- 45.Blasi F, Aliberti S, Tarsia P. Clinical applications of azithromycin microspheres in respiratory tract infections. Intl J Nanomed. 2007;2:551–9.Google Scholar
- 47.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.PubMedCrossRefGoogle Scholar
- 51.Bond W, Hussar D. Detection methods and strategies for improving medication compliance. Amer J Hosp Pharm. 1991;48:1978–88.Google Scholar
- 55.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.Google Scholar
- 57.Weber F, Richards R, McCallum R. Erythromycin: a motilin agonist and gastrointestinal prokinetic agent. Amer J Gastroenterol. 1993;88:485–90.Google Scholar