Discovery And Biosynthesis Of Cholesterol Biology Essay

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Lipitor is one of the greatest discoveries in the pharmaceutical industry. After generating a whopping $12.9 million dollars in previous years and reaches the number one staus of belling selling drug between 3002- 2004, it is going to face a downslide as itl oses its oatent exoiry in Novemebr 2011. Lipitor reduced low density lipoprotein levels in patienst sudffering from familial hyppercholesteeromia a rare genetic disoreder.From the molecule reglected by a marketingcompany to a drug giant. Pfizer settles its patenst dispute with Ranbaxy over generic forms. This report looks at the satages of the development and the future of the drug.


Cholesterol is one of the most intrinsic structures found in the mammalian body. Cholesterol falls under the category of lipids; these are molecules responsible for cellular function, storing energy, metabolism of bile acids and precursors for the production of steroid hormones and fat soluble vitamins (Vance D., 2000). Over thirteen scientists have received so many Nobel prizes owing to their discoveries in science of cholesterol (Cabit and Jasinka, 2005).

According to Li (2009) the very first samples of cholesterol were gotten in 1784 by French scientist Francois Poulletier from gall stones. From his discovery, he suggested that the substance (cholesterol) was a type of wax. However in 30 years, Michel E. Chevruel another French scientist, disagreed and proved that cholesterol could not be a wax because it could not undergo saponification like all other waxes do Li (2009). He named the substance cholesterine meaning solid bile. Austrian scientist Friedrich Reitnitzer also spent most of his years studying cholesterol and later in 1888; he discovered the empirical formula of cholesterol to be C27H45OH (Reinitzer, 1989). Following this discovery, two German scientists Heinrich O. Wieland and Adolf Windaus received nobel prizes in 1927 and 1929 for their great research which lead to the determination of the structure of cholesterol (Vance, 2000).

Fig. 1.0 Structure of cholesterol. Sourced from Li, (2009).

Unfortunately, this discovery was declared invalid by Dorothy Crowfoot Hodgkin in 1945, who disclosed the structure using the x-ray diffraction data technology (Li, 2009). However, honour was still given to the two German scientists because such a technology was unavailable. After several years of research, two scientists Robert Robinson and Robert Burns Wood ward discovered the pioneer laboratory biosynthesis of cholesterol. Konrad Bloch a German scientist, in 1959 elaborated the different stages involved in the biosynthesis of cholesterol and was given a nobel prize in 1964 He disclosed that acetic acid was the starting molecule and the biosynthesis involved a total of 36 steps consisting of various enzymes at various steps (Konrad B, 1987).

Figure 1.1. (Simplified sequence of the biosynthesis of cholesterol). Li (2009)

Cholesterol molecules are lipids, they have poor aqueous solubility; therefore they require molecules to circulate them in the blood. These molecules are known as lipoproteins. These lipoproteins enable the transfer of cholesterol in the blood from sites such as the liver to all other organs in the body. There are different types of lipoproteins which include the High density lipoprotein, the Low density lipoprotein, Very low density lipoprotein, cholimycron and the Intermediate lipoprotein (Freeman M.W and Christine J, 2005).

High Density Lipoproteins (HDL)

According to the American heart foundation, these lipoproteins enable mobility of cholesterol from the body tissues into the liver where they are converted into bile acids and excreted. HDL passes through blood vessels, thereby picking up cholesterol and transferring it into the liver. HDLs have a high ratio of proteins to fat. The American heart association recommends the level of HDL in the body should about 60mg/dl and not lowerthan40mg/dl. (,)

Low Density Lipoprotein (LDL)

These lipoproteins mediate the newly synthesized cholesterol from the liver to other organs. A molecule of LDL carries about 1500 moles of cholesterol. (Dominiczak H., 2000) They are the major circulators of cholesterol around the body. The American heart association recommends a level of 100mg/dl ldl in the body, however it has been shown that an average individual has about 127mg/dl which is quite unhealthy. High levels of LDL results in the deposition of cholesterol in the blood vessels (arteries) thereby causing a condition known as Artheresclerosis. Artheresclerosis and cholesterol were first linked by Russian scientist Nikolai Anitschkov (Anitschkov, 1965).

