Discovery, Development, and Commercialization of Carbidopa Levodopa

Discovery, Development, and Commercialization of Carbidopa Levodopa

Carbidopa levodopa is a combination of two different medicines: carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid.[1] Levodopa occurs naturally in plants, such as fava beans. However, a semi-synthetic form of levodopa is used in medicine.[2] Similarly, semi-synthetic methods are also used in the preparation of carbidopa.[3] The combinatory product carbidopa levodopa is taken by mouth 3 to 4 times daily, with its primary function being to manage the symptoms of Parkinson's disease, a chronic and progressive movement disorder. 

Parkinson's disease is thought to be caused by a deficiency of dopamine in the brain. However, because dopamine cannot cross the blood-brain barrier, the administration of dopamine is ineffective in the treatment of Parkinson's disease.[1] Consequently, levodopa helps to control movement by converting into dopamine in the brain. Levodopa is converted to dopamine via aromatic L-amino acid decarboxylase both peripherally and in the central nervous system after levodopa has crossed the blood-brain barrier. Levodopa is generally combined with carbidopa, an inhibitor of aromatic amino acid decarboxylase that cannot cross the blood-brain barrier.[4] Carbidopa thus prevents the breakdown of levodopa in the bloodstream so that more levodopa can enter the brain. 

Carbidopa can also reduce some of levodopa's side effects. While the activation of central dopamine receptors improves symptoms of Parkinson’s disease, the activation of peripheral dopamine receptors causes side effects, such as nausea and vomiting.[5] Thus, levodopa is usually combined with carbidopa to prevent the peripheral conversion of levodopa and decrease the chance of negative side effects.[6][7]

Common side effects in patients taking carbidopa levodopa include nausea, vomiting, loss of appetite, trouble sleeping, weight loss, hallucinations, dyskinesias, and depression.[1] In addition, some products may interact with the medication; these include antipsychotic drugs (such as chlorpromazine, haloperidol, thioridazine) and certain drugs used to treat high blood pressure (such as methyldopa). Furthermore, taking certain monoamine oxidase (MAO) inhibitors with carbidopa levodopa may cause a serious and potentially fatal drug interaction.[8] Alternative medications include dopamine agonists, like pramipexole, which may be used in the early stages of Parkinson’s disease. These drugs have many of the same side effects; however, such dopamine agonists do not require modification from brain enzymes to stimulate dopamine receptors, as levodopa does.[9] Nevertheless, carbidopa levodopa is still largely considered the most effective medication in the treatment of Parkinson’s disease.

            In 1960, Austrian biochemist Oleh Hornykiewicz was the first to suggest that Parkinson’s disease is associated with, or caused by, a reduction in the levels of dopamine in the brain. Since dopamine cannot enter the brain, he attempted to treat twenty patients with a racemic mixture of dihydroxyphenylalanine (DOPA), which could enter the brain and be converted to dopamine via the action of aromatic L-amino acid decarboxylase. His results were positive, as were those in another trial run by André Barbeau in Montreal. In the late 1960s, Curt Porter at Merck discovered that levodopa was the active stereoisomer of racemic DOPA, which enabled the dose to be effectively reduced to half. In 1962, Victor Lotti at Merck synthesized and patented carbidopa, and in 1971, Lotti showed that the use of the L-form of carbidopa further reduced the necessary dosage of levodopa. The combination of L-carbidopa and levodopa was marketed under the brand name of Sinemet, which was approved by the Food and Drug Administration in 1975.[10]

In addition to Sinemet, carbidopa levodopa is marketed today by over 26 other brand names, including Parkimet, Pardopa, Syndopa, Neocare, Rytary, and Duopa.[11] Among these brand names, there are many different dosage options. Sinemet was and is offered in tablet form only. Sinemet CR is offered as an extended release tablet, and Parcopa is offered as a disintegrating tablet. Among the newer advancements in Parkinson’s Disease treatment with carbidopa levodopa are Rytary, an extended release capsule, and Duopa, an extended release enteral suspension administered intrajejunally.[12] Rytary and Duopa are the most recently approved of these brand names, both approved by the FDA in 2015. Duopa, however, was approved as an orphan drug for the treatment of motor fluctuations in people with advanced Parkinson’s Disease. Duopa’s status as an orphan drug means it was given seven years of market exclusivity as is standard of approved orphan drugs.[13] It is marketed by Abbvie, a global, research-based, publicly traded biopharmaceutical company formed in 2013. In 2017, Abbvie generated 28.22 billion USD in revenue.[14]

Duopa’s approval was based on a Phase 3, 12-week, double-blind, double-placebo, active control, parallel group trial (N=71) that compared the efficacy and safety of Duopa to oral, immediate release carbidopa levodopa tablets, such as Sinemet, in advanced Parkinson's disease patients. The study showed that Duopa significantly reduced daily mean “off” time (periods when the medication is not working and symptoms are not controlled) at 12 weeks by four hours, thus resulting in an average of about 2 fewer hours of “off” time when compared to the IR tablets. Furthermore, dyskinesia, a troubling adverse effect of most carbidopa levodopa medications, was not observed as a side effect of Duopa.[14] The most common adverse events included those commonly observed for carbidopa levodopa medication, as well as complication of device insertion, incision site erythema, and post procedural discharge.

In the United States, carbidopa levodopa is available by prescription only. It is not subject to the Controlled Substances Act of 1970, and it falls into pregnancy category C. In animal studies, pregnant animals were given carbidopa levodopa, and some of the babies were born with problems. However, no adequate and well-controlled studies have been done in humans, thus carbidopa levodopa may be used while pregnant if the potential benefits outweigh the potential risks to the fetus.[17]

The generic of carbidopa levodopa is marketed by over 9 different companies. There were 2,918,441 prescriptions for carbidopa levodopa per year as of 2015, and the Parkinson’s Disease treatment market was worth 4.24 billion USD in 2017.[15][16] The Parkinson’s disease therapeutic drugs market is divided by drug class, segmented into carbidopa levodopa, dopamine receptor agonists, and MAO inhibitors, among others. By drug class, carbidopa levodopa dominated this market in 2017. The treatment market is projected to increase to 5.69 billion USD by 2022, at a compound annual growth rate of 6.1%.[15]

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