Fluconzole

Darius Meiman

11/2/18

Drug Discovery, Commercialization, and Outcomes

Dr. David Feola

Fluconazole, a member of the imidazole antifungals, was originally discovered in the early 1980’s by a group of Pfizer scientists lead by Dr. Ken Richardson. The program, founded in 1978, set out to modify a previously known azole antifungal tioconazole. Other antifungals at the time consisted of amphotericin B and flucytosine, but the adverse effect profile and limited range of fungal targets limited their uses respectively. As a class the imidazole antifungals have a unique mechanism of action by inhibiting lanosterol 14 alpha-demethylase. This is an essential step in the the biosynthesis of ergosterol, a key component of fungal cell membranes. Mammalian cells membranes are much less susceptible to C14 demethylation and do not contain ergosterol in cell membranes so targeting this fungal specific sterol prevents most of the undesired effects that come with inhibiting cell membrane biosynthesis.

Most of issues that arose with earlier azole drugs was due to their lipophilicity and high protein binding. Although a high volume of distribution is favorable in many circumstances, a low free fraction can limit the amount of drug available to interact with its desired target. Oral bioavailability was a major concern as azole antifungals undergo high first pass metabolism in the liver and only a fraction of the given dose is able to reach systemic circulation. A plethora of drug interactions have been reported while taking fluconazole because of its interactions with cytochrome P450 monooxygenases, effectively raising or lower subsequent drug concentrations.

Fluconazole, trade name Diflucan, is used today to treat a wide array of fungal infections including infections of the mouth, throat, lungs, abdomen, blood, and brain. It is most predominantly prescribed for yeast infections caused by Candida Albicans. Commercially it is available in various oral and IV dosage forms, most commonly a 150 milligram oral tablet that requires one time dosing to maximize ease of administration to the patient. Due to its broad yet specific profile, it is considered first line for most common fungal infections. Common adverse effects include headache, dizziness, diarrhea, stomach pain, heartburn, vomiting, and rash. Women who are in the first trimester of pregnancy should avoid high doses of fluconazole as it has recently been changed from category C to category D with known risks to the fetus.

Areas that need the most improvement with fluconazole and future azole antifungals are mostly related to their pharmacokinetic profile. Today due to generics coming into the market, fluconazole can be used as a convenient and cheaper first line option to treat broad fungal infections. However, patients should be aware of its adverse effects and interactions with other medications.

Fluconazole was patented in the United Kingdom in 1981 by Pfizer and reached commercialization in 1988. An oral tablet and suspension was later approved by the FDA in 1990 and 1993 respectively for use in the United States. Original NDA number 019949 was approved by the FDA on January, 29th 1990. Today generic fluconazole is marketed by twelve different manufacturers which has drastically increased market competition, driving down prices. Diflucan sales were exceeding 1 billion yearly in the early 2000s. By 2005 sales had already decreased to half that at 498 million. Pfizer countered declining sales with Vfend (voriconazole), a pharmacokinetically improved azole antifungal used primarily via IV for more serious fungal infections.

In 2011 the FDA issued a warning about fluconazole use during pregnancy and advised against giving high doses due to an increased risk of birth defects. In 2016 the FDA issued a second warning stating that even at low doses the drug could increase the chances of having a miscarriage. As a result the company has been the target of multiple class action lawsuits over the years. However, this was not the first time the company has been scrutinized for dispensing medication that has led to serious life-threatening side effects. In 2009, the company agreed to dish out 2.3 billion in a settlement over the mismarketing of Bextra, along with other drugs, due to their increased risk of causing serious cardiovascular events. Bextra was removed from the market in 2005 after a similar drug, Vioxx (Merck), came under scrutiny for causing the same issues. At the time this was the largest healthcare settlement in history, only to be passed by GSK’s settlement in 2012 of 3 billion that was associated with a failure to disclose safety data and kickbacks to physicians prescribing their drugs.

Many times the cost of developing a drug, and their subsequent failures is so immense that it is much easier for a company to buy out partners with a promising pipeline. Pfizer has successfully mastered this model, being apart of 3 of the largest pharmaceutical acquisitions in history. In 2000, Pfizer acquired Warner-Lambert for approximately 110 billion, making the company the largest and fastest growing pharmaceutical company worldwide. This was followed in 2002 and 2009 when they acquired Pharmacia (64B) and Wyeth (68B) respectively.

Pfizer is a publicly traded company under the ticker symbol PFE. In 2017 Pfizer reported revenues of 52.5 million, just behind Johnson & Johnson (76.5B) and Roche (57.4B). Today research and development has approximately 100 candidates within its pipeline mainly focused towards vaccines, various cancers, and autoimmune diseases. In 2017, Viagra, Pfizer’s greatest revenue generator went generic, putting added pressure on the company to generate sales outside of their more traditional spaces of cardiovascular and antibiotics. While sales of blockbuster drugs have been able to surmount a vast amount of cash on hand the company will become increasing more dependent on the success of it’s pipeline, adding a sizeable to risk for investors.

Works Cited:

Richardson, K., Cooper, K., Marriott, M. S., Tarbit, M. H., Troke, F., & Whittle, P. J. (1990). Discovery of Fluconazole, a Novel Antifungal Agent. Clinical Infectious Diseases. 24(1), 10-27.

Debruyne, D., & Ryckelynck, J. (1993). Clinical Pharmacokinetics of Fluconazole. Clinical Pharmacokinetics. 12.

Richardson, K. (1990). The Discovery and Profile of Fluconazole. Journal of Chemotherapy. 2(1), 51-54.