Very Low Density Lipoproteins (VLDL)

These lipoproteins transport newly manufactured lipids from the liver to various tissues in the body such as the adipose tissue (Freeman W. M and Christine E.J, 2005).

Intermediate Density Lipoprotein (IDL)

These set of lipoproteins acts as an interface between the VLDL and LDL. (Dominiczak H., 2000).


Their main function is the transport of lipids to the cardiac, skeletal tissue, and other body tissues (Dominiczak H., 2000).


A high level of High density lipoproteins (hdl) does not possess such a detrimental effect as having high levels of low density lipoprotein. HDL is responsible for disposing off excess cholesterol found in the body (Dominiczak H., 2000). High levels of hdl is good for the heart while high levels of ldl is toxic. When there is excess ldl in the blood stream, it gets deposited in the walls of the arteries. These deposits cause a build-up in the vessels thereby narrowing the passage of blood to organs such as the heart (Steinberg, 2005). This causes in appropriate circulation of blood in the body. Abnormally high levels of ldl is the major cause of cardiovascular diseases such as myocardial infarction (heart attack), hypercholesterolemia, atherosclerosis, angina. Hdl is the preferably lipoprotein. Studies also show that lack of physical exercise and unhealthy diets have a huge role in increasing the levels of cholesterol. (Freeman W. M and Christine E.J, 2005).


In Atherosclerosis, the walls of the arteries are filled with plaques which are as a result of ldl bonded to the walls. However, in familial hypercholesterolemia the patients lack certain mutations in a gene responsible for the removal of ldl in the blood thus causing an increase in the ldl levels in the blood (Costet, 2010). This condition is genetic. Angina pectoris causes severe chest pain which is caused by the blocking of the blood vessels which is a result of obstruction of free circulation of oxygen and blood. High ldls also stiffens the arteries thereby reducing its flexibility (Epstein FH, 1990).


Ever since the establishment of the knowledge that high level of ldl cholesterol is responsible for so many heart diseases, it had become paramount to look for ways to promote cholesterol reduction. There were so many scientists involved in this area of research and relatively crude methods compared to the available technology now, were employed. For instance, according to Li (2009) the thyroid gland; a gland responsible for the secretion of hormones was removed through surgery. Studies revealed that hypothyroidism caused a condition when the thyroid gland malfunctions thereby enabling the liver produce high levels of cholesterol. This had a severe side effect as it increased the cholesterol level so it was discontinued. A thyroid hormone dextro-thyroxine was also used in lowering cholesterol although it caused ischemic heart disease. At a point, scientists discovered that a female sex hormone estrogen could reduce cholesterol level in men. This procedure was discontinued because male patients administered with estrogen began to develop female characteristics such as breasts development, loss of male sexual desire and so on (Li, 2009). Nicotinic acid in high concentrations and resins were also used in lowering cholesterol but they all posed severe side effects (Rudolf Altschul et al, 1955).


Akira Endo was the first scientist to develop the first set of cholesterol reducing drugs known as statins. Despite this, his discovery might not have been able to occur if not for three great scientists namely Paul Ehrlich, Michael S. Brown and Joseph Goldstein. Paul Ehrich proposed the receptor theory which indicated that membrane molecules and drugs had a specific interaction (Brown et al, 2001). These findings claim that a drug can get specifically bonded to a protein membrane. This discovery is the basis for many pharmaceutical drug formulations; the drugs are created to have the right shape and property to bind to the receptor protein. In this case, the receptor protein is an enzyme, 3 Hydroxy 3 methyl glutaryl Co-enzyme A discovered by Michael Brown and Joseph Goldstein. They worked extensively in the biosynthesis of cholesterol and they identified the key steps in the synthesis and recognized 3HMGCOA enzyme to be the rate limiting step (Brown M. and Goldstein J., 1986).

