The issue of clarithromycin and increased cardiac deaths #4 - Where are the potential sources of variability?

1. Bioavailability
Regardless of its touted lipophilicity, clarithromycin has a reported average bioavailability of only about 50%. Generally, as a guiding principle, the lower the bioavailability, the greater the potential for variability in systemic availability.

2. Uncertain target site concentrations
There are two associated problems here.

Firstly, clarithromycin has an elimination half life of about 3-5 hours at low doses and 5-7 at higher doses. At a 12 hourly dosing intervals, there will be significant fluctuations in the plasma concentration profile. Even if it is administered at 8 hourly intervals, and if half-life is assumed to be at the high end of the range, say 8 hours, there will be at least a 2 fold fluctuation between peaks and trough. While this may meet the needs of anti-bacterial efficacy (assuming we keep trough levels above MIC), the levels of the peaks may predispose to cardiac toxicity if it is able to inhibit HERG potassium channels. To some extent, we can mitigate the fluctuations by using extended release formulations, but this may be at the expense of even more variability in bioavailability.

[source:http://medlibrary.org/lib/images-rx/clarithromycin-24/img-0238.jpg]

Comparison between normal formulation and extended release formulations

Secondly, since we do not routinely measure either plasma or tissue concentrations, we have little idea if adequate concentrations are being achieved at the target site. Here, there is some more uncertainty. Tissue and cellular concentrations tend to be higher than plasma unbound concentrations, but concentrations in the extra-cellular fluid (where the bugs are) are variable and may be lower than unbound concentrations of clarithromycin. These are functions of variable protein binding and the variable net activities of specific influx and efflux membrane transporters.

Consequent upon the previous two points, the differential effects of clarithromycin on the bacteria and on HERG channels may be variable between individuals not only because they relate to different effect compartments but the latter may relate to heights of the peak while the former to trough concentrations being above the MIC.

[Source:http://www.fda.gov/ohrms/dockets/ac/03/briefing/Image66.gif]

Relationship between QT prolongation ad clarithromycin concentrations

Although the IC50 for clarithromycin on the HERG channel is about a 100 times higher than the MIC, arrhythmic risk is associated with lower extent of inhibition. Hence cardiac risk is seen at much lower IC10 or IC20 concentrations

Added to all these, is the uncertainty contributed by an active 14-OH metabolite of clarithromycin.

3. Inter-individual variability in pharmacokinetics
Clarithromycin is both a substrate and inhibitor of CYP3A4. This metabolic pathway is also responsible to generating the active 14-OH metabolite. Variable CYP3A4 activity therefore results in a variable mix of clarithromycin and its active 14-OH metabolite.

There is a very high extent of variabilty in CYP3A4 activity in any population studied. There are also significant differences in activity between men and women (women generally higher). While there are genetic polymorphisms associated with CYP3A4, no single genetic variant has been able to account for the variability within a population. On the other hand, CYP3A4 is also vulnerable to many food and drug interactions.

To make matters more complicated, clarithromycin inhibits its own metabolism by CYP3A4, and exhibits a non-linear pharmacokinetic profile.

4. Inter-individual variability in susceptibility to QT prolongation
The HERG potassium channel gene is genetically polymorphic and variants may predispose to variable susceptibility to QT prolongation. Added to this is the uncertainty about appropriate dosing regiments between different ethnic populations, who may have different body weights and distributional volumes, as well as different exposures to CYP3A4 food and drug interactions.

5. Variability in microbial susceptibility
Apart from differences in anti-microbial efficacy due to variability in drug permeation to target sites, bacteria do differ in how susceptible they are to concentrations of clarithromycin. While sensitive bacteria generally have MICs in easily achievable range, resistance genes have become more prevalent and differences in bacterial sensitivity has become more common.

6. Compliance issues
One must never forget the variability that may be caused by failure of the patient to medicate according to instructions, leading to highly irregular dosing intervals and therefore variable degree of fluctuations in circulating drug concentrations.


Taking all these uncertainties into consideration, the question is how to ensure the patient gets optimal dosing? Think about it.

[To be continued]

Phytochemicals, pharmacogenetics and pharmacokinetics

When one appreciates the extensive range on interactions that exist between phytochemicals essentially entering our bodies through our diet, and the various processes involved in host protection, it becomes very clear that dietary modifications of pharmacokinetic process should be a relative given in our understanding of drug ADME. In fact it should be a central theme in our understanding of interindividual and interpopulational variability in drug behaviour, rather than just being accorded the occasional consideration as a determinant of drug behaviour.

