From Acid to Drug Product: Ciprofloxacin

              Ciprofloxacin is a potent anti-bacterial drug of the fluoroquinolone drug class. The drug is a few generations removed from its parent drug, Nalidixic Acid. Nalidixic Acid was discovered serendipitously in the 1960’s as an impurity in the manufacturing of quinine which is a product of the cinchona tree found in South America and has been used to treat Malaria. [1] Since its discovery, Nalidixic Acid has been used successfully to treat urinary tract infections. However, the drug has limited anti-bacterial applications as it is excreted in the urine, has variable systemic absorption, and lacks activity against Gram-negatives. [2]

               There were a number of drugs discovered and developed between the discovery of Nalidixic Acid and Ciprofloxacin. Cinoxacin, Norfloxacin, and Ofloxacin were all developed prior to Cipro, and Cipro was actually a derivative of the Norfloxacin, the first fluoroquinolone approved by the FDA. As such, Ciprofloxacin possess a number of key functional group changes and additions that make it a significantly more active and potent anti-bacterial agent than Nalidixic Acid. The first major difference can be noticed at “pharmacore” position 8 where Nalidixic Acid has Nitrogen and Ciprofloxacin has a Carbon. Nalidixic Acid is classified as a naphthyridone and Ciprofloxacin is classified as a fluoroquinolone as a result of this difference. One of the earliest functional alterations was the addition of a fluorine atom at position 6. This simplistic change resulted in a 10-fold increase in gyrase inhibition and up to a 100-fold improvement in minimum inhibitory concentration (MIC). An addition of a piperazine molecule at C7 improved the drug’s activity against Gram-negative organisms such as E. Coli, Salmonella, and Pseudomonas. [2] Lastly, in the 1980’s, scientists at the Bayer company working on improving Norfloxacin found that converting the methyl group at position 1 to a cyclopropyl group further increased the drug’s Gram-negative potency. This observation marked the “discovery” of Ciprofloxacin and in 1987 and 1991 the oral and intravenous dosage forms respectively were approved by the FDA. [3]

               Ciprofloxacin has two bacterial targets: DNA gyrase and DNA topoisomerase IV which are both essential enzymes. Cipro forms complexes with the topoisomerase enzymes, effectively trapping them and preventing bacterial growth. Cipro also increases the number of reactive oxygen species, thereby catalyzing oxidative death. [4] Its use is widespread because its mode of action is extremely effective against a wide breadth of bacterial infections. A few of the FDA approved uses for Cipro are UTI, Cystitis, chronic bacterial prostatitis, skin and skin structure infections, bone and joint infections, Typhoid Fever, and STI’s. [5]

               According to Bayer documentation, the phase three trials involving 444 patients had lower than a 10% report rate of adverse effects. The majority of effects reported consisted of nausea and headache, with the rarer but more serious effects consisting of abdominal pain, photosensitivity reaction, migraine, constipation, decreased appetite and food intake, diarrhea, dyspepsia, flatulence, thirst, vomiting, hyperglycemia, hypoglycemia, maculopa, pular rash, pruritus, rash, skin disorder, vesiculobullous rash, taste perversion, dysmenorrhea, vaginal candidiasis, and vaginitis. [6] Additional issues with include low effectiveness against Gram-negative bacteria. There are a number of new drugs on that have been developed with heightened effectiveness but have encountered issues in toxicological studies.
               Some of Cipro's adverse effects have resulted in lawsuits filed against the manufacturing companies responsible for drug production. The most recent case comes from a claim that fluoroquinolone class drugs including Levaquin, Cipro, Avelox and their generic versions are causing peripheral neuropathy [7]. This lawsuit comes on the tails of a class action suit that resulted in a $74 million settlement. The suit alleged that Bayer Inc. conspired with other brand name drug companies to keep the price of generic formulations from being competitive on the market. Bayer has also been forced to defend its rights granted by the U.S. patent office. Prior to the expiration of the patent, Canada violated patent laws by ordering a generic form of Cipro to protect against anthrax attacks. Canada was forced to pay twice for the order of drugs after Bayer Inc. threatened legal action [8]. These lawsuits are indicative of some of the largest challenges facing drug producers. The astronomical cost to bring a drug to market must be recovered in order for the process to be profitable. However, payback periods can easily be interrupted by unexpected adverse effects and generic production.
               As recently as 2018, the FDA has continued to strengthen the warnings for powerful antibiotics such as Cipro. In particular, the FDA has approved class-wide labeling changes for all fluoroquinolone antibiotics to strengthen the warnings related to mental health side effects and the risk for severe low blood sugar, including hypoglycemic coma [9]. As such, Cipro has continued to be phased out as a general use drug. However, the compound's effectiveness at treating serious bacterial infections has allowed it to find a niche as an emergency treatment. It is not uncommon for the administration of extremely potent drugs to be inseparable from the onset of adverse health effects. This makes monitoring adverse effects an important part of drug administration.
               With the expiration of Bayer Inc. patent in 2004, the company has been actively seeking ways to innovate on delivery in order to prolong patent life. Most recently, Bayer pushed for the approval of a DPI delivery system which was ultimately rejected by the FDA. The project has been abandoned for the time being by Bayer while they pursue other options [10]. As prices for Cipro continue to fall due to generic production and issues with bacterial resistance climb, continued innovation will become a key factor in the drugs marketability. Cipro is currently involved in fifty-seven NDAs. There are eight patents protecting this drug and two Paragraph IV challenges [11]. The generic form of Cipro is included in sixty-three NDAs. There are fifteen patents protecting this compound and one Paragraph IV challenge [12].

               Since the patent for Cipro expired in 2004, it has been distributed widely and affordably to treat a whole cohort of bacterial infections. It has even been listed on the World Health Organizations list of essential medicines. [3] Resistance has become both more likely and more devastating because of its large-scale use. Thus, finding a way to make Cipro less susceptible to bacterial resistance is both a compelling and essential project.