S2: Pharmacogenetic and genomic applications for safety and therapeutic efficacy assessment
Pharmacogenetic and genomic applications for safety and therapeutic efficacy assessment in drug development
Hannover Medical School, Centre for Pharmacology and Toxicology
The pharmacogenetics of ADME genes, receptors, transporters, ion channels and immune response greatly improved an understanding of genetic determinants of adverse drug reactions (ADR). Tangible results with high clinical relevance are the discovery of SNPs in ADME genes that result in changes in drug pharmacokinetics to cause drug accumulation and ADR, particularly, if the therapeutic window is narrow. Given that ADRs rank among the top causes of death in the USA and Europe there is urgent need to improve an identification of individuals at risk of developing ADRs prior to medication.Most ADME genes exhibit clinically relevant polymorphisms and frequencies of variant alleles differ among ethnic groups. For instance, isoniazid-induced neuropathies and lupus erythematosus differ between Japan and USA. Similarly, arylamine associated bladder cancer and sulfonamide hypersensitivity are linked to the slow acetylator phenotype.
In my presentation I will focus on SNPs of ADME genes and the use of pharmacogenetics for a better understanding of the pharmacokinetics of drugs and subsequent adverse drug reactions. I will provide an overview of human enzymes that code for Phase I and Phase II functions, e.g. modification of functional groups by oxidation or conjugation with endogenous substituents, and then provide examples of clinical relevant genetic polymorphisms. This will include a detailed discussion on severe and potentially fatal hematopoietic toxicity that can occur when thiopurine methyltransferase (TMPT) deficient patients are treated with standard doses of 6-mercaptopurine or its pro-drug azathioprine. I will also discuss the utility of dosage reduction by 90 – 94 % to result in successful treatment of acute lymphoblastic leukaemia without severe toxicity. Further examples include Irinotecan, a camptothecin analogue with strong anti-tumor activity; however carriers of the UGT1A1*28 allele are at high risk for severe toxicity with this drug. I will also allude to the possibilities of rapid genotyping assay based on FRET technology with homozygous carriers of the TA7TAA allele having a high risk in developing camptothecin induced toxicity. Finally, I will sum up with a brief discussion as how pharmacogenetics and pharmacogenomics will impact precision medicine.