As a corollary, pharmacogenetics cannot hope to fully explain the pharmacokinetic behaviour of any drug in an individual. Environmental chemicals, largely phytochemicals, modify pharmacokinetic processes according to the genetic constitution of the individual, while the genetic makeup of the individual can only be fully expressed in response to environmental chemical effects.

Which leads us to automatically consider what the epigenetic mechanisms might be, in shaping the PK environment of the individual. Perhaps these might be more important than the occasional loss/gain of function variants that we find in the population.

The Han Chinese - fiction or biological reality?

The Chinese people have been called various names. Once we were called Orientals; the word 'orient' referring to the East. The original reference to Orientals by the west was with respect to people from the middle east or asia minor- regions East of Europe. In time, the definition shifted eastwards and became more associated with East Asia. Clearly the term has no meaning today and should be completely dropped from the scientific literature. Another term, 'Asians' was sometimes used, although in the United Kingdom, this has come to refer to people from the Indian subcontinent. The term East Asians attempts to shift the definition towards people from China, Korea and Japan. For the most part, Chinese were just referred to as Chinese.

More recently however, another term 'Han Chinese' has emerged. The implication appears to be that the concept of Chinese was inadequate and that somehow a 'Han' preface was needed to distinguish Han Chinese from non-Han Chinese. I suspect this has arisen as a result of more scientific work from China, where it was necessary to distinguish the main Han ethnic group from the other 56 ethnic groups which were not 'Han'. The following chart shows the increasing use of the term 'Han Chinese' in the literature beginning from about 1980 and rising steeply over the last 10 years.

In Singapore we don't really care to be Han Chinese, other than using the term to be consistent with 1 billion other people who want to use the term. For us, we are just plain and simple Chinese.

The term Han Chinese actually takes reference to a wish to be associated with the legendary 1000 year Han dynasty which ended in 220CE. I think this is more important to the mainland Chinese, more of the northern sorts. Interestingly for many of us more southern type Chinese, of the Min-nan dialects, the term 'Tang people' '唐人' is more frequently used. This is in reference to another wonderful period of Chinese history called the Tang dynasty (618-904).

So there isn't a whole lot of consistency with respect to how Chinese people want to refer to themselves. Tracing an ancestry back to a dynastic period is not an ethnically reasonable proposition since there can be no assumption that people from that dynasty were necessarily ethnically homogeneous.

It is somewhat of a wishful thinking that the Chinese people, whether Han or Tang, are a biologically homogeneous bunch of people. For large stretches of Chinese history, the country had to deal with more belligerent northern neighbours, and had been conquered by Mongols and Manchus from the North. These people, clearly of a different ethnicity from the indigenous Chinese, not only tended to displace the populations southwards and also widely assimilated with the resident Chinese. The more southern Chinese didn't have the benefits of the Great Wall so there was really nothing to keep them from mingling with their more southern non-Han neighbours.

As a result of these admixtures, there is a north-south cline in East Asian populations. In China itself, there would appear at the very least, among the "Han Chinese", to be a distinction between northern and southern Chinese. The watershed for these two groups is not a clear one, but appear to be somewhere in the vicinity of the Yangtze or Chang Jiang river divide.

It is important to be aware of the existence of this cline because it affects the way we look at "East Asian" population data. While for the most part, Chinese data tend to cluster quite closely together (which is not surprising), we need to be careful about too readily extrapolating northern data to a southern Chinese population, and vice versa. In many situations, northern Chinese data seem to be more in alignment with data from Japan and Korea, while southern Chinese data aligns with Hong Kong, Taiwan and Singapore.

Singapore, being the most southern of the major 'Han Chinese' populations, may have some unique features potentially because of some degree of genetic admixtures with the resident austronesian populations in south east Asia.

Pharmacogenetics and genetic polymorphisms

In the theoretically correct application of the term, Pharmacogenetics is the study of inherited variations in drug response. Strictly, it would apply to germ line mutations (genetic polymorphisms) and not to somatic mutations or to epigenetic mechanisms (unless these can be inherited).

Genetic polymorphism occurs when the "simultaneous occurrence in the same locality of two or more alleles is in such proportions that the rarest of them cannot be maintained just by recurrent mutation". This conventionally assumes that the rarest allele should be more than 1%.

