Amoxicillin

Amoxicillin: From Discovery to Commercialization

Discovery

     In 1928, Alexander Fleming discovered that penicillin, a substance being produced by the mold, Penicillin notatum, appeared to inhibit bacterial growth. [1] Likely unbeknownst to Fleming at the time, this discovery would revolutionize the treatment of infectious diseases caused by bacteria. Later, the use of penicillin as a therapeutic agent, while certainly a landmark event which lead to subsequent clinical breakthroughs, was not without its deficits. Most notably, penicillin has a limited spectrum of bacteria against which it is able to exert its effect, as was observed by its inactivity against gram-negative pathogens such as Escherichia coli and Klebsiella pneumoniae. [2] As such, researchers looked for ways to improve the structure of penicillin such that the impact of its disadvantages might be mitigated. Through chemical modification of the structure of penicillin, specifically, addition of an amino group to its side chain, the aminopenicillins were created. 

     Aminopenicillins have the same mechanism of action as their parent compound, which is inhibition of bacterial cell wall synthesis via binding to penicillin-binding proteins (PBPs). [3] The first aminopenicillin was ampicillin; a drug which was later further modified via addition of a hydroxyl group. Hydroxylation of ampicillin yielded amoxicillin, a compound with greater polarity, and therefore, greater oral absorption. [4] The synthetic modification described allows aminopenicillins to exert effect against some gram-negative bacteria by allowing them to pass through the outer layer of the pathogen. [5] With extended spectrum of activity, amoxicillin is an effective therapeutic agent against ailments caused by these bacteria, such as in treatment of lower respiratory tract infection and infections of the ear, nose, and throat. [6]

     

     It is important to draw contrast to the nature of the discovery/synthesis of amoxicillin and its predecessor. Penicillin is considered a natural product, as it is naturally occurring in nature; in contrast, amoxicillin is considered to be semi-synthetic, as it is synthesized via modification of a natural product (penicillin). [7] While the improvements in its design lessen amoxicillin’s adverse effect profile relative to other related compounds, patients may still experience hypersensitivity, diarrhea, confusion, and abdominal pain. [6]

Commercialization

     Amoxicillin arrived on the market for the first time in 1974 as the branded product Amoxil^®. The patent for the product is held by GlaxoSmithKline (GSK), a company which resulted from the consolidation of SmithKline Beecham and Glaxo Wellcome in 1995. [8] In 2010, GSK transferred ownership of its penicillin manufacturing plant in Bristol, Tennessee, as well as the rights for its Amoxil^®and Augmentin^® (amoxicillin and clavulanic acid) brands in the United States (U.S.) to Dr. Reddy’s. GSK retained the existing rights to these brands outside the U.S. [9] The transfer to Dr. Reddy’s was one that seemed logical as Dr. Reddy’s already had authorized generic products on the market in tablet form (1978) and powder for oral suspension (1999).  [10] Dr. Reddy’s is an Indian multinational company with its headquarters in Hyderabad, Telangana, India. According to a report to its investors, as of June 2018, the company had experienced revenues of $2,181M in 2018 with earnings before interest, taxes, depreciation, and amortization (EBITDA) of $370M. [11]

     Amoxicillin is now available in capsule, tablet, chewable tablet, and powder for suspension and is available from eight generic manufacturers (Table 1). [12] The drug is approved for a variety of conditions, including infections of the ear, nose, throat due to Streptococcusspp., H. pylori, and infections of the lower respiratory tract due to Streptococcusspp., Staphylococcus spp., or H.influenzae, among other conditions. Drug resistance due to beta-lactamase production by some of these pathogens limits the drug’s use in certain conditions. [13] 

Most recently, an extended release version of the therapeutic was approved for treatment of tonsillitis and/or pharyngitis in patients 12 years and older. The approval was based upon a phase 3, double-blind, double-dummy, randomized, parallel-group study involving more than 600 pediatric and adult patients. In the study, once daily amoxicillin 775 mg was found to be non-inferior to penicillin VK 250 mg four times daily for the treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes. The extended release tablet is the only once daily formulation of amoxicillin and is branded as Moxatag^®, the license for which is held in the U.S. by Vernalis Therapeutics. [14] 

Despite growing concerns of resistance, the drug continues to experience success, especially within the pediatric population. As was proven by the recent approval of a once daily regimen, while amoxicillin's prime may have passed with regard to its patent status, the drug still has a lot to contribute to modern medicine. Nearly a century later, Alexander Fleming’s discovery continues to greatly impact the market for infectious diseases treatment across the globe. 