According to information sourced from Time magazine 3rd April, 1964 (,9171,939476,00.html 3 1964 ) ,triparanol was a molecule used in the inhibition of sterol synthesis, however it inhibited a very important stage (penultimate stage) which caused desmerol to be accumulated in the plasma and tissues of patients treated with it.

Fig 2. Structure of triparanol (Roth, 2002)

Curan and Azarnoff in 1957 postulated that inhibition of earlier stages in the cholesterol biosynthesis was appropriate. They noted that a stage before the synthesis of squalene would be safe. On the basis of these previous discoveries, Akira Endo invented mevastatin, the first cholesterol reducing drug. He did this by isolating a metabolite from a fungi penicillium citrinum that could hinder biosynthesis of cholesterol. This was the first natural statin made (Endo, 2004). There are two types of statins, the synthetic and the natural, Mevastatin was efficacious but had severe side effects; it caused severe tumours in the intestine, so it never got FDA approval. The next statin made was levacor which was isolated from fungi aspergillus uterus. This statin was the first to be approved by the FDA and sold as mevacor. Simvastatin (Zocor) and Pravastatin (provachol) are examples of other natural statins produced from modification of mevacor and lovastatin .lescol was the first synthetic statin.


Statins function by inhibiting the slowest step in cholesterol synthesis. This step involves the conversion of HMG to mevalonate a precursor responsible for the formation of cholesterol. Statins bind to the active site of the enzyme HMG CO A, and changes the conformity thereby preventing any other substrates (Fuberg D.C, 1999). They induce the activation of a protease which cuts through the sterol regulatory element binding proteins. This allows a decrease of cholesterol in the hepatocytes, thus increasing the ldl receptors which causes a reduction of the cholesterol in the blood. (Camellia Stancu and Anca Sima, 2001).


This enzyme is a reductase and the target for so many cholesterol reducing drugs. It is found to exists as the the 3R stereoisomer. It is a membrane bound enzyme and catalyses a major step in the biosynthetic pathway. (Roth, 2002).

Conversion of (S) 3-hydroxy-3-methylglutaryl-coenzyme A to 3 (R)-mevalonic acid through a putative hemi-thioacetal.

Fig 3; Reduction of HMG-CoA by HMGR (Roth, 2002).


Biologist Roger S. Newton and Chemist Bruce D. Roth are the two prominent scientists involved in the discovery of the most successful drug Lipitor. Prior to their discovery, they had to isolate the target enzyme HMG CoA reductase by feeding rats with cholestyramine (an anion exchange resin which increases HMG-COA enzyme) (Akira, 2004). This material was chosen so as to provide them with sufficient amounts of the enzyme (Li, 2009). Mevastatin was used as their exemplar drug molecule because it used the same mechanism they intended on using. Instead of isolating potential target molecules from organisms such as fungi, they decided to manufacture their own molecules. As discussed earlier there are two types of statins; the natural and synthetic. All natural statins have a hexahydronapthalene core structure. Zocor, an example of a semi synthetic statin, has its hexahydronapthalene core replace with a diphenyl group. Faizular kathawala synthesized the first completely synthetic statin called Lescol. He replaced the core structure found in the natural statins with an indole giving rise to fluvastatin sodium (Kathawala, 1991). Unfortunately, it did not survive in the market because the chemical structure (double bonds) in its formulation caused undesirable side effects. Another scientist who paved the way for the innovation of atorvastatin was Alvin K. Willar who replaced the hexahydronaphthalene core structure with diphenyl possessing four substituents. These findings revealed that it was not necessary to have the complex hexahydronapthalene core structure and the key structures responsible for the inhibition of HMG CO a were a mevalonolactone/3,5 hydroxy-heptanoic with an adequate spacing with a lipophilic group held by a template (Roth, 2002). This was the basis of the scientists' research.On their research, they replaced the hexahydronapthalene structure with a 1H pyrrole ring because it could be easily prepared by 1,4 diketones using Paal-knorr condensation,(Li, 2009). As a result, a huge amounts of 1,2,5 trisubstituted pyrroles and flourophenylpyrrole were produced as shown in the scheme below (Roth, 2002).