There are two parts to this definition.

a] it must refer a population in equilibrium; although I use this term guardedly, since no population is static and is truly ever in 'equilibrium'.

b] the frequency of the rarest allele is at least 1%. This is very empirical as it is not certain what is the barest minimum frequency for the allele to be propagatable in a given population. It would seem that 1% is too high a value, and genetic polymorphisms do refer to alleles with frequencies much less than 1%. It does not however, include mutations that occur sporadically and randomly. Consequently allele frequencies for a genetic polymorphism are often tested against the Hardy-Weinberg Equilibrium. If it does not fit the HWE, it does not necessarily mean it is not a genetic polymorphism. It just cautions the investigator to look reasons why the HWE has been violated.

One particular consideration that is often overlooked in determining allele frequencies in a genetic polymorphism (which may or may not cause deviations from the HWE), is whether the population is stable and if there is a real equilibrium with respect to the transmission of alleleic variants. This is a particular problem for Singapore, whose population has been growing at a phenomenal rate through immigrations, and the expansion of our foreign worker pool. Recent additions to the population now may begin to outnumber those that are born locally. This raises questions about whether the population genetic pool is too labile to be in any sort of equilibrium. It could only be if we are able to assume that the larger population base of people of similar "race/ethnicity" are in equilibrium globally. But this is not a valid assumption.

The race-ethnicity confusion

Definitions of race and/or ethnicity are spectacularly confused and lack any kind of precision whatsoever.

The FDA in its guidance, for example, make a distinction between race and ethnicity, but allow them to be combined in a one step self declaration.

Race refers to 5 categories:
American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White
Ethnicity has 2 categories, either Hispanic/Latino or not Hispanic/Latino

Such definitions do not have any scientific logic and were actually developed by the Office of Manpower and Budget.

The major problem for us is that because this guidance is used by pharmaceutical companies in drug development studies, we cannot hope to have any meaningful ethnicity data that we can use. The only data are those lumped under a generic "Asian" umbrella, which essentially denies the vast ethnic diversity in our communities.

Singapore is not any wiser and contributes to the confusion by ambiguously mixing ideas of race, ethnicity and even language into the definition. We identify 4 major categories from census definitions: Chinese, Malay, Indians and Others. The categories of Chinese, Malays and Indians are defined using fairly circuitous logic about origins which also incorporates language/dialectual characteristics. To make matters worse, race/ethnicity based medical studies often rely heavily on hospital records which for citizens are almost entirely based on recorded information from the National Registration Identification Cards. The information here do not use the same definitions as the census, but are almost completely self declarations according to self perceptions.

Race or ethnicity?

Race and ethnicity are terms which are often used interchangeably. To a large part, I believe it is due to the increasing political incorrectness of using race as a descriptor, thus moving the notion of race more towards that of ethnicity.

A 1950 UNESCO declaration "The Race Question", succinctly puts it:

"National, religious, geographic, linguistic and cultural groups do not necessarily coincide with racial groups: and the cultural traits of such groups have no demonstrated genetic connection with racial traits. Because serious errors of this kind are habitually committed when the term 'race' is used in popular parlance, it would be better when speaking of human races to drop the term 'race' altogether and speak of 'ethnic groups'."

Race in its original intent referred to the "roots" of population groups (etymology: Germanic 'reiza' - bloodline). This to a large extent referred to biological characteristics and the external appearance of the population groups. The term 'race' therefore carries heavy connotations about biology and heredity.

We know now that these notions are fallacious, and believe that there are no biological bases for classification of peoples into racial groups. Race is little more than a socio-political construct that allow societies to manage resource allocations.

The UNESCO declaration was correct. The term 'race' should actually be dropped from our vocabulary altogether as it is meaningless from a biological perspective, and its continued use just continues to perpetuate the myth that people can be sub-classified according to biology.

The more correct and useful term is 'ethnicity'. Ethnicity refers to population groups that are unified by social and cultural characteristics as well as geographic origins. That different ethnic groups have differing phenotypic features do not make them definable by these characteristics.

Pharmacogenetic studies as well as studies looking at inter-populational variability in drug responses, should refer to ethnicity as a descriptor of the population rather than to race. This would then include allele frequencies, anthropometric information, environmental exposures and other societal pressures. The academic challenge presented is how do we standardize these ethnicity descriptors so that that we can understand and apply the data being generated from these studies. Correctly however, ethnicity data have limited applicability across populations. For example, data on Chinese in Singapore do not necessarily apply to Chinese populations in China, Africa, Europe or US. Likewise, we should not too readily apply Chinese data generated in Beijing to a Singapore therapeutic context.

