Prulifloxacin

Prulifloxacin

Systematic (IUPAC) name
(RS)-6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	Rx-only (Japan, Italy)
Routes	Oral
Pharmacokinetic data
Metabolism	By esterases, to ulifloxacin
Half-life	7.7 to 8.9 hours
Excretion	Renal and fecal
Identifiers
CAS number	123447-62-1 Y
ATC code	J01MA17
PubChem	CID 65947
UNII	J42298IESW Y
Chemical data
Formula	C21H20FN3O6S
Mol. mass	461.463403 g/mol
Y (what is this?)  (verify)

Prulifloxacin is an older synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class^[1][2] undergoing clinical trials prior to a possible NDA (New Drug Application) submission to the U.S. Food and Drug Administration (FDA). It is a prodrug which is metabolized in the body to the active compound ulifloxacin.^[3][4] It was developed over two decades ago by Nippon Shinyaku Co. and was patented in Japan in 1987 and in the United States in 1989.^[5][6]

It has been approved for the treatment of uncomplicated and complicated urinary tract infections, community-acquired respiratory tract infections in Italy and gastroenteritis, including infectious diarrheas, in Japan.^[3][7] Prulifloxacin has not been approved for use in the United States.

History

In 1987 a European Patent (EP 315828) for prulifloxacin (Quisnon ) was issued to the Japanese based pharmaceutical company, Nippon Shinyaku Co., Ltd (Nippon). Ten years after the issuance of the European patent, marketing approval was applied for and granted in Japan (March 1997). Subsequent to being approved by the Japanese authorities in 1997 prulifloxacin (Quisnon) was co-marketed and jointly developed in Japan with Meiji Seika as licensee (Sword).^[6]

In more recent times, Angelini ACRAF SpA, under license from Nippon Shinyaku, has fully developed prulifloxacin, for the European market.^[8] Angelini is the licensee for the product in Italy. Following its launch in Italy, Angelini launched prulifloxacin in Portugal (January 2007) and it has been stated that further approvals will be sought in other European countries.^[9][10]

Prulifloxacin is marketed in Japan and Italy as Quisnon (Nippon Shinyaku); Sword (Meiji); Unidrox (Angelini) and generic as Pruquin.

In 1989 and 1992 United States patents (US 5086049) were issued to Nippon Shinyaku for prulifloxacin. It was not until June 2004, when Optimer Pharmaceuticals acquired exclusive rights to discover, develop and commercialize prulifloxacin (Pruvel) in the U.S. from Nippon Shinyaku Co., Ltd., that there were any attempts to seek FDA approval to market the drug in the United States. Optimer Pharmaceuticals expects to file an NDA (new drug application) for prulifloxacin some time in 2010. As the patent for prulifloxacin has already expired, Optimer Pharmaceuticals has stated that this may have an effect on the commercial prospects of prulifloxacin within the United States market.^[11]

Licensed uses

Prulifloxacin has been approved in Italy and Japan, (as indicated), for treatment of infections caused by susceptible bacteria, in the following conditions:

Italy

• Acute uncomplicated lower urinary tract infections (simple cystitis)
• Complicated lower urinary tract infections
• Acute exacerbation of chronic bronchitis

Japan

• Gastroenteritis, including infectious diarrheas

Other countries

• Prulifloxacin has not been approved for use in the United States, but may have been approved in other Countries, other than that which is indicated above.

Availability

Prulifloxacin is available as:

• Tablets (250 mg, 450 mg or 600 mg)

In most countries, all formulations require a prescription.

Mechanism of action

Like other fluoroquinolones, Prulifloxacin prevents bacterial DNA replication, transcription, repair and recombination through inhibition of bacterial DNA gyrase.

Quinolones and fluoroquinolones are chemotherapeutic bactericidal drugs, eradicating bacteria by interfering with DNA replication. The other antibiotics used today, (e.g., tetracyclines, lincomycin, erythromycin, and chloramphenicol) do not interact with components of eukaryotic ribosomal particle and, thus, have proven not to be toxic to eukaryotes,^[12] as opposed to the fluoroquinolone class of drugs. Safer drugs used to treat bacterial infections, such as penicillins and cephalosporins, inhibit cell wall biosynthesis, thereby causing bacterial cell death, as opposed to the interference with DNA replication as seen within the fluoroquinolone class of drugs.

Quinolones are synthetic chemotherapeutic agents that have a broad spectrum of antimicrobial activity as well as a unique mechanism of action, resulting in inhibition of bacterial DNA gyrase and topoisomerase IV. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily via porins and, therefore, are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria, DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV. However, there is debate concerning whether the quinolones still have such an adverse effect on the DNA of healthy cells, in the manner described above, hence contributing to their adverse safety profile. This class has been shown to damage mitochondrial DNA.^{[13][14][15][16][17][18][19][20]}

Contraindications

There are only four contraindications found within the package insert: ^[21]

• "Prulifloxacin is contraindicated in patients with anamnesis of tendon diseases related to the administration of quinolones."

• "Prulifloxacin is contraindicated in persons with a history of hypersensitivity to Prulifloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components."

• "Prulifloxacin is contraindicated in subjects with celiac disease."'

• "Prulifloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, and in patients with epilepsy or other seizure disorders."

