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Posts Tagged → Teva

On Birth Control,“Plan B,” and…Batman

The “morning-after” pill, used to prevent conception when other planning methods fail, became a political lightning rodlevonorgestrel this week. Reports by Pharmalot, NPR, Reuters, and many others relate how the Secretary of the U.S. Department of Health and Human Services blocked an FDA recommendation to provide over-the-counter access to this treatment to a wider range of patients (currently, women under the age of 17 must have a prescription to obtain Plan B).

After the uproar generated by the announcement, I wondered what, exactly, was this contentious molecule, and what did it do?

In the US, hospitals administer Plan B as two small pills, each with a 750 μg dose of the synthetic hormone levonorgestrel. First approved by the FDA in 1999, levonorgestrel prompted several companies, among them generic manufacturers Barr, Watson, and Teva, to jump in as suppliers in the ensuing decade. According to a 2011 Teva patent, Plan B is most effective when taken within 72 hours of when a person’s first-line contraceptive fails. The FDA estimates its success rate at 80-90%.

Levonorgestrel binds to the same receptors as other sex hormones (think estradiol or progesterone), and prevents ovulation or impairs fertilization of egg cells. Some researchers believe that Plan B prohibits already-fertilized eggs from adhering to the endometrium (uterine inner wall), which might prevent further embryonic development leading to pregnancy. In fact, a large dose of 17-α-ethinylestradiol (EE) – the main ingredient in most birth control pills – can sometimes be used “off-label” to achieve the same effect.

DESThe uncertainty over whether Plan B actually terminates pregnancies brings it onto similar ground with mifepristone (RU-486) and diethylstilbestrol (DES). These two drugs, previously popular options for emergency contraception, have mixed public perception today; many associate RU-486 with abortion, and DES with endocrine disorders and tumor formation in offspring.

Chemistry Note: It’s humbling to watch Mother Nature re-use the same chemical templates over and over, and that small changes in the overall steroid structure lead to huge biochemical consequences. Like Batman, with his never-ending supply of utility-belt gadgets, the steroid core structure can be tweaked in seemingly endless ways to produce biologically active molecules. I would have to devote (several) more posts to just how many modifications, but think about the effects simple oxidation (bile acids), ring expansion (cortistatins), or conjugation (sulfonated sterols) have on biological processes.

Desogestrel

The sex hormones have been puzzling synthetic chemists for nearly 100 years; in fact, two prominent chemists spent large portions of their careers perfecting the introduction of a single methyl group into the steroid core! Levonorgestrel claims “second-generation” hormone status; next-gen progestins, such as desogestrel, do away completely with C-3 oxygenation, and sport a new alkene at C-11. These new atomic decorations lead to improved side-effect profiles and lower the overall EE dose in combined pill formulations.

Update (6:05PM, Dec 9, 2011) – Changed “mg” to “μg”  (Thanks, Ed!) 

Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12

Biogen Idec made a splash last week when its oral medication for multiple sclerosis (MS), BG-12, was found to reduce relapses in 44-53% of nearly 3,800 patients in two separate Phase 3 clinical trials (CONFIRM and DEFINE, respectively). Continued hopes for an orally available, non-injectable MS treatment have created a race between Biogen Idec and several other firms, as C&EN’s Lisa Jarvis examines in a 2009 MS cover story. In fact, so much has changed in 2 years that two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition.

So what’s the secret sauce behind BG-12? Many pharmaceuticals are small molecules with multiple heteroatoms and aromatic rings, but not BG-12: it’s just dimethyl fumarate! A search for ‘fumarate’ on pubs.acs.org returned >4800 hits, which gives you an idea of its common use in several organic reactions: [3+2] cycloadditions, Diels-Alder reactions, and Michael additions. Interestingly, dimethyl fumarate is the all-E stereoisomer; the Z-configuration, where the two esters are on the same side of the central double bond, goes by the tagline ‘dimethyl maleate’ and does not seem to possess anti-MS effects.

Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects (see Derek Lowe’s 2005 article regarding the FDA “approvability” of several common drugs today). Toss in BG-12’s alkylating behavior to boot (fumarates can interact with nucleophilic amines or sulfides at multiple sites, including enzyme active sites), and you have to wonder how it functions in the body. Well, so do scientists. A 2011 review implicates up to 3 potential biochemical mechanisms – the Nrf2 pathway Lisa mentioned in the 2009 piece, T-helper phenotype 2 interleukin upregulation (IL-4, IL-10, IL-5, which “change gears” for immune system functioning), and CD62E inhibition, which controls adhesion of blood cells to inflammation sites.

Side notes: Flavoring chemists have added fumaric acid, the parent diacid of BG-12, to industrially-prepared foodstuffs such as baking powder and fruit juices since the 1930s. A darker side of dimethyl fumarate emerges when you consider its non-medicinal use: certain furniture companies applied it to new upholstered chairs and sofas to stop mold growth. This unfortunately caused several cases of severe skin irritation, which a 2008 exposé in London’s Daily Mail likened to actual burns.

 

Generic Lipitor Is All In The Crystal Forms

Lipitor’s got generic competition… at least in Canada. Reuters Health is reporting that three companies-Apotex, Teva, and Watson Pharmaceutical- have been authorized to distribute their generic cholesterol-battling wares in the U.S.’s neighbor to the north, where brand-name Lipitor last year enjoyed annual sales just over $1 billion. Pfizer says it plans to launch its own generic.

It’s a story that will get many pharma-watchers thinking about November 2011. That’s when Lipitor, the #1 drug in the world in terms of sales, loses its marketing exclusivity in the U.S., making it possible for still more generics to get a piece of that pie.

What’s interesting from a chemical standpoint is how Apotex told Reuters it was able to find a loophole in Pfizer’s patents. The company says it developed its own crystal form of Lipitor, which they’re selling under the name of Apo-Atorvastatin. The active ingredient in Lipitor is a molecule by the name of atorvastatin calcium. Here is a patent filed in 2001 from Teva for Atorvastatin hemi-calcium form VII. It has a decent discussion of the different crystal forms of atorvastatin known at the time and the pros and cons of their different properties.

The crystal form strategy is nothing new, as C&EN’s Ann Thayer wrote back in 2007.

Drug developers also want to identify and characterize as many [crystalline] forms of their proprietary compounds as possible. Beyond offering choices for optimal physical properties, each form may be patentable.

Drug companies usually file patents on all the different forms during development. Thus, when initial patents on the compound itself expire, they can conceivably extend a product’s life by moving to another form. In turn, generic drugmakers will target unprotected forms to avoid patent infringement. Nevertheless, high-profile lawsuits around GlaxoSmithKline’s Zantac and Paxil and Bristol-Myers Squibb’s cefadroxil have hinged on solid-form issues.

Read the entire article to learn more about the importance of different crystalline forms in drug development. Still want more? Here’s a particularly acrimonious tale about different forms of aspirin.