While in 2001 the major cause of attrition in drug discovery was pharmacokinetics, however by 2014 increased knowledge of the factors influencing the ADME properties plus increasingly sophisticated in vitro and in vivo assays had dramatically reduced this as the cause for attrition. In contrast attrition due to Lack of Efficacy in Man increased, perhaps underlining the importance of Target Validation.
Cardiovascular toxicity
This is the occurrence of heart dysfunction, it can be caused by many mechanisms and different classes of drugs. Many ion channels have been implicated including hERG, NaV1.5 and CaV1.2, Kir2.1, KV4.3_KChIP and KV7.1_MinK.
Worth reading
CIPA Initiative
The CiPA initiative began following a workshop in July 2013 at the US FDA. The objective of the CiPA initiative was to engineer an assay for assessment of the proarrhythmic potential of new drugs with improved specificity https://cipaproject.org
hERG activity
Inhibition of the HERG channel is linked to QT prolongation in vivo and subsequent sudden cardiac death.
Mutagenicity
Mutagenicity refers to the induction of permanent transmissible changes in the amount or structure of the genetic material in cells or organisms. These changes may involve a single gene (point mutations), a block of genes or entire chromosomes (structural or numerical chromosome aberrations). In many cases, genotoxicity may lead to cancer. Thus, genotoxicity testing is performed to assess the potential of substances to induce genotoxic effects which may cause heritable damage or lead to cancer in humans.
Drug-Drug Interactions (DDI)
Many drug interactions are due to the impact one drug can have on the metabolism of a second drug’s metabolism. One major system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases. This system may be affected by either enzyme induction or enzyme inhibition or in some cases both. ▪ Enzyme induction – Drug A induces the body to produce more of an enzyme which metabolises drug B. This reduces the effective concentration of drug B, which may lead to loss of effectiveness of drug B. Drug A effectiveness may or may not altered. ▪ Enzyme inhibition – Drug A inhibits the enzyme metabolising drug B, thus an elevation of drug B occurs possibly leading to an overdose. ▪Bioavailability – Drug A influences the absorption of drug B perhaps by blocking active uptake mechanism or inhibiting active transport mediated excretion in the gut. See Also CYP450 Interactions
Hepatotoxicity
Drug-induced liver injury is a major health problem that impacts the pharmaceutical industry, drug regulatory agencies and doctors. Drug induced hepatotoxicity accounts for more than 50% of acute liver failure, and is the major cause of drug withdrawals. Because of the significant patient morbidity and mortality, many drugs have been withdrawn from the market, including bromfenac, ebrotidine, and troglitazone. Other hepatotoxic drugs, such as risperidone, trovafloxacin, and nefazodone,have been assigned “black box” warnings.
Idiosyncratic toxicity
Idiosyncratic toxicity refers to rare, unpredictable adverse drug reactions that are not dose-dependent and occur in a small subset of the population, and may only be observed in humans, often leading to post-marketing restrictions.
Worth reading The Identification of Toxicophores for the Prediction of Mutagenicity, Hepatotoxicity and Cardiotoxicity