II-39Invited lectures – abstracts
PHARMACOGENETICS BASED THERAPEUTIC
RECOMMENDATIONS – READY FOR CLINICAL PRACTICE?
Julia Kirchheiner, MD
University of Ulm, Institute of Pharmacology of Natural Products & Clinical Pharmacology
Helmholtzstr. 20, D-89081 Ulm, Germany; julia.kirchheiner@uni-ulm.de
genotyping in this field would be very helpful for the
aim of introducing pharmacogenetic diagnostic into
drug therapy.
In cardiovascular disease, oral anticoagulants, beta-
blockers, statins and other drugs such as phenytoin,
losartan, and torsemide are affected by genetic poly-
morphisms of the cytochrome P450 drug metaboliz-
ing enzyme CYP2C9. Studies in patients or healthy
volunteers revealed up to 10-fold differences in phar-
macokinetic parameters such as oral clearance or elim-
ination half-lives due to genetic polymorphisms of
CYP2C9. For oral anti-diabetics, decreased oral clear-
ances can lead to hypoglycemia, which is a severe ad-
verse drug effect in diabetic patients. In oral anticoag-
ulant therapy, CYP2C9 polymorphisms have already
been shown to cause differences in anticoagulant effi-
cacy measured by the INR ratio, which lead to differ-
ences in the frequency of bleeding complications. Non-
steroidal anti-inflammatory drugs have a high risk for
gastrointestinal bleeding complications and ulcer-
ations, and differences in pharmacokinetic parameters
of these drugs caused by CYP2C9 polymorphisms
might result in a higher risk for these adverse effects in
individuals carrying genetic polymorphisms.
Data appear established enough for routine consid-
eration of CYP genotypes in certain longterm drug
therapies. Nevertheless, before routine genotyping
can be incorporated into the clinical setting, the ben-
efits of genotype-based therapeutic recommenda-
tions have to be tested by a randomized controlled
clinical trial comparing therapy with pharmacogenetic
diagnostics with therapy as usual in a randomized
controlled fashion. The typical primary outcome pa-
rameters in such studies should be efficacy parame-
ters and parameters like long-term outcome, adverse
drug effects and direct cost-related parameters such
as duration of hospital stay or disability.
For many drugs, pharmacogenetic polymorphisms
are known affecting biotransformation and clinical
outcome. The clinical importance of these variants
depends on allele-frequency and the effect size of the
clinical outcome parameters. Further, it depends on
the therapeutic range of the drug which is affected,
on predictability of drug response as well as on dura-
tion until onset of therapeutic efficacy. Consequenc-
es which arise from genotyping might be: adjustment
of dose according to genotype, choice of therapeutic
strategy or even choice of drug.
In antidepressant drug treatment, most drugs are
metabolized via the polymorphic cytochrome P450
enzymes CYP2D6 and CYP2C19. Huge differences
in pharmacokinetic parameters have been consis-
tently shown for many tricyclics, some SSRIs, and
other antidepressant drugs. However, the effects on
therapeutic efficacy and adverse events have been
described controversially. Pharmacokinetic differen-
ces caused by genetic polymorphisms can be over-
come by adapting the drug dosages and dosing in-
tervals. Similar to bioequivalence studies, the aim to
achieve similar plasma concentration time courses
of antidepressants might help to reduce side effects
and therapeutic failure.
In the field of antipsychotic drug treatment, genetic
polymorphisms in drug metabolizing enzymes as well
influence pharmacokinetic parameters to a large part.
In these kinds of drug therapy, a more clear dose de-
pendency of side effects such as extrapyramidal side
effects exists, and the consideration of genetic poly-
morphisms might be more beneficial. Recent studies
showed a relationship between the occurrence of
adverse antipsychotic drug effects and CYP2D6 gen-
otype. A prospective evaluation of the cost-benefit of