Ethnic Differences in Drug Responses and their Impact on Drug Development

Abstract

Interethnic and racial differences in drug responsiveness are well recognized, and a resurgence of interest and concern has recently developed. The Pharmacogenetics Research Institute has investigated the differences in disposition of and response to a number of drugs both between Chinese and Caucasians and among Chinese nationalities that should encourage further investigations to elucidate the extent of such differences, their causes, and their therapeutic impact.

Chinese have greater sensitivity than Caucasians to the effects of propranolol on heart rate and blood pressure. Decreased protein binding and increased sensitivity to plasma renin activity suppression in Chinese may partially explain their increased sensitivity to propranolol. It was subsequently found that Chinese subjects are more sensitive to the effect of atropine, which is not related to the. contribution of autonomic tone to the heart. In a recent study, the results showed that Chinese subjects and Caucasian subjects differ in their ability to metabolize morphine and that the Chinese subjects have a significantly higher clearance of morphine caused by increased glucuronidation. In contrast, the Chinese subjects were less sensitive to the respiratory and vasodepressant effects of morphine but not to the nausea-producing effects.

In addition to the comparison of Chinese with Caucasians, the differences in drug disposition between Han and Chinese minorities have also been determined. All the minorities have their own unique genetic origin, cultural background, diet source and habits, and geographic environment. There is great potential for drug disposition and sensitivity that display a dissimilar profile among them. The first evidence for the difference obtained from these studies is that the frequencies of poor metabolizers in Han versus Bai subjects was 19.8% versus 13.4%, respectively. Han extensive metabolizers showed slightly higher mephenytoin ratios than the Bai extensive metabolizers. Han subjects have a higher frequency for the mutant CYP2C19_ml allele and a lower frequency for the wild-type allele compared with Bai subjects, which is consistent with the difference in the frequencies of poor metabolizers between the two ethnic groups.

The multinational drug manufacturers and development companies should recognize the need for separate clinical assessments of new drugs in major countries and racial populations in order to find and provide appropriate dosage range and regimen for particular ethnic populations. The bioavailability and pharmacokinetic profile of new drugs in particular ethnic populations and the specific adverse drug reactions that researchers should be aware of in particular ethnic populations should be determined and provided. Pharmaceuticals should support the pharmacogenetics study that elucidate the extent of racial differences in drug responses and the impact on therapeutic development, and should support cooperative and global study.

China is a large drug market with over one billion potential drug consumers. The country has been open to Western pharmaceuticals and it will be more open in the future. Many Western pharmaceuticals have been recognized and have gained entry in China. They must face the challenge that an effective and safe dosage regimen that is suitable to Chinese patients should be provided. The Chinese government and members of the Drug Evaluation Committee request pharmacokinetics data for new drugs.