PICME

• Research type

  Research Study

• Full title

  A Pharmacokinetic Investigation Into the Formation of Carbamazepine Metabolites and Carbamazepine-Protein Conjugates in Healthy Volunteers

• IRAS ID

  112522

• Contact name

  Munir Pirmohamed

• Sponsor organisation

  Royal Liverpool and Broadgreen University Hospital NHS Trust

• Eudract number

  2012-004700-35

• Research summary

  Carbamazepine is an effective drug that is commonly used in the treatment of epilepsy, neuralgia and psychiatric disorders. Although generally well tolerated it can cause hypersensitivity reactions, such as skin rash, in up to 10% of patients. These reactions can result in hospital admission, long-term complications such as blindness, and can cause death in up to 30% of patients. These reactions are caused by the immune system and recent research has identified that patients with specific genes are at significantly increased risk of developing hypersensitivity with carbamazepine. Once carbamazepine is ingested it is converted by the liver to other chemical products known as metabolites. It is believed that one or more of these metabolites are responsible for activating the immune system. However, our current understanding of how carbamazepine and/or its metabolites trigger the immune system in genetically susceptible individuals is lacking. This study aims to improve our mechanistic understanding of carbamazepine hypersensitivity by using high sensitivity mass spectrometry to characterise and quantify the stable and toxic products formed in the blood and urine of healthy volunteers following carbamazepine ingestion. This will enable identification of the chemical entities responsible for triggering the immune system in susceptible individuals. Genetic variation in drug metabolising enzymes and drug transporter proteins will also be analysed to determine their effects on carbamazepine metabolism. These results will be incorporated into a mathematical model that will enable clinicians to explain the variation in carbamazepine metabolism and susceptibility to carbamazepine hypersensitivity between different patients. Lessons learned from this research will also provide valuable information for other drugs that are known to cause similar hypersensitivity reactions (e.g. penicillins). Improved understanding of the mechanism of carbamazepine hypersensitivity will enable safer drug design in future and the development of predictive tests that can diagnose and identify patients susceptible to adverse reactions.

• REC name

  North West - Greater Manchester Central Research Ethics Committee

• REC reference

  12/NW/0780

• Date of REC Opinion

  18 Dec 2012

• REC opinion

  Further Information Favourable Opinion