gADME™ (Genomic ADME)
Cyprotex’s gADME™ technology combines genomics with ADME to define phenotypes of drug metabolising enzyme genetic variants, and to generate pharmacokinetic models to forecast clinical outcomes and personalized dosing strategies. The gADME™ service utilises Cyprotex’s panel of proprietary enzyme systems providing a comprehensive range of drug metabolising enzymes, including genetic variants of these enzymes.
Contact us to learn more about how Cyprotex’s gADME™ can help your drug development efforts.
Genetic Polymorphisms
Genetic polymorphisms (variants) in drug metabolism cause pharmacokinetic variability in vivo, which can result in either adverse drug reactions or lack of drug efficacy in humans. This is a particular concern for drugs with narrow therapeutic windows.
The cytochrome P450 enzymes, CYP2D6, CYP2C19, and CYP2C9, are well-recognised examples of enzymes that exhibit polymorphisms in drug metabolism with differences observed among ethnic backgrounds.
Reaction phenotyping studies are recommended in early development to identify which cytochrome P450 enzymes are involved in the metabolism of a compound. This information is useful for predicting possible drug-drug interactions with co-administered therapies, and in identifying whether polymorphic enzymes play a significant role in the drug metabolism.
Rescuing and Repositioning of Drugs
Many potentially valuable drugs are being discarded in early development because they are metabolised by polymorphic CYPs, which puts the drugs at risk of excessively variable drug plasma levels among patients.
Cyprotex’s gADME™ service allows drug developers to understand the effect of genetic polymorphisms on drug toxicity and efficacy. This understanding will enable clinicians to compensate for the variability by identifying appropriate dose adjustment strategies personalised for an individual’s genotype. This in turn can enable failed drugs to be rescued, existing therapies to be repositioned, and successful development of drugs that would have otherwise been discarded.
Predicting Inter-Individual Variability in Pharmacokinetics Using gADME™
As different drugs show differing sensitivities to genetic polymorphisms1, predicting dose based on an individuals’ phenotype or genotype also requires prior testing of the drug. Cyprotex can identify which enzymes play a role in the drug metabolism, and help drug developers understand the impact of genetic polymorphisms and to develop dose adjustment strategies via a 3-step process.
- Step 1: Phase I (CYP and non-CYP) and Phase II metabolising pathways are identified using Cyprotex’s proprietary collection of hepatic and extra-hepatic drug metabolising enzymes
- Step 2: Polymorphic enzyme screening focused on enzymes responsible for metabolism of the drug
- Step 3: Discussion with client and suggested doses adjustment
Available Enzyme Systems
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Phase I:
- Cytochrome P450 enzymes (CYP)
- Flavin monooxygenases (FMO)
- Monoamine oxidases (MAO)
- Carboxylesterases (CES)
- Aldehyde oxidases (AOX)
- Aldehyde dehydrogenases (ALDH)
- Aldo-keto reductases (AKR)
- Alcohol dehydrogenases (ADH)
- Hydroxysteroid dehydrogenases (HSD)
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Phase II:
- UDP-glucuronyltransferases (UGT)
- Sulphotransferases (SULT)
- N-Acetyltransferases (NAT)
- Glutathione S-transferases (GST)
- Polymorphic Enzymes
Contact us to learn more about how Cyprotex’s gADME™ can help your drug development efforts.
References
1 Shen et al., (2007) DMD 35:1292-1300
By Dr. Katya Tsaioun, Chief Scientific Officer, Cyprotex
Wiley & Sons, March 2011
