143Tranilast-Induced Hyperbilirubinemia
due to Gene Polymorphism
PRESTO (Prevention of REStenosis with Tranilast) was a double-blind
placebo- controlled trial of Tranilast (GlaxoSmithKline) for the treatment of resteno-
sis after percutaneous transluminal coronary angioplasty. Tranilast inhibits the
release or production of cyclooxygenase-2 and restores cytokine-induced nitric oxide
production. Hyperbilirubinemia developed in 4 % of the patients. Pharmacogenetic
studies showed that it to be Gibert’s syndrome due to polymorphism in the uridine
diphosphat glucuronosyltransferase 1A1 gene − mild chronic hyperbilirubinemia that
can occur in the absence of liver disease and hemolysis and is not life-threatening.
The trials continued although the fi nal results were lack of effi cacy.
Linking Pharmacogenetics with Pharmacovigilance
Genetic Susceptibility to ADRs
A simple method has been devised that is acceptable to members of the general
population to enable estimation of the risks that specifi c genetic factors confer on
susceptibility to specifi c ADRs. Buccal swabs are a minimally invasive method to
obtain cells for DNA extraction. A pilot study using this approach was conducted in
the New Zealand Intensive Medicines Monitoring Program to link prescription
event monitoring (PEM) studies with pharmacogenetics. Use of buccal swabs was
acceptable to patients and provided DNA of suffi cient quantity and quality for geno-
typing. Although no differences in the distribution of genotypes in the case and
control populations were found in this small study, case-control studies investigat-
ing genetic risks for adverse drug reactions using drug cohorts from PEM studies
are possible, and there are several areas where population-based studies of genetic
risk factors for are needed:
- Genetic variations affecting P-gp function
- Variations affecting drugs metabolized by CYP2C9 and other polymorphic CYP
enzymes - Genetic variation in β-adrenergic receptors and adverse outcomes from
β-adrenoceptor agonist therapy - Genetic variation in cardiac cell membrane potassium channels and their asso-
ciation with long QT syndromes and serious cardiac dysrhythmias.
Linking Genetic Testing to Postmarketing ADR Surveillance
FDA is interested in collaboration with consumer personal genomics companies for
tracking post-marketing ADR surveillance. In marketing ancestry and disease-
predisposition genetic testing services directly to consumers, personal genomics
Use of Pharmacogenetics in Clinical Pharmacology