According Roth (2002), exposure of the latent aldehydes by Dibal reduction was employed followed by condensation with dianion of methyl or ethylacetoacetate using the Weiler method to also introduce the remaining carbons needed in the compound. 5 hydroxyl was produced unknowingly as a racemixture , however the configurations of 3 and 5 were controlled by addition of synthetic selective reduction of β hydroxyl ketones. This produced about 10:1 syn/antidiasteromers. Recrystallization was used to exclude the pure transdiastereomer form and dihydroxy acids were added to it by hydrolysis. After the correct spatial arrangement was deduced it was found that a compound containing 4-flourophenyl in the position 2 and isopropy;l in the position 5 would be potent. Surprisingly, this compound was not as potent, so the pyrrole compound was further added into the willards diphenyl statin, however it was unable to fill up the required spacing in the core. Two compounds (3,4 dichloropyrrole analog PD 120167 and 3,4 dibromopyrrole analog PD 121149) were created by the addition of a reductase to occupy the space(Roth, 1990) . These compounds were very potent but PD-121149 was preferred because it showed greater efficacy. After this discovery, there was celebration because the scientists believed they had achieved their target molecule (Li, 2009). This celebration was cut short because early clinical trials in rats showed the compounds were toxic. The team dropped the analogs, but Roth persisted, He substituted the 2 halogens in the pyrrole structure with phenyl and phenyl amide at positions 3 and 4 respectively into a new compound named PD-123582 (Roth, 2002). Another scientist Drago Robert Sliskovic working under Roth used another methodology; he decided to substitute the pyrrole structure with pyrazzole (Sliskovic, et al, 1990). This compound was named PD-123588 but did not make it to later stages because the synthesis involved 9 steps in which two out of it produced 2 different unwanted products (Sliskovic, 1990). It was also found out another company in Switzerland had an existing patent for the compound, hence Roth's compound was chosen as the model to work on. Roth's compound was a racemixture a compound containing two stereoisomers where one is more than active than the other. This compound excelled in early clinical trials involving cholesterylamine-primed dogs that were diagnosed with hypercholesterolemia (Endo, 1992). It was then assigned a clinical number CL 971. As studies progressed, it was shown that the compound lacked bioavailability so it is was paramount to initiate chiral synthesis. Chiral synthesis was not a major challenge; however increasing the achiral parts was the problem (Roth, 2002). Accorging to Roth, (2002,) CL971 possessed two different enantiomers, and it was revealed using x-ray crystallography and total synthesis the positive stereoisomer had the inhibitory properties so it was only proper to have the active one and discard of the less active or inactive one. Seperation of these enantiomers was a great task. Scientist Sliskovic had to react the racemate with an optically pure amine R-(+)-methyl benzyl amide to produce two disesteraisomers which were separated by hydrolysis with a base NaOH alongside refluxing with ethanol (Roth, 2002). Two opticaly pure forms were obtained, the positive which was assigned PD 134298. This was concluded to be the potential lead compound. Most drug compounds are manufactured in a salt compound so as to increase the dissolution, solubility, stability and physical appearance. Atorvastatin was initially prepared with sodium (Na+) salt but it failed, it was highly hygroscopic (Li, 2009). After several trials with other ions, calcium combined with the molecule and gave it the desired properties. This compound was assigned PD-124488; it was very stable, potent and showed minimal side effects. It was also bioavailable and was finally registered as CL981 and finally became the lead compound (Li, 2009)

Structure of Atorvastatin calcium (Lipitor). (Endo, 2004)


Bruce D. Roth and Roger S. Newton worked for Parke-Davis the initial inventor company of Lipitor. They had to discover a route feasible in the lab and in large scale industry. Donald E. Butter was faced with the challenge of developing another industrial route because Roth's initial route comprised of long 17 steps. This synthetic route was not robust. It failed because it didn't produce the desired yield and the temperatures of the reactions were as low as -700C. It also failed to ascertain the appropriate level of purity (Li, 2002). Alaan Miller soon became an expert on Paal-Knorr synthesis of pyrrole. He developed a route using this reaction of a highly substituted ketone and an addition of pivalic acid as a catalyst to produce 75%yield of the pyrrole core structure both feasible in the lab and industry. A reactor had to be purchased to ensure high selectivity.


