Voriconazole

1.     Development

In order to explain how Voriconazole was discovered, we first need to think about the drug that Voriconazole was derived from, Fluconazole. Fluconazole is an anti-fungal that inhibits fungal sterol C-14 demethylation which directly affects the fungi’s ability to reproduce. Pfizer lead the research to find a convenient and safe antifungal for systemic infections. The researchers decided to focus their work on azoles (found as a microbial natural product [1]) which were already known to inhibit C-14 demethylation. Around this same time, ketoconazole was announced to be active when administered orally. This discovery lead researchers to investigate compounds similar to ketoconazole. It was soon found that triazole tertiary alcohol derivatives had better activity in animal models and were less susceptible to metabolism. After varying the functional groups, four compounds were found to have a long enough half life to be useful in a human. Only one of these compounds turned out to be water soluble, Fluconazole. [2]

            However, Fluconazole came with some major problems. Some of the major problems with Fluconazole included a limited spectrum of antifungal activity and Fluconazole-resistance fungi. It was clear that a modification was needed in order to fix the problems associated with the old compound. Voriconazole was derived from Fluconazole by replacing one functional group with another. This switched made it so that this antifungal is effective against a very wide range of fungi. Voriconazole can be administered intravenously and orally which makes it a very attractive drug on the market. [3]

2.     Drug Interactions and Adverse Effects

            Despite all of the ground-breaking work that went into the development of Voriconazole, there are some major problems associated with its use. One of these problems includes its potential for drug interactions. Because Voriconazole is metabolized by CYP450 isoenzymes, inducers of this enzyme should not be co-administered. Co-administration can result in high losses of Voriconazole levels thus making it virtually ineffective. In addition to this, Voriconazole can inhibit metabolism of other drugs causing toxic levels in some cases. Along with adverse drug interactions, Voriconazole has various adverse effects. Some of these include reversible disturbance of vision, mild skin rashes, and elevations of hepatic enzyme levels. [3]

            The most compelling aspect of the discovery pathway for future modification for Fluconazole is modification of the spectrum of fungi affected by this drug. It is interesting to see that a such a small change like switching the functional group can cause a drug to become just generally better than the previous drug. However, the improvements don’t stop here. Voriconazole still has a major drug interaction problem that could cause a patient to have to use lower doses of their regular drugs. Future advancement in this area should still be researched whether it be finding a new drug or modifying an old one.

3.      Commercial Aspects

Prior to the release of voriconazole, the medical field lacked a medicine that was broad spectrum enough to eradicate many severe fungal infections. One of the most common branches of API’s for fungal infections was azoles. While azoles did a good job of inhibiting fungi, they were not functional on many species of fungi which thus required a new API to be discovered. Knowing about this common problem, Pfizer Inc. decided to begin modifying previously known azoles. This research led them to a Fluconazole-derived compound called Voriconazole.

            In September of 1999, Pfizer was rewarded a patent on Voriconazole and then subsequently began work on the development. [4] After many clinical trials, the FDA approved the drug for Oral, I.V., and Oral Suspension use on the market in December 2003. [5] The early 1990’s proved to be a very profitable few years for Pfizer because of the many drugs that were discovered in those years. Being that voriconazole was developed on the tail end of that period, Pfizer had many funds to pilot unpopular drugs through to the market in the early 2000’s. According to the United States Securities and Exchange Commission (SEC), Voriconazole (branded as Vfend) earned Pfizer a total revenue of $203 million in the first nine months of 2004. While this seems like a large revenue for a drug, the SEC also reports that Pfizer’s Lipitor earned $7,598 million and Diflucan (Fluconazole) earned $805 million in the same period. [6] With the large number of other drug products on the market at the time, Pfizer earned a total revenue of $ 37,593 million in the first nine months of 2004 making it one of the largest biopharmaceutical companies at the time. [6] Also, at this time, Pfizer was in the middle of merging with Pharmacia in order to gain full rights to Celebrex. This merger was predicted to increase revenues by 14% in 2004. [7]

