events at lower doses than Caucasians, even after
body weight was accounted for (Lin, 1986: 1991;
Wood and Zhou, 1991). With tricyclic agents, the
picture is more confusing between Asians and
Caucasians, but Asians appear to show more varia-
bility overall and African-Americans tend to have
higher plasma levels, faster therapeutic effect, but
more side-effects than either (Stricklandet al.,
1991).
Essential hypertension is a symptom of modern
society, and its treatment accounts for a sizeable
portion of global prescriptions. As a result, there is
a great interest in reported ethnic and racial differ-
ences reported in the literature. The use of appro-
priate therapy in Black patients has been best
studied. As monotherapy, calcium channel block-
ers and diuretics appear to be most effective in
Blacks, whereasb-blockers and ACE inhibitors
produce smaller reductions in blood pressure
(Kiowiskiet al., 1985; Freis, 1986; Hall, 1990).
However, this may more reflect the lower plasma
renin, salt and water retention and intercellular
sodium and calcium in Blacks, compared to other
groups (Kiowiskiet al., 1988). There are individual
exceptions amongst patients and among drugs,
even within these classes; for example labetalol,
a combineda-blockers and b-blockers, can be
equally effective in both African-Americans and
Caucasians and, as mentioned previously, the Chi-
nese appear twice as sensitive to propranolol as
Caucasians (Osteret al., 1987; Zhouet al., 1990).
Receptor sensitivity
Salzman described a downregulation of benzodia-
zepine andb-blocker receptors linked to ageing. It
has been postulated that Asians have fewer benzo-
diazepine andb-blocker receptors than Cauca-
sians. Downregulation of these receptors with age
(Salzman, 1982) has been described and postulated
by Zhouet al.(1990), but hard evidence of racial or
ethnic differences is still awaited. If the Chinese are
more sensitive to propranolol in spite of their high
catabolic rate, it might be linked to adrenergic
receptor sensitivity.
Looking at the broader picture, part of today’s
discovery process is the incorporation of isoen-
zyme detector screens and computer predictor
modeling, to eliminate potential drugs posing
major metabolic and ethnic problems or interfer-
ence patterns. This is being done as part of the
screening process for lead candidates prior to pre-
clinical screening. Drugs such as terfenidine and
mibefradil would not pass these screens today.In-depth drug case studies
The European Federation Pharmaceutical Associa-
tion (EFFPA) commissioned a third party, the
Centre for Medicines Research (CMR, UK), to
collect data on a small number of targeted drugs.
By direct appeal to manufacturers through an
independent third party, compliance information
between regions was made available, as well as
PK data. In addition, data on efficacy and safety
were also requested from firms operating in the
three major areas.
The CMR conducted this study amongst
European and American companies to assess the
significance of interethnic differences in clinical
responsiveness and to determine the implications
of such differences for international clinical devel-
opment. Information was collected for all three
phases of clinical development. Data from 21 com-
pounds developed since 1985 in the West and
Japan, and covering a wide range of therapeutic
categories, were analysed. Overall, there was no
indication that the metabolism of any of these
drugs was affected by genetic polymorphism.
One compound is known to be eliminated by an
enzyme which is polymorphic, but there was no
evidence of altered phenotype or subset population
within any ethnic group. Although three com-
pounds displayed some regional variability in
PK, further analysis of the data provided rational
explanations for all such perceived differences. All
the regional variations were attributable to differ-
ent pharmaceutical formulations, reduction of
initial doses and alteration in sampling times and
techniques, and none of these differences had any
significant impact on clinical development.
There was considerable regional variation in
dosing or frequency of dosing, with a tendency
toward lower Japanese doses, due to cultural236 CH18 RACIAL AND ETHNIC ISSUES IN DRUG REGISTRATION