Atorvastatin calcium had two initial patents, basic patent US PAT US4681, 893 and enantiomer patent USPAT 5273995 (Israel Agranat, and Silvya R. Wainschtein, 2010). In this patent US4681,893, Roth (2002) elaborates the actual process involved in the production of the active ingredient a class of trans-6-[2-(3-or4-carboxamidosubstituted pyrrrol-1-yl)alkyl]-4-hydroxypyran-2-ones. This reaction is one in which the pyyran-2-one moiety is linked through an alkyl chain (ethylene) to the substituted pyrrole ring. The compounds structure has two asymmetric carbon centers, at positions 4 and 6 of the pyraan-2-one ring. Phenyl and a substituted phenyl are substituted at position 2, whereas the position 5 is replaced with triflouromethyl with isopropyl. Cycloaddition of the disubsituted acetylene (where one of its substituents is a carboxamido or N-substituted carboxiamido) to an adequately replaced N-acyl aminocarboxylic acid to synthesize a substituted pyrrole. The reaction may give rise to two products whereby each carboxiamido resides on the carbon 3 or 4 of the pyrrole ring. Positions 3 or 4 are linked with -CONR5R6 Where R5 and R6 are hydrogen, phenyl or a substituted phenyl.

According to US PAT 4681,893, the available α-haloesters of compound with structural formula II (in the scheme below) is coupled with 2-(1-2-aminoalkyl)-1,3-dioxalane III using triethylamine to synthesize N-alkyl- α-aminoesters, IV which undergoes acylation to produce N-acyl-N-alkyl amino acids. This product is reacted with an adequately substituted carboxiamido acetylenic compounds VI to produce stereoisomers VIIa and VIIb which are separated using crystallography and further purified by recrystallization. The next step is the hydrolysis of these compounds to synthesize an aldehyde which are reacted with either dilithium or lithio sodio salt of methyl acetateto produce 7-(substituted pyrrol)-5-hydroxy-3-oxoheptanoates. These compounds are dissolved in tetrahydrofuran and a small of trialkyl borane is added and the product is cooled to a certain temperature between 0oC and 780 C. After which it is stirred for 1-3 hours and later undergoes oxidation by adding aqueous hydrogen peroxide to produce the final product.


Fig. 4 Reaction sequence of the production of the active ingredient. (Roth, 2002)


In the US PAT 5,273,995, Bruce Roth describes how the transenantiomer form of the drug can be formed by simply dissolving the product compound (Trans-6-[2-(3-or4-carboxamidosubstituted pyrrrol-1-yl) alkyl]-4-hydroxypyran-2-ones) from USPAT 4,681,813 in an aqueous solvent with a corresponding base such as CaOH. Following is the isolation of the salt by evaporation or by a reaction involving the lactone and a base in an organic solvent where the salt can be obtained easily by concentrating the solution. This process was more precise and industrially scales able. The compound derived from process in USPAT 4,681,813 was a race mixture while this is a pure form.

Although the route discussed in USPAT 4,681,813 produced the desired product, it was not very easy to scale up in the industry. In USPAT 5003080, Alan Miller et al, (1991) describes a new and improved method of producing atorvastatin calcium. It can be produced from the conversion of 4-methyl-3-oxo-N phenylpentamide in 8 steps. The previous USPAT 4,681,813 had major setbacks because its process was more expensive, not very robust, the reactions occurred at very low temperatures and the use of reagents was too high.

