Deuterated Compounds: Optimizing Drug Stability

28 Jun 2018

Deuterated Compounds: Optimizing Drug Stability

Drug discovery has been a very time consuming and expensive process as out of every 10,000 compounds, only one becomes a drug. Poor metabolic stability and toxicity has been a major bottleneck for any drug discovery program and to overcome these issues, medicinal chemists have started investigating deuterated compounds as new chemical entities with improved properties.

A deuterated drug is a small molecule in which one or more of the hydrogen atoms are replaced by deuterium. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made to a molecule.

Advantages:

• As a deuterated drug is broken down slower, it stays longer in the body and hence requires less frequent dosing (in terms of strength & regimen)
• Because of the kinetic isotope effect, deuterated drugs have significantly lower rates of metabolism, and hence a longer half-life
• Deuterium replacement may also lower toxicity by reducing toxic metabolite formation
• In addition, the deuterated drug is more stable in the presence of other drugs, resulting in reduced drug-drug interactions

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. 

A strong research pipeline:

• Research across varied indications like Cystic fibrosis, Nacrolepsy, Schizophrenia, Alzheimer’s, cancer, liver diseases, Parkinson’s disease etc., with majority of drugs in the oral formulation
• A total of 29 small molecules (21 – clinical; 8 – discovery) make the current pipeline of deuterated drugs which include 22 orphan drugs

Growing Opportunity for Deuterated Drugs

As per the companies in this research, the current market value of “deuterium switching” could be more than $1 billion, and the greatest discoveries in the field are yet to occur.

It is estimated that less than 10% of all FDA-approved drugs are amenable to deuteration because of their chemical structure, or because the body breaks them down in a way that isn’t affected by deuterium.

 

Market Outlook:

With FDA finally approving the first deuterated drug – Deutetrabenazine in Apr’17, after 4 decades of clinical trials over deuterated compounds, can this be adopted as a bigger lifecycle management strategy?

From an initial desire to extend drug clearance times, companies are now finding a broad range of potential uses for deuterium in drug molecules. As a result, claiming deuterated versions of new molecules in patent applications is emerging as a trend for the large pharma companies.

The growth of “deuterium switch” not only depends on the success of the current molecules in research but also the ability of the companies to explain the significantly higher advantages of this switch for lifecycle management of existing blockbusters.

Deuterated API Capabilities:

Piramal Pharma Solutions, with its FDA approved facilities across North America, Europe and Asia, provides API development and manufacturing services across the globe. Our US FDA approved facility in Torcan, Canada is well equipped to handle deuterated APIs:

• Process R&D for deuterated APIs
• Up to 100s’ kg of deuterated APIs under GMP
• Full analytical testing and release

Piramal healthcare Canada Limited is licensed through the Canadian Nuclear Safety Commission (CNSC) for the following activities:

• General import of deuterated materials
• General export of deuterated materials
• Possession of deuterated materials
• Specific port export licenses (required for all actual exports) with India, Israel, & USA
• Prior notification license for US (must let CNSC know the sample destination prior to shipment)
  • Completed CNSC Type II Inspection with no observations