In our lab we use the terms Chinese, Malay and Indians because these are terms used by our National Registration Office. However in our studies we recruit subjects based on self-declaration of ethnicity (Chinese, Malay and Indians) consistent over three generations. The data we generate will be correct for our population as at this time, and we make no assertions that they can be representative of Chinese, Malay and Indian populations across the globe, or even for Singapore population groups for later generations.

Grapefruits and ....Pomelos

Few people in the west will know about pomelos. Apart from being a really yummy fruit, it is as potent as grapefruit in inhibiting CYP3A4, and MDR1 as well.

Here's my interpretation of the family tree of the pomelo and how it relates to the grapefruit.

Boyanese (Baweanese) in Singapore

Here's an interesting aside following from our previous discussions on ear wax and ethnicities.

A casual discussion with a Boyanese lady revealed that she had wet ear wax. Just an interesting association despite n= 1.

The other interesting nugget of information was that apparently the Boyanese do not classify themselves as Malays on their NRIC (National Registration Identify Card). They are either listed as 'Boyanese' or 'Others'. This is of interest because when we are collecting ethnicity/race information for purposes of medical case studies etc, any 'Malay' data may be under-represented.

The Boyanese originate from a small island off the north coast of East Java. It is of interest to us because many Singaporean Malays trace their heritage back to the original Boyanese settlers. Ethnically they are austronesians like the other Malays. If hospital records use NRIC classifications for ethnicity, and if the Boyanese do not classify themselves on the NRIC as Malays, it may be expected the the Malay data from hospital records will not be very representative.

So, who are the Thais anyway?

I was thinking about this when I was in Khon Kaen.

It is not an easy question to resolve, as despite the Thais now being numerically so much larger than the Khmers, the Khmers were so much more dominant historically because of the Angkorean civilization. The earliest recognition of a Thai entity only surfaced when the Angkor civilization started to decline.

In early prehistory the region was populated by a Mon language speaking people. Who were they? Most likely people of a Sino-Tibetan stock. On top of this was a distinct amount of 'indianization' as evidenced by civilizations like the Dvararati (pre-angkorean). What 'indianization' really means is not clear, and it is not certain if this was a cultural thing or there was actually an influx of Indian genes as had happened in Cambodia (through the Kambujas from India). In any case, during the Angkor period, the region was 'Khmer-ized', so I am sure there was a substantial of genetic admixture. (See 'So, who are the Khmers anyway?')

As the Khmer civilization ebbed, the Thai people emerged as a distinct entity through the Lavo and Sukhothai kingdoms. A large part of this may have resulted from an influx of Southern Chinese people from Yunnan, fleeing the Mongol invasions.

Thailand now does not recognize differnt ethnicities within the country and everyone is regarded as Thai, although unofficially different ethnic groups are apparent. In a very broad sense, indigenous Thais are generally a sino-tibetan people with a variable amount of Indian admixture. There may be some degree of contribution from the austronesian gene pool, especially in Southern Thailand. On top of these are more recent contributions from Southern China.

So how do we regard pharmacogenetic data from Thailand? I think it becomes important for us to evaluate the source of the data. If it is generated in large urban centres, the contribution of Chinese genes is quite substantial. Indigenous Thai data is best seen in studies conducted in rural communities. In Southern Thailand, one must expect a significant amount of similarity to 'Malay' genetics. In the southern provinces, there still remain pockets of negrito peoples.

This is so far my limited understanding of the situation. I may be wrong. But this is how the current understanding appear to leading us. Perhaps there may be others with a better understanding of Thai ethnicity who can share their experiences and understanding with us?

What's with the Japanese - wet or dry ear wax??

Another interesting bit of trivia I discovered when I visited RIKEN. There is a genetic polymorphism affecting the ABC (ATP-Binding Cassette) transporter ABC11, that determines if your ear wax comes out dry or wet. This was discovered by Yoshiura et al in 2006. See also report in the New York Times. Apparently the Japanese and Koreans (and Northern Chinese) exclusively have the 'dry ear wax' variant while African and West Europeans have the "wet ear wax" phenotype. The rest of the world have mixed proportions of dry and wet waxes. In Southern China and South East Asia, the frequency of wet wax increases. It is thought that the dry wax allele originated in Northern Asia, thus giving rise to an exclusive distribution of the allele in North China, Korea and Japan.

Wet is black, dry is white

The Japanese use the dry wax phenotype to distinguish the Yamato Japanese from the other Japanese arising from Hokkaido (Ainus) and Ryukyu (Okinawans).

Why not take the ear wax poll?

Who are the Japanese, anyway?