According to Srinath et al, who described how an amorphous form of atorvastatin calcium involves of the addition of an aqueous NaOH to a class of group (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrroli-din-1-yl] -ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid tert-butyl ester to produce a sodium salt followed by dissolving the solution in ethyl acetates. After this is the addition of calcium acetate by simply stirring, then collecting the organic layer in order to attain a residue which is further dried to get the compound. In this case the calcium salt is readily formed.


As discussed earlier, atorvastatin (Lipitor) reduces the low density plasma cholesterol. It functions by disrupting the activities of the rate limiting enzyme. It causes a rise in the hepatic Ldl receptors thus enhancing catabolism of the Ldl. It reduces the level of triglycerides, vldl, apiloprotein B, however causing an increase in the level of hdl. Lipitor reduces the level of familial Hypercholesterolemia unlike most of the other statins. It reduces the cholesterol levels in patients associated with the disease. Atorvastatin is administered via the oral route where absorption occurs in the blood after 1 or 2 hours, and it attains peak concentration in 4hours. Absorption increases as the administered dose increases. The site for the synthesis is the liver as well as other drugs. Lipitor is best taken on an empty stomach as food decreases its absorption. It is also advised to be taken at night because studies show that high levels of ldl are secreted during this period. Lipitor is slightly soluble in water and has a bioavailability of approximately 14%. It has a low bioavailability because of its interactions in the gastro intestinal tract. Atorvastatin calcium is manufactured in different dosages such as 10mg, 20mg, 40mg, 80mg. Dosage taken depends on the level of hyperlipidaemia and age of the individual, 10mg or 20 mg is usually the initial dose (Corsini A. et al, 1999).

Atorvastatin calcium has a strong affinity for proteins; up to 98% is bound to a protein. This affects their distribution. Atorvastatin is metabolized through cytochrome P450 3A4 hydroxylation to produce an active ortho- and parahydroxylated metabolites. These metabolites account for 70% of HMG-CoA reductase activity. Atorvastatin also inhibits cytochrome 3A4. Excretion of atorvastatin occurs in the bile and very minute (less than 2%) amount is found in the urine. Studies reveal that positive results are observed within 2- 4 weeks after continuous administration of the drug atorvastatin calcium.


Atorvastatin has proven to be efficacious in humans of all ages except patients over 70 years where it has shown some negative effects. Minor side effects of lipitor include weakness, rash, headaches, chest pain, abdominal pain, dizziness, infection in the urinary tract. Atorvastatin has a serious negative effect with patients suffering from liver disease (Clarke and Mills, 2006). It is also not recommended in breastfeeding women. Rhabdomolysis is one of the severe negative effects although it is quite rare, it causes tearing of the muscle tissues (Rodriguez, 2000). It is often a result of an interaction between atorvastatin and another drug. Other severe effects include deafness and breast enlargement in men. Atorvastatin has fatal drug interactions with antibiotics such as erythromycin, clarithromycin, and certain antifungals, ketoconazole, itraconazole, posaconazole. Atorvastatin also has fatal effects when taken with fibrates. Adverse drug reaction reports from the UK Committee on Safety of Medicines reveal that four deaths due to hepatobiliary disease (0.5deaths per annum) have been reported in association with atorvastatin treatment over 8 years.



After the drug was proven to be safe and effective in animals, it became necessary to test it in human beings before approval would be given. This involved a series of clinical trials. The phase 1 clinical trial involved a total of 24 men with no signs of any illness, who were also employees of the company (Parke Davis). They were administered 2.5g, 5g, and 10mg of atorvastatin for a single day. As this administration progressed, blood tests, E.C.G and urinalysis were carried out on the men. The one day dosage had no adverse effects on the individuals. This trial was assigned CL-981. The next step was to increase the administered dosage to 20, 40, 80 and 120mg per day. The 120mg dose created an adverse effect, hence it was suspended immediately and concluded that 80mg/day would be the maximum dosage. Following this early success, the same dosages were administered for a longer duration (1-2 weeks daily). The results were also impressive and turned out to be more efficacious in man than animals. At 80mg/day, the cholesterol level in the individuals dropped by 58%. No previous statin had achieved this result (Lie, 2009).