4.     Intellectual Property

      In 1999, Pfizer was awarded a patent for pharmaceutical formulations containing Voriconazole meaning that Voriconazole was restricted to use by Pfizer only. [4] This patent allowed Pfizer to continue work on Voriconazole until they could get it approved by the FDA. Interestingly, this patent was filed internationally in 1998 in order to protect the drug from early generics. The company received a patent from the European Patent Office and also one from the World Intellectual Property Organization. [4] All three of these patents helped to protect the drug and quickened the amount of time it took to market. Because Voriconazole was pursued to be sold in international markets Pfizer pursued a PCT patent specifically making it easier to file for protection in any of the participating countries. [4]

      Once it was more certain the Voriconazole was going to make it to market, Pfizer decided on a name for the medication and filed for a trademark. Pfizer was granted a trademark on the Vfend design in June 2001. [8]

5.     Regulatory Information

            Voriconazole has not experienced any recalls while it has been on the market but does have some noteworthy adverse effects as listed in section 2. Concerning the preclinical data, Voriconazole main concern in toxicity is with the liver. Because voriconazole is cleared almost entirely hepatically, it is important to avoid overdosing the drug to avoid building up the liver. [9] Despite this finding Voriconazole is not toxic to the body at low concentrations.

The clinical data has shown that there were a few uncommon instances when volunteers had severe hepatic reactions and had to discontinue use. It was found that these reactions occurred more frequently in patients that had underlying medical conditions. [10] Another important finding in clinical trails is that Voriconazole is not safe for children under 12. Due to the variability of hepatic enzymes in the population, it is too difficult to dose small children safely. While testing voriconazole in pediatric patients, there were three cases of accidental overdose in the clinical trials. [11] Voriconazole was tested on a wide variety of population sizes. [11]

Because of the limited time period of patents, it was inevitable that Voriconazole’s patent protection would expire at some point. The patent expired in June of 2018 thus relinquishing Pfizer’s control over Voriconazole. [4] Because generic products are so desirable to the consumer and reduce the overall cost of the drug, Pfizer’s patent was challenged on many notable occasions. The most notable ended in Pfizer cutting a deal with Mylan Pharmaceuticals Inc. and Matrix Laboratories Ltd. in 2009 allowing them to produce a generic version of the tablet form of Voriconazole. [12]

References

1.         Vicente, M.F., et al., Microbial natural products as a source of antifungals. Clin Microbiol Infect, 2003. 9(1): p. 15-32.

2.         Richardson, K., et al., Discovery of fluconazole, a novel antifungal agent. Reviews of infectious diseases, 1990. 12(Supplement_3): p. S267-S271.

3.         Saravolatz, L.D., L.B. Johnson, and C.A. Kauffman, Voriconazole: A New Triazole Antifungal Agent. Clinical Infectious Diseases, 2003. 36(5): p. 630-637.

4.         Pfizer Inc. (2003). Pharmaceutical formulations containing voriconazole. US6632803.

5.         Drugs@FDA: FDA Approved Drug Products. (2018). Retrieved from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021630

6.         Pfizer 3 Q 2004 10-Q. (2004). Retrieved from https://www.sec.gov/Archives/edgar/data/78003/000007800304000338/q3-04pfe1.htm

7.         PHARMACIA CORP./PFIZER INC.: TEXT OF PRESENTATION. (2002). Retrieved from https://www.sec.gov/Archives/edgar/data/67686/000095012302009108/y64098e425.htm

8.         VFEND Trademark of Pfizer Inc. Serial Number: 76269065 :: Trademarkia Trademarks. (2018). Retrieved from https://www.trademarkia.com/vfend-76269065.html

9.         Vfend, INN-voriconazole-Scientific Disccusion. (2005). [PDF]. Retrieved from https://www.ema.europa.eu/documents/scientific-discussion/vfend-epar-scientific-discussion_en.pdf

10.       Vfend Information, Side Effects, Warnings and Recalls. (2016). Retrieved from https://www.recallguide.org/drug/vfend/

11.       21630 Vfend label. (2003). [PDF]. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/21630_vfend_lb.pdf

12.       Daly, E. (2009). Pfizer Settles With Mylan Units Over Generic Vfend - Law360. Retrieved from https://www.law360.com/articles/128191/pfizer-settles-with-mylan-units-over-generic-vfend