Drug Regulators, EMA (EMEA), Publish Draft Guidance on the Use of PharmacoGenetic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products.
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This guideline addresses the influence of pharmacogenetics on drug pharmacokinetics, encompassing considerations and requirements for the design and conduct of investigations during drug development. In particular, guidance is given regarding studies required and recommended at different phases of drug development to ensure satisfactory efficacy and safety in pharmacogenetic subpopulations that have variable systemic exposure of active substances.
The pharmacokinetics of many medicinal products is prone to interindividual variability, which is caused by several factors such as gender, age, weight, renal and hepatic function, and genetics. In recent years, a rapid development in our understanding of the influence of genes on interindividual differences in drug action has occurred. This development encompasses the area of pharmacogenomics, including pharmacogenetics, where interindividual variability in genes influencing or predicting the outcome of drug treatment (e.g., genes encoding drug transporters, drug metabolising enzymes, drug targets, biomarker genes) is studied in relation to efficacy of drug treatment and adverse drug reactions. A great deal of this interindividual variability is caused by genetic polymorphism, i.e. the occurrence in the same population of multiple allelic states. Genetic variations are demonstrated by the identification of Single Nucleotide Polymorphisms (SNPs), insertions/deletions and variation in gene copy number (copy number variation, CNV).
With respect to pharmacokinetics, the highest level of polymorphism is found in genes involved in drug metabolism; phase I metabolism of approximately 40% of clinically used drugs is due to polymorphic enzymes. Currently, the most important polymorphic enzymes are the cytochrome P450 enzymes such as CYP2C9, CYP2C19 and CYP2D6. Subjects who have extensive and poor metabolising capacity for these enzymes are present in the general population. For CYP2D6, besides the poor metaboliser phenotype, the ultrarapid metaboliser phenotype is relevant as well. With respect to phase II enzymes, the genetic variability of UDP-glucuronosyltransferases, N-acetyltransferase-2 and some methyltransferases has been linked to interindividual pharmacokinetic variability. The metabolising enzymes account for 80% of the drugs which currently include pharmacogenetic data in their labelling.
Among the major clinically relevant issues is pharmacogenetic variability causing increased or decreased metabolism of the parent drug and the subsequent formation of active or toxic substances. Decreased metabolism can cause too high levels of the parent drug and adverse drug reactions. Elevated drug metabolism can cause loss of response or, in case of prodrug activation, too high levels of the bioactive compound.
The interindividual genetically linked differences in pharmacokinetics may cause, clinically, very relevant alterations in drug action. Optimal efficacy is dependent on appropriate dosing, often based on the specific genotype. Thus, the effective dose may vary greatly due to increased or decreased drug elimination rate. For instance, due to CYP2D6 polymorphism, the rate of hepatic metabolism of drugs which are substrates for this enzyme can vary 1000-fold between individuals. Among many antidepressants and antipsychotics, the plasma levels of the drug at the same dosage often vary 5-20-fold. A 9-fold higher risk of suicide has been reported among ultrarapid metabolisers of CYP2D6 and there are also many reports of increased frequency of adverse drug reactions among subjects with the poor metaboliser phenotype, due to increased systemic exposure of the parent drug. Furthermore, increased side effects after treatment with analgesic drugs, which are activated by CYP2D6, are seen among ultrarapid metabolisers. The efficacy of prodrugs which are activated by polymorphic enzymes varies depending on the pharmacogenetics of the patients. An example of this is clopidogrel, for which an increased frequency in serious side effects due to excessive prodrug activation has been seen in patients with increased formation of the active metabolite and a corresponding lack of effect in subjects without the appropriate enzyme. Dosing of some important anticoagulants is dependent on the CYP2C9 genotype of the patient and the platelet inhibition action of some drugs is dependent on the CYP2C19 genotype. Overall, it can be estimated that 20-25 % of the efficacy of all drug treatment is significantly affected by interindividual differences in genes encoding drug metabolising enzymes.
In recent years, journal articles have been published describing specific polymorphisms in drug transporters and their possible effect on the efficacy and safety of medicinal products. However, in the majority of cases the influence of transporter polymorphism on drug pharmacokinetics has not yet been clarified. The effect of transporter polymorphism on drug pharmacokinetics is thought to be of less importance, or is still unknown, compared with polymorphic enzymes. This is partly due to the fact that the role of specific transporters in vivo is difficult to quantify due to the lack of specific inhibitorsand the polymorphism seen in the transporters is often substrate specific in its effects. The possibility of transporter polymorphism as a cause of altered pharmacokinetics must, however, always be considered in all phases of drug development. It is anticipated that this area will expand a great deal in the near future, as knowledge of the role of drug transporters is rapidly developing.
At present, an increasing proportion of lead compounds selected for further development are metabolised by enzymes or transported by transporter proteins upon which the impact of pharmacogenetics is unknown. New technologies, such as rapid genome sequencing, whole genome wide association studies (GWAS) and targeted absorption, distribution, metabolism and excretion (ADME) gene SNP/CNV analyses, are expected to have an integral role in clinical drug development in the future.
Until now, it has been difficult to transfer knowledge of the effect of polymorphism into specific recommendations in affected genetic subpopulations1. In this respect, genetic subpopulations have been treated differently than other subpopulations or circumstances in which the exposure of active or toxic substances is increased. The aim of including pharmacokinetics-related pharmacogenetics in drug development is to evaluate whether exposure in genetic subpopulations is different to such an extent that this would require a change in the posology or treatment recommendation of the drug for the specific subpopulation. This document, therefore, aims to clarify the studies needed to investigate these issues.
Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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