• Pregnancy

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason the fluoroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The fluoroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child, which may increases the risk of the child suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.^[22][23]

• Pediatric population

Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of fatalities^[24] as well as permanent injury to the musculoskeletal system, with two exceptions. However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Within the United States, the FDA has stated that it is their intention to pursue the licensing of the fluoroquinolones for pediatric use in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population.^[25]

• Depression and anxiety disorders

Prulifloxacin has highly pronounced side-effects in people suffering from panic disorder or/and depression. There have been reported cases of psychosis, suicide attempts, panic attacks and acute anxiety, all occurring during or shortly after fluoroquinolone treatment. Patients with previous or current psychiatric conditions, are prone to experiencing this type of side-effect. Caution is highly advised.

Special precautions

"As with other quinolones, exposure to the sun or ultra-violet rays may cause phototoxicity reactions in patients treated with prulifloxacin."^[21]

"When treated with antibacterial agents of the quinolone group, patients with latent or known deficiencies for the glucose-6-phosphate dehydrogenase activity are predisposed to hemolytic reactions."^[21]

Adverse Events

There is limited data to be found within the literature, (other than older animal studies) regarding the tolerability of prulifloxacin and what is stated appears to be contradictory.

Within one review prulifloxacin was stated to have a similar tolerability profile to that of ciprofloxacin.^[26] Within another study it was found that prulifloxacin patients experienced a larger number of adverse reactions as compared to those in the ciprofloxacin group (16% vs 12.5%). Of the four serious adverse events in the prulifloxacin group one was diagnosed as cardiorespiratory insufficiency which resulted in the death of the patient, although this death was not believed to be related to prulifloxacin.^[27] Ciprofloxacin has an adverse drug reaction rate (one or more reactions) of 16.5%^[28] as well as a Black Box Warning concerning spontaneous tendon ruptures.^[29] The FDA has requested that all drugs within this class carry such a Black Box Warning, and prulifloxacin would be no exception should it be approved for use in the United States in the future.^[30]

As previously noted the FDA had recommended that sponsor conduct a study to determine the effect of prulifloxacin on the prolongation of the QT interval, a condition that is associated with potentially life-threatening cardiac arrhythmias and death.^[31] The results of one such cardiac study stated that "...prulifloxacin at steady state after therapeutic doses has no significant effects on the QTc interval and thus should prove to have no cardiac liability."^[32] The results of this trial were challenged by Malik et al. who questioned the validity of using an ECG study to prove the cardiac safety of the drug.^[33] Other drugs within this class (i.e. grepafloxacin, sparfloxacin, moxifloxacin, levofloxacin, gatifloxacin, gemifloxacin) have also been associated with QT interval prolongation, resulting in sudden death of the patient. Grepafloxacin and Sparfloxacin were removed from clinical use due to this adverse event. ^[34]

The United States sponsor reports that patients treated with prulifloxacin have experienced serious drug-related side effects including renal toxicities, cardiac arrhythmias, photosensitivity, and central nervous system effects, such as seizures.^[31]

Future clinical trials, which will involve testing in larger patient populations, may reveal a high prevalence of these or other side effects. In such an event, clinical trials would be interrupted, delayed or halted by the U.S. FDA or comparable foreign regulatory authorities. Such regulatory agencies could then prevent further development of prulifloxacin or ultimately deny its approval. The sponsor of prulifloxacin has stated that such a delay or denial would significantly harm the commercial prospects of prulifloxacin.^[35]

History of the black box warnings

Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid.^[36] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.^[37] In response to a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated that the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."^[38]

By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA prompting the agency to act.^[39] Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.^[40]

Nine years later, in 2005, the Illinois Attorney General filed a second petition with the FDA again seeking Black Box Warnings and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter.^[41] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for Black Box Warnings by filing a third petition requesting such changes be made.^[41][42] When the FDA failed to respond to these two petitions as required by law Public Citizen, in January 2008, filed suit to compel the FDA to respond to their 2006 petition.^[43][44] On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding spontaneous tendon ruptures, and to develop a Medication Guide for patients.^[45] The package inserts for Ciprofloxacin, Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on September 8, 2008 to include these new warnings.^[46] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.^[47] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.^[48] through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.

Interactions

• Probenecid: Prulifloxacin urinary excretion decreases when concomitantly administered with probenecid.^[21]

• Fenbufen: The concomitant administration of fenbufen can cause increased risk of convulsions.^[21]

• Hypoglycemic agents: May cause hypoglycemia in diabetic patients under treatment with hypoglycemic agents.^[21]

• Theophylline: May cause a decreased theophylline clearance.^[21]

• Warfarin: May enhance the effects of oral anticoagulants such as warfarin and its derivatives.^[21]

• Nicardipine: May potentiate the phototoxicity of prulifloxacin.^[21]

Overdose

In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage; the patient should be carefully observed and given supportive treatment.^[21]

Pharmacokinetics

Prulifloxacin 600 mg achieves peak plasma concentration (Cmax) of ulifloxacin (1.6μg/mL) in a median time to Cmax (tmax) of 1 hour. Ulifloxacin is ≈45% bound to serum proteins in vivo. It is extensively distributed throughout tissues and shows good penetration into many body tissues. The elimination half-life (t1/2) of ulifloxacin after single-dose prulifloxacin 300–600 mg ranged from 10.6 to 12.1 hours. After absorption from the gastrointestinal tract, prulifloxacin undergoes extensive first-pass metabolism (hydrolysis by esterases, mainly paraoxonase to form ulifloxacin, the active metabolite). Unchanged ulifloxacin is predominantly eliminated by renal excretion. Quoting from the available package insert.^[21]

See also

• Adverse effects of fluoroquinolones

References

Bibliography

• "Annual Report 2008". Optimer Pharmaceuticals, Inc. Retrieved 2010-04-08. 

PDF File

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