Race has been reported to contribute to variability in dosing requirements for warfarin in anticoagulation, with African Americans requiring higher doses and Asians requiring lower doses than whites. CYP2C9 is the enzyme primarily involved in warfarin PK. Variant CYP2C9 genotypes are associated with an increased risk of major hemorrhage, and the frequency of variant genotypes is significantly higher in European Americans than in African Americans. Variations in the VKORC1 gene that encodes for the pharmacologic target of warfarin, vitamin K epoxide reductase, contribute to differences in sensitivity to warfarin. One of the variants in VKORC1 associated with lower dose requirements is 1639 G>A. the AA genotype is found in warfarin-sensitive patients. The frequency of the warfarin-sensitive AA genotype is higher in Chinese than in whites, with frequencies of 82% in Chinese and 14% in whites. A genomic basis found in recent mechanistic studies supports the previously observed ethnic differences in warfarin dose requirements. This serves as an example of the need to understand potential reasons for pharmacokinetic or pharmacodynamic variability in clinical pharmacology or phase II studies so that dosing can be adjusted for relevant populations in later clinical studies.⁷

The pharmacologic activity of rosuvastatin (a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor) in treating dyslipidemias is due primarily to the parent compound. Approximately 10% of a radiolabeled dose is recovered as metabolite, which is formed primarily by CYP2C9. Because of the small contribution of CYP2C9 to rosuvastatin exposure, and because the most common variant alleles of CYP2C9 are not found in the Asian population at a higher frequency than in whites, a higher systemic exposure in Asians than whites on the basis of P450-mediated metabolism would not be predicted.

Immunomodulators are used in the prophylaxis of tissue rejection in organ transplant patients. Cyclosporine, sirolimus, and mycophenolic acid are often used in combination with steroids for this purpose. Tacrolimus, cyclosporine, and mycophenolic acid are all substrates for CYP3A4 and P-glycoprotein. Individual dosing regimens are prepared using therapeutic drug monitoring for cyclosporine, sirolimus, tacrolimus, and mycophenolic acid to maintain target trough concentrations or exposures. In the use of cyclosporine for the prophylaxis of tissue rejection in organ transplant patients, it was found that Black patients had higher rates of organ rejection than Caucasians when using the same dosing regimen. Assessments of the bioavailability of various oral formulations of cyclosporine in different ethnic groups have shown lower bioavailability in Blacks and higher bioavailability in Hispanics as compared to Caucasians. However, similar bioavailability between Blacks and Caucasians has also been reported for the microemulsion formulation. Observed differences in bioavailability are likely due to differences in intestinal CYP3A4 activity.

The absolute bioavailability of tacrolimus was lower in Blacks (11.9%) and Hispanics (14.4%) as compared to Caucasians (18.8%). Differences in intestinal CYP3A4 and/or P-glycoprotein were suggested probable reasons for the observed differences [5].

Amonafide and 6-mercaptopurine (6-MP), metabolic pathways involving polymorphically regulated enzymes (N-acetyltransferase [NAT] and thiopurine methyltransferase [TPMT], respectively) have provided some guidance regarding potential ethnic differences. As it relates to Amonafide, acetylator phenotype affects the generation of the active N-acetyl-Amonafide metabolite such that fast acetylators experience greater toxicity and thus should receive lower doses. Known ethnic differences in the NAT genotype suggest that Amonafide would likely have a differential therapeutic profile across different ethnic groups.

Among extrinsic factors, the effects of food ingestion with drug administration are the most extensively studied. The effects of food on drug disposition have been recently reviewed. Co administration of food with selected drugs can affect the rate and degree of drug absorption; this can involve enhancing, decreasing, or delaying absorption. It is further recognized that different types of food (e.g., the so-called high-fat and low-fat food used in food effect studies) can have different effects on absorption [5]. Grapefruit juice inhibits Metabolism of alprazolam, atorvastatin, cisapride, cyclosporine, midazolam and Triazolam [9]. There are numerous examples of the effect of food ingestion on drug disposition, including antimicrobials, hypoglycemics, and hypocholesterolemic agents, just to name a few.

