Pharmacogenetics And The Global Development Of Drug
Pharmacogenetics is given its due respect and importance in drug development
. In our time, the program on development of drugs is undertaken at a global aspect. The program seeks to decrease the costs, accelerate the process of drug development and, and addresses the concerns of global prescription of drugs.
Nevertheless, the relative frequency of several alleles of drug-metabolizing enzymes differs in varying populations. As a result, the frequencies of the poor metabolizer or PM phenotype and those with intermediate drug metabolizing capacity manifest a marked global heterogeneity.
For instance, the frequency of CYP2D6 PM phenotype is higher in population groups from Western Caucasian descent-with 5-10%--than in Far East and Asian ethnic groups-with 0-2%. The said frequency of PMs of CYP2C19 is lower in Western Caucasians at 2 to 4% in comparison to the frequencies among the Asian at 15 to 25%.
The global heterogeneity and inter-ethnic differences have also been observed in the frequency of divergent alleles of the genes that express many other drug-metabolizing enzymes and of the gene expressing P-glycoprotein.
For instance, while MDR1*2, a variant allele, occurred in 62% of European Americans, it was manifested in only 13% of African Americans, though the clinical significance of most of the alleles of MDR1 is not yet sufficiently characterized.
In drug-metabolizing enzymes, there happens to have inter-ethnic differences in the mutations of a few of pharmacological targets. As an example, the frequencies of Arg16/Gly16 mutation of B2-adrenoceptor in Caucasians, Asians and Black are 0.61, 0.57 and 0.50 respectively. When it comes to haplotypes of mutations of B2-adrenoceptor, 13 of the SNPs on B2-adrenoceptor gene are categorized into 12 haplotypes from the 8192 combinations.
Four of the observed haplotypes were seen in all four populations-Caucasian, African American, Hispanic Latino and Asian), though at markedly varying frequencies. One of the populations show more than 20 fold variations in its frequencies. Also, although the frequency of long allele of 5-HTT may be as high as 87% in certain African Americans, it is as low as 56% in certain European Americans.
In addition, the regulatory guidelines also recognize the possible inter-ethnic variations in pharmacokinetics and pharmacodynamics that might emerged from the global genetic heterogeneity. Therefore, information on the ethnic demography of clinical trial populations and possible ethnic influences on drug renspose is required.
When it comes to drug development, the importance of the said requirements can be due to the following facts:
1. The existence of increasing globalization of drug development having clinical trials initiated in a geographical population which may not really be the ultimate target of the drug;
2. There are more NCEs seen to be substrates of polymorphic drug-metabolizing enzymes and aimed towards polymorphic receptors;
3. that modern medicines are highly potent with narrow therapeutic indices and thus, only small variations in pharmacodynamics or pharmacokinetics may become very significant clinically.
The inter-ethnic variations in drug response are popular, and thus, the sponsors of NCEs are anxious to address the issues that emerge from global prescription of their drugs.
by: Charles Godbout
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