The Japanese ethnic group is deceptively homogeneous.The dominant ethnic group however is recognizable as the Yamato people. These are whom we have come to commonly recognize as 'Japanese'. However, some minor ethnic groups do find their home in Japan. Apart from the obvious transplants such as Koreans, Chinese, Taiwanese etc, these are the Ainus, Ryukyuans and the Nivkhs.

The Yamatos are people who derive originally from the North Chinese mainland, having crossed over through the Korean peninsula. Consequently, there is a genetic thread that runs through and links the Northern Han Chinese and Koreans with the Yamato Japanese. By contrast the Ainu and Ryukyuans are earlier peoples who antedate the arrival of the Yamato people. RIKEN has data that show the genetic similarity between the Ainu and the Ryukuans (Okinawans). It is thought that the arrival of Yamato cleaved the distribution of the original Austronesian population to create a northern Ainu group and a southern Okinawan group. The Nivkhs are a small minority who derive from Siberia.

That said, the Japanese are pretty much of the Yamato group (>98% of toal 130 million). The Ryukuans probably account for about 1% and the Ainu even less (0.3%).

From a practical perspective, when one examines Japanese PGx data we should make mental links with data originating from Northern China and Korea. Accordingly, some caution is necessary when we try and connect the dots between Japanese and essentially Southern Chinese and South East Asian data.

The following excerpted from Wikipedia (Japanese_people):

A recent study for the origins of Japanese people is based on the "dual structure model" proposed by Hanihara in 1991. He concludes that modern Japanese lineages consist of the original Jōmon people and immigrants from the Yayoi period. The Jōmon people originated in southeast Asia, moving to the Japanese Archipelago in the Palaeolithic period. In past several decades, the Japanese people was proposed to relate to Yi, Hani and Dai people based on folk customs or genetic evidences.

Another southeast Asian group moved to northeastern Asia. The population of this group increased in the Neolithic period and some moved to the archipelago during the Yayoi period. The miscegenation prevailed in Kyūshū, Shikoku and Honshū islands but not in Okinawa and Hokkaido, respectively represented by the Ryukyuan and Ainu people. This theory was based on the study of the development of human bones and teeth. The comparison of mitochondrial DNA between Jōmon people and medieval Ainu also supports the theory.

Ethanol pharmacokinetics

Ethanol is a small molecule that has a strong affinity for water. It is absorbed efficiently and rapidly after consumption. Regardless of how it is consumed and in what form of spirits, the effect of alcohol on the central nervous system is closely correlated with the circulating concentrations of alcohol in the blood. This allows enforcement authorities to set certain tolerable (legal) limits of blood alcohol concentrations (BAC) as a surrogate limit for alcoholic intoxication (Singapore's legal limit is 0.08%, or 80 milligrams of alcohol per 100 millitres of blood). As the alcohol in the blood equilibrates very rapidly with the alveolar concentrations, breath alcohol concentrations (BrAC) are often used by the traffic police as an alternative to measuring blood alcohol concentrations. In Singapore, the BrAC limit is 35 micrograms of alcohol per 100 millilitres of breath. See Singapore Traffic Police.

It is therefore of some interest to the public to know how much alcohol one can drink without exceeding the BrAC limits.

The peak (maximum) BrAC after consuming alcohol depends on a number of factors:

a] the total amount of alcohol consumed (not the volume of beverage). Obviously the larger the quantum of alcohol, the higher the BAC will be.

b] the rate of absorption of the alcohol. The rate will be faster if the stomach is empty, and if the concentrations are high but not too high. Higher concentrations of spirit (alcohol) will produce a greater concentration gradient to drive the absorption. However, if the concentrations are too high, there may be slower gastric emptying of stomach contents into the small intestines where absorption of the alcohol is faster and more complete. Men theoretically therefore absorb more alcohol then women.

c] the amount of first pass metabolism in the linings of the stomach. There is some controvery about how important this actually is. Women are said to have less alcohol dehydrogenase expressed in the stomach walls and therefore have less first pass metabolism. The less metabolism, the greater the absorption.

d] the 'volume of the body' into which the alcohol is distributed. Pharmacokinetically this is referred to as the volume of distribution. Men have a higher water content in their body compared to women, and since alcohol is distributed primarily into body water, men will weight for weight, develop lower BrACs.

e] the rate of elimination of alcohol. The ADH genetic polymorphims have been discussed elsewhere. If consumed quickly, the rate of elimination will not affect the BrAC much, but if the consumption is protracted over a period of time, long enough for elimination to occur, the rate of elimination may have a significant effect on the BrAC.