Table 1. Available dosage forms of amoxicillin
Dosage form	Strength(s)	Manufacturer(s)	Brand Available	Generic Available	Price [6]
Capsule	250 mg	Dr. Reddy’s, AM Antibiotics, Dava Pharms Inc, Teva, Sandoz, Hikma, Aurobindo	Y	Y	$0.13-$0.25 per cap
	500 mg				$0.19-$5.88 per caps
Tablet, chewable	125 mg	Teva	N	Y	$0.34 per tab
	250 mg				$0.67 per tab
Powder for reconstitution (suspension)	125 mg / 5 mL	Dr. Reddy’s, Dava Pharms Inc, Teva, Sandoz, Hikma, Aurobindo, Wockhardt Bio AG	Y	Y	$0.04 per mL
	200 mg/ 5 mL				$0.09 per mL
	250 mg / 5 mL				$0.06 per mL
	400 mg / 5 mL				$0.10 per mL
Tablet, extended release	775 mg	Vernalis Therapeutics	Y	N	$18.90 per tab
Tablet	500 mg	Teva, Sandoz, Hikma, Aurobindo	N	Y	$0.50 per tab
	875 mg				$0.87 per tab

References

1. American Chemical Society International Historic Chemical Landmarks. Discovery and Development of Penicillin. http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html(accessed September 22, 2018).  
2. Kok-Fai K, Schneper K, Mathee K. Beta-lactam Antibiotics: From Antibiosis to Resistance and Bacteriology. APMIS: acta pathologica, microbiologica, et immunologica Scandinavica. 118.1 (2010): 1-36. 
3. National Institutes of Health. Aminopenicillins: Third generation penicillins. https://livertox.nih.gov/Aminopenicillins.htm(accessed September 23, 2018). 
4. Sjovall J, Alvan G, Akerlund JE, Svenson JO, Painstaud G, Nord CE, Angelin B. Dose-dependent absorption of amoxicillin in patients with an ileostomy. Eur J Clin Pharmacol. (1992) 43:277-281.
 5. Hauser A. Antibiotic Basics for Clinicians: The ABCs of Choosing The Right Antibacterial Agent, 2^ndEdition. (2007): 23-36. Lippincott Williams & Wilkins: Philadelphia, PA. 
6. Amoxcillin: Drug Information. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. www.uptodate.com/contents/amoxicillin-drug-information. (Accessed September 23, 2018). 
7. Bardal SK, Waechter JE, Martin DS. Applied Pharmacology. (2011): 233-291. Elsevier: Amsterdam, Netherlands.
8. GlaxoSmithKline. “Creating the GSK of Today: 1950 – 1999.” Available at: https://www.gsk.com/en-gb/about-us/our-history/creating-the-gsk-of-today-1950-1999/. (Accessed November 2, 2018).
9. GlaxoSmithKline. Press Release: “GlaxoSmithKline and Dr. Reddy’s agree to the sale of US Penicillin Facility and Products.” (2010). (Accessed November 2, 2018).
10. U.S. Food and Drug Administration. “FDA Listing of Authorized Generics, as of September 27, 2018. (Accessed October 29, 2018). 
11. Dr. Reddy’s Laboratories Limited. Investor Presentation. (2018). Available at: http://www.drreddys.com/media/639830/dr-reddys-investor-presentation-june-2018.pdf. (Accessed November 1, 2018). 
12. U.S. Food and Drug Administration. FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. (Accessed October 27, 2018). 
 13. Amoxicillin [package insert]. Bridgewater, NJ: Dr. Reddy’s Laboratories; 1999. 
14. Moxatag [package insert]. Berwyn, PA: Vernalis Therapeutics, Inc.; 2016.