Figure 4. the early clinical trial of Lipitor; Comparisons of the LDL-Cholesterol by dose and week of study Pfizer. (Li, 2009).


The next agenda was the phase 2 clinical trials which involved 81 patients and six separated trials. 81 patients were given 2.5, 5, 10, 20, 40,80mg and placebo at random daily for 8 weeks. It was discovered that the blood cholesterol level declined in patients administered with the minimum dosage 2.5mg/day and maximum dosage 80mg/day by 25% to 60% (Narwocki et al, 1995).Phase 2 clinical trials were brilliant, so phase 3 clinical trial was deemed necessary.


This took another turn than the regular phase 3 clinical trial; Parke Davis decided to test the efficacy with other statins in the market. This data was gotten from Donald Black safety's profile data, he was in charge of clinical trials at Parke davis .They conducted over 21 clinical trials and recruited about 3802 individuals from all over the globe. They administered atorvastatin calcium and other statins to the patients and ensured that none of the individuals could give birth at that period (Nawrocki et al, 2000). 2502 patients were administered atorvastatin at different dosages. The remaining 1300 patients were administered the three other statins. In this clinical trial, there was no death; however some patients were withdrawn because they showed adverse effects. Out of the 21 clinical trials, 15 involved patients who had hypercholesterolemia with an ldl level greater than 135mg/dl. Within 2years results were out and it showed the atorvastatin was efficacious within a large number of people and was also equally or even a better cholesterol drug (Black et al, 1998). An unusual phase4 clinical trial was conducted. This will be discussed later.


After all the positive results were compiled, and sent to the FDA, there was an obstacle the Parke Davis team had to face. There were already four statins in the market so the FDA felt it was not reasonable to bring Lipitor in the market unless it proved different. At the time, familial hypercholesterolemia of cholesterol was not treatable by any statin. Shortly after this, clinical trials were conducted on children suffering from the disease and the results were excellent.Li(2009) Lipitor reduced the ldl levels thus increasing the life expectancy rate in the babies. After the efficacy of Lipitor was well accepted, approval was given in 1996; however it wasn't licensed until 1997 in the UK.


The company could not achieve this goal because they lacked the finance and strength to give the desired aggressive marketing. They decided to consult different pharmaceutical giants such G.S.K, Pfizer, Rhome poulene and so onut it turned it down because they had no faith in Lipitor (Li, 2009). After series of hurdles, Pfizer agreed to be the backbone behind the marketing of the drug. Preceding this Warner lambert and Parke davis had already merged. After this collaboration, the drug was finally launched and it performed beyond expectation in sales. Pfizer went further buy purchasing both companies for an enormous 90.27 billion dollars after so many court battles with other potential buyers (Morrow, 1999).

One of the gimmicks employed by Pfizer was taking Lipitor above the phase 3 clinical trials into a phase 4 clinical trial so as to prove the efficacy and show the world it is a better stain than the others in the market. This clinical trial involved 80,000 people from all over the diaspora. The trial was titled "PROVE IT". The people were patients suffering from cardiovascular diseases. This trial boosted the hierarchy of Lipitor to be the most efficacious statin, because it was the only statin to enable patients regain a healthy status quicker than other statins. Lipitor performed better than any other statin in the market. A series of other synthetic stains were produced after Lipitor. Statins such as cerivastatin (baycol), rosusvastatin (Crestor). However, studies revealed these statins weren't as efficient as Lipitor and even baycol had to be removed from the market because of its severe side effects and catastrophic interactions when administered with lopoid (Li, 2009). Lipitor's sales continued to top the charts. Lipitor dominated the statin market with a whopping 55% while a drug like Crestor dominated with only 7%.