Ethanol use has been shown to affect the elimination of many drugs, including diazepam, lorazepam, chlorazepate, oxazepam, meprobamate, pentobarbital, chlormethiazole, and rifamycin, based on induction of hepatic enzymes. Tobacco smoking has also been shown to affect the metabolism of several drugs, including theophylline, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, and estradiol, also through enzyme induction. While major cultural or regional differences in the composition of meals and in ethanol and tobacco use may potentially affect population drug exposure and thus explain ethnic differences, it is not clear to what extent such effects are population specific. While socioeconomic status in different geographic regions of the world is an important determinant of access to pharmacologic therapy, the role such factors may play with respect to acceptability of foreign clinical data is less obvious. Socioeconomic and cultural factors may be important in determining expectations and efficacy of specific pharmacologic therapies specifically, psychotropic medications. Differences in regional medical practices do exist, and to the extent these influence outcomes from global clinical development programs, they need to be considered when determining acceptability of foreign clinical data. Variations in compliance have also been cited as factors explaining ethnic differences.Other possible extrinsic factors cited in the ICH E5 guidelines, such as exposure to pollution and sunshine, remain largely unexplored as factors responsible for ethnic differences. In general, therefore, it appears there are only a limited number of documented cases in which extrinsic factors are responsible for ethnic differences, and we are not aware of any systematic examination of these issues.

Given all these, there are a few examples of suspected ethnic differences in pharmacokinetics or pharmacodynamics. Noteworthy examples include the following: Chinese are more sensitive to the cardiovascular pharmacologic effects of propranolol than Caucasians, Chinese have lower daily warfarin dose requirements than Caucasians, and slow acetylators (more common in Caucasians and Blacks than Asians) are more likely to experience adverse events than fast acetylators of drugs that are eliminated by N-acetylation due to greater exposure. In most of these cases, the underlying molecular mechanisms are not known; in some cases, body weight appears to be at least a contributing factor, and in a few cases, documented CYP polymorphism difference does not appear to provide an explanation.

The ICH E5 guidelines of 1998 are intended to facilitate drug and biologics registration in the different ICH regions by recommending a framework for evaluating the impact of ethnic factors on a drug’s safety and efficacy at a particular dosage and dose regimen, involving regulatory and development strategies that will enable appropriate evaluation of ethnic factors, minimize unnecessary duplication of clinical studies, and expedite the drug approval process. However, considering the general nature of these guidelines, there is clearly the potential for different regions or countries to apply different interpretations, thus potentially defeating some of the goals of the guidelines [5].

There has been significant impact of ethnic factors on drug development after release of ICHE5 guidelines and completion of human genome project. Some of the examples are enlisted in the following tables.

Table lists examples of currently marketed drugs with labeling that includes specific race or genetic information intended to facilitate the optimal use of medications in various population groups. Some of the observed racial differences may be explained by the genetic differences listed in labeling (e.g., warfarin and carbamazepine). Possible mechanisms for others either have not yet been included in labeling (e.g., rosuvastatin and tacrolimus) or are as yet unknown (e.g., isosorbide dinitrate– hydralazine, which is effective in heart failure in black patients) [12].

ACE, angiotensin-converting enzyme; CCR5, chemokine (C-C motif) receptor 5; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; HLA, human leukocyte antigen; PM, poor metabolizer; TPMT, thiopurine methyl transferase; UGT, uridine diphosphate glucuronosyl transferase; UM, ultra-rapid metabolizer; VKORC, vitamin K reductase complex.

Impact of ICH E5 guidelines was observed across the ICH regions (Japan, USA & EU) as well as non-ICH regions such as Taiwan. Taiwan one of the few countries which are embracing the ICH E5 in a big way by bringing the guidelines to determine the need for bridging studies during the drug approval process. The flowchart to determining ethnic sensitivity and waiver for clinical trial as follows [13].