Based on the above understanding, it is a reasonable expectation (assuming that the amount of alcohol consumed is exactly the same) that a muscular Chinese man sipping several glasses of wine over the course of a 4-course meal will produce substantially lower BrACs compared to an Indian lady quaffing down a series of stiff drinks on an empty stomach.

Alcohol pharmacogenetics in Singapore

The news about the alcohol related death at the National University of Singapore triggered some thinking about the interesting aspects about how alcohol (ethanol) is handled by the Chinese in Singapore.

Ethanol regardless of the form it comes in, is metabolized fairly efficiently in the body by means of an enzyme, alcohol hydrogenase (ADH). Although there are other enzymes that can also do this (e.g. CYP2E1), the most important pathway for alcohol degradation is really ADH. ADH itself is encoded by 7 genes but the major enzyme in the stomach mucosa and liver is the Class 1 enzyme, encoded by the ADH1B gene.

CH₃CH₂OH + NAD⁺ → CH₃CHO + NADH + H⁺

What is important for us to realize is that there is a common genetic polymorphism affecting the ADHB1 gene in Chinese. An 'atypical' ADH was first described in 1968 by Von Wartburg and Schuerch (Ann. N.Y. Acad. Sci. 151: 936-947, 1968). Subsequently Stamatoyannopoulos in 1975 found the atypical variant in 85% of Japanese. The variant is now identified as ADH1B*47 (previously ADH2*2) and exchanges a histidine for arginine in the protein, resulting in an enzyme with very much enhanced activity (100 fold difference in Vmax). A recent study (Alcohol Clin Exp Res. 2004 Jan;28(1):10-4) in Jewish carriers of this variant showed increased rate of elimination of alcohol from the blood (8.09 vs 7.14 g/hr).

This genetic variant is particularly common in South East and East Asia and is an important genetic 'protector' against alcoholism because it is thought to result in more unpleasant outcomes because of higher levels of aldehyde production . The frequency among Taiwanese Han Chinese is about 75% (Hepatology. 1997 Jan;25(1):112-7 ).

A recent report was able to show this global distribution of ALD1B*47 variant (Am J Hum Genet. 2007 Oct;81(4):842-6. Epub 2007 Aug 24). Note the interesting cluster in West Asia. Also the absence of this variant in the Indian subcontinent. More about this later, and its implications for us in Singapore.

Global contour plot of the ADH1B*47His allele frequency

Carbamazepine - Stevens-Johnson Syndrome

In 2004, a Taiwanese group (Chung et al, Nature 2004, 428:486) reported a very strong association between the HLA-B*1502 allele with the development of Stevens-Johnson Syndrome with the anti-epileptic drug carbamazepine.

This is actually a very interesting story about an drug SAE (serious adverse event) associated with a specific HLA genotype. Not only genetics, but also an intriguing tale about ethnicity and populations.

So far all the clinical data verify the association in Han Chinese (Taiwan, Hong Kong) and Thai. No associations have been found for Europeans....and here is what is also interesting...not for Japanese as well. Ferrel and McLeod (2008) have reviewed the data, and there have also been a number of more recent studies reporting on the HLA-B*1502 allele frequencies from different populations.

A Table of these frequencies from Ferrel and McLeod is reproduced here.
There are a couple of more recent data not only showing the same patterns but also showing how the Northern Chinese group pulls apart from the Southern Chinese. Han Chinese from Shaanxi, Koreans and Japanese have a Caucasian type frequency while Southern Chinese in Guangdong cluster with the rest of South East Asia (Philippines, Java). The Indian subcontinent occupies an intermediate position, and depending on the population sampled, with frequencies ranging between Caucasian frequencies to those similar to South East Asians and Southern Chinese. The association between HLA-B*1502 and carbamazepine SJS appears not in doubt, but apparently only for Southern Chinese (Taiwan, Hong Kong, most of Singapore) and people of South East Asian ancestry. It does not seem to apply for Caucasians, and remains doubtful for Northern Chinese, and people of a more northern ancestry such as the Japanese (and possibly the Koreans). There remains a big question mark for people from the Indian subcontinent.

The FDA did us a major injustice when in their haste they recommended that genotyping for HLA-B*1502 be done prior to dosing, for people of an "Asian ancestry". We have no idea what this means. For Singapore, it is probably reasonable for Chinese and Malays (although it may not apply to the more northern Chinese among us), but we are totally in the dark with regards to "Indians" and "Eurasians".