The liver is a vital organ for synthesis and detoxification. A severe and important cause of liver injury is adverse drug reactions (ADRs). It is estimated that ADRs cost as much as drug treatment itself, that it they causes withdrawal of 4% of new chemical entities from the market and is the 4th-5th leading cause of death in the Western world [1,2]. A meta-analysis revealed that serious adverse drug reactions occur among 7% of all hospitalized patients and that 0.3% of all in-patients develop fatal adverse reactions, causing more than 100,000 deaths annually in the US . The costs for ADRs, including on average 2 days of prolonged hospitalization and reduced productivity, has been estimated to 100 billion € in Europe.
Besides being detrimental for society, inappropriate pharmacokinetics, ADRs and safety issues are prime causes for termination of new chemical entities during drug development and ADRs are responsible for the withdrawal of 4% of drugs in post-marketing stages [1,2]. They can arise from unanticipated interactions with co-administered medications, be the consequence of sensitization due to acute or chronic concomitant diseases or be facilitated by genetic factors, such as variations in cytochrome P450 genes and drug transporters, which have been shown to be highly polymorphic [4,5].
Failure of compounds in clinical trials is a major cost factor for the pharmaceutical industry. The average cost per clinical trial of a new chemical or biological entity is conservatively estimated at 30-40 million US$. Yet, as the overall success rate of novel drugs to pass clinical trials (phase I-III) is only 1.3% , this results in tremendous costs for the pharmaceutical industry. Drug safety is the main reason for the termination of drug development programs in clinical stages and the liver is amongst the organ systems most relevant for safety failures . Importantly, a review of the developmental pipeline of a major pharmaceutical company revealed that the quality of pre-clinical safety assessments can strongly reduce the risk of safety failures in developmental stages.
1. Eichelbaum et al., Annu Rev Med, 2006
2. Ingelman-Sundberg, N Eng J Med, 2008
3. Lazarou, et al., JAMA, 1998
4. Fujikura et al., Pharmacogenet Genomics, 2015
5. Kozyra et al., Genet Med, 2016
6. Waring et al., Nat Rev Drug Discov, 2015
7. Cook et al., Nat Rev Drug Discov, 2014