Since the birth of simvastatin, most medical practitioners now rank simvastatin to atorvastatin (Lipitor). This caused slight downside in the growth of lipitor. Emerson (2006) observed that while Lipitor declined by 10% between June 30 and July 07, 2006, its counterpart simvastatin grew by 80%.



Manufacturing Company

Sales (2005)














Merck &co.







BMS 500







Astra Zeneca














Merck &co.









Table 1. Market assessment of the various statins between 2004 and 2005

BMS - Bristol Myers Squibb Source: IMS MIDAS sales data, IMS Health, March 2006. (Emerton, 2006)

The recommended cholesterol levels were revised by the National Institutes of health and concluded new recommended levels of cholesterol in the body. The levels were lowered, and this boosted the sales of Lipitor because more people fell under the category of people with potential cardiovascular disease. The recommended level was now 130mg/dl.


After Pfizer's 400 phase 4 clinical trials, Lipitor became the highest selling drug between 2002 and 2004. According to annual sales date from Pfizer, its sales grew enormously over the years from $1billion in 1997, to $2.2 in1998 to $2.7 in 1999, to $5.03 in 2000, $6.45 in 2002, $7.9 in 2003, $ 9.23, 10.9 2005, 12.2 in 2006 12.9 in 2007 12.8 billion in 2008.

Annual sales of data from 1997 to 2007, information from Pfizer. (Li, 2009)







Lipitor (Atorvastatin)





Zocor (Simvastatin)





Plavix (Clopidrogel

BMS and Sanofi Adventis




Norvasc (Amoldipine)





(Magoon k, 2005)

Lipitor tops the chart in 2002 to 2004 as the highest grossing drug.


Lipitor was under protection by two patents, US Patent 4,681,893 and US Patent 5,273,995. A patent protects the rights of the inventor of the drug so as to regain all the funds spent on r&d /clinical trials and also make profit (Hammond, 2010). A patent protection usually lasts about 20 years. Years before the expiry of the patent of Lipitor, an Indian pharmaceutical company Ranbaxy, planned a release a generic form of the drug before the expiry of the patents. Generic is a copycat of the inventive patent formulation. Ranbaxy summarized that the claim on the enantiomer form of the drug was invalid and there was no evidence of a key steps for its invention (Agrant I and Wainchestein S.R, 2010). Different countries have different patent laws. When this case was filed in Australia and the UK, the courts ruled out stating the enantiomer patent of the drug was invalid because it lacked novelty, however the basic patent would be infringed on by any generic at that time (Agrant I and Wainchestein S.R, 2010). In the U.S, the court declared that Ranbaxy's generic was an infringement to both the basic and enantiomer patent. After several appeals, it was reached that Ranbaxy's generic only affected the basic patent (Berenson, 2005).

After several court battles, Pfizer and Ranbaxy reached a concession. Pfizer insisted that the release of the generic form of Lipitor be postponed to November 2011 and Ranbaxy was given an exclusive opportunity to sell caduet (a combination of Lipitor and amlodipine) seven years before its patent expiration (Li, 2009). This was a victory for Pfizer because it was still going to be able to sell Lipitor and Ranbaxy was going its products as well.


The expiry of a patent is every pharmaceutical company nightmare. It is predicted that Pfizer would experience an inevitable profit loss in sales of Lipitor since other competitors would be able to market and sell the same drug using other brand names and possibly improving on it. Sales of Lipitor and market value of Lipitor are expected to drop by 50 %( Duncan Emerton, 2005). The company is predicted to lose its share values as it loses patent protection (Berenson and Pollack, 2006).


Lipitor has continued to be the preferred statin. However there are has being some minor setbacks for the company. Pfizer had to recall over 360,000 bottles because of an error during processing. The Lipitor packs had a pungent smell so most of it was recalled. Chewable forms of Lipitor have been recently approved by the FDA. Pfizer has continued to carry out several clinical trials in adults, children and elderly people so as to increase awareness about the drug's efficacy before it loses its patent in November 2011.