Deuterated compounds – in which a drug molecule’s carbon-hydrogen bond is replaced with a carbon deuterium bond to extend the drug’s half-life – continue to show promise in potentially boosting the bioavailability and safety of some drugs.

The deuterated compound market has attracted many new companies looking to develop and patent deuterated versions of various existing, non-deuterated therapeutic compounds—known as the “Deuterium Switch.”

What is a Deuterated Drug?
A deuterated drug is a small molecule with medicinal activity. It is made by replacing one or more of the hydrogen atoms contained in the drug molecule with deuterium – a hydrogen isotope whose nucleus contains one neutron and one proton. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made to a molecule.

To Deuterate or Not to Deuterate – That’s the Regulatory Question
Developers of deuterium switch compounds must show significant clinical benefits over existing non-deuterated versions to justify why they should replace existing or less expensive therapies. However, such a switch can:

• Take advantage of the clinical knowledge concerning the non-deuterated version of the compound
• Benefit from new patent protections
• Result in improved therapies and patient outcomes.

Did you know that most large pharmaceutical companies today also claim deuterated versions of new molecules in their patent applications?

Benefits of Deuterated Versions of Drugs
Deuterated versions of existing drugs can benefit from improved pharmacokinetic or toxicological properties. Because of the kinetic isotope effect, which is the change in rate of a chemical reaction when one of the atoms in the reactants is substituted with one of the isotopes, drugs that contain deuterium may have significantly lower metabolism rates. As the C-D bond is ten times stronger than the C-H bond, it is much more resistant to chemical or enzymatic cleavage and the difficulty of breaking the bond can decrease the rate of metabolism. Lower metabolism rates give deuterated drugs a longer half-life, making them take much longer to be eliminated from the body. This reduced metabolism can extend a drug’s desired effects, diminish its undesirable effects, and allow less frequent dosing. The replacement may also lower toxicity by reducing toxic metabolite formation.

A major potential advantage of deuterated compounds is the possibility of faster, more efficient, less costly clinical trials, because of the extensive testing the non-deuterated versions have previously undergone. The main reasons compounds fail during clinical trials are lack of efficacy, poor pharmacokinetics or toxicity. With deuterated drugs, efficacy is not in question – allowing the research to focus on pharmacokinetics and toxicity. Deuterated versions of drugs might also be able to obtain FDA approval via a 505(b)(2) NDA filing, a faster, less expensive route.

Manufacturing Deuterium Exchanged APIs

With our expertise in deuteration technology, Neuland Labs uses a synthetic approach where deuterium-enriched material is combined with the drug to produce deuterated drugs. Another approach, called an exchange approach, uses a catalyst to produce a deuterated molecule.

The most popular process for sourcing deuterium for drugs is extracting D2O from regular water via the Girdler sulfide (also known as the Geib-Spevack) process, which uses a temperature difference and hydrogen sulfide to enrich deuterium in water by up to 20%.

Deuterated Molecules Advance in Clinical Trials

While Deuteration has been around literally for decades, I mentioned in an article last year at PharmTech (Pharma APIs: It’s Still a Small World) that most deuterium chemistry efforts are currently in the pre-formulation stage.

Those deuterated compounds that have advanced are generally performing well in clinical trials. In July, a deuterated drug reached Phase III testing for the first time, in a study to treat Huntington’s disease. Known as deutetrabenazine, the drug was found to reduce the disease symptoms and the frequency of administration, and it is currently being considered for approval by the FDA.

Recently, another investigational new drug targeting nonalcoholic steatohepatitis & adrenomyeloneuropathy (a deuterium-stabilized [R]-enantiomer of pioglitazone) recently completed FDA review and appears headed towards a Phase 1 study.

Growing Opportunity for Deuterated Drugs

The current market value of companies specializing in this technology suggests that the value of “deuterium switching” could be more than a $1 billion, and that the greatest discoveries in the field have yet to occur.