Pharmacogenetics And The Framework For Regulatory

Pharmacogenetics is the scientific study of gene types and gene variations which

have the likelihood of influencing the reaction of the human body to a certain medicine. While it is given that genetic factors identify the inter-individual and inter-ethnic variations in pharmacokinetics and pharmacodynamics of a drug, it is not a wonder that regulatory authorities have already long recognized the importance of pharmacogenetics in developing drugs. In fact, they are directing their attention to addressing issues that may emerge from genetic heterogeneity of the target patient population.

A few of the guidelines given by the European Union's Committee for Medicinal Products for Human Use or CHMP, and the International Conference on Harmonization have made direct or indirect references to the need for addressing genetic factors in developing an NCE.

The guidelines on 'Pharmacokinetic studies in man' adopted by the CPMP recommends that metabolic studies must determine whether the metabolism of a drug may be significantly altered in a case of genetic enzyme deficiency, and whether saturation of metabolism may exist, which in turn, leads to non-linear kinetics, within the levels of dose used.

The International Conference on Harmonization guideline on 'Dose-response information to support drug registration' indicates how useful the knowledge of the shape of individual dose-response curves is, and it differentiates individual curves from the population curve. The said guidelines warn of a "choice of a starting dose might also be affected by potential inter-subject variability in pharmacodynamic reaction to a certain blood concentration level, or by expected inter-subject pharmacokinetic variations. it recommends that in using dose-response information, the influences of several demographic features, concurrent drugs, individual characteristics and diseases must be determined.

Because the drug interactions are genotype-dependent, the CPMP's guideline on 'investigation of drug interactions' advises that in performing mechanism-based in vivo studies, consideration must be afforded to pharmacogenetic factors. Participants in vivo interaction studies must be properly genotyped and or phenotyped before the study commences to determine whether any of the enzymes that mediate the metabolism of the interacting drugs are polymorphically disseminated in the population.

The genotype of the donor liver utilized for in vitro microsomal studies must be determined as well. The CPMP guideline advises examination of drug interactions at sites besides the metabolic route like the excretion and transport by efflux pumps and P-glycoprotein.

Pharmacogenetic factors are significant in considering and analyzing drug interactions at these transporters and or P-glycoprotein. The guidance note provided by the CPMP on 'investigation of bioavailability and bioequivalence' suggests that phenotyping and genotyping of subjects may be considered for safety or pharmacokinetic reasons.

On the other hand, the US Food and Drug Administration issued their own guidance note on 'Drug metabolism/drug interaction studies in the drug development process: studies in vitro. It states that "identifying metabolic differences in patient groups according to genetic polymorphisms, and other readily available factors like the age, race, and gender could be helpful in designing the dosimetry studies for these population groups.

New knowledge on pharmacogenetic differences in drug disposition or responsiveness of pharmacological targets will result to additional requirements for pharmacogenetic documentation for NCEs.

by: Charles Godbout

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