CHICAGOObtaining an individual patient’s genetic profile
for genetic polymorphisms known to affect drug responsiveness or risk of drug
toxicity will become a routine part of medical care over the next 25 years and
will dramatically transform the prescribing process, Mark J. Ratain, MD,
predicted at the Vanderbilt University Symposium. Dr. Ratain is professor of
medicine and chairman of the Committee on Clinical Pharmacology at the
University of Chicago.
"Determining the patient’s genomic sequence will soon
become a part of standard practice and will affect both selection of drugs and
selection of dosages," Dr. Ratain said. "The cost is now under $1 for
each genotype, and I expect that cost to drop quickly as medical databases that
relate genotypes to effects on drug function become available. I think
therapeutics will be very different 25 years from now," Dr. Ratain said.
Several clues point to genetic polymorphisms in the metabolism
of a particular drug, Dr. Ratain noted. These include a high coefficient of
variance (CV), unpredictable toxicity, evidence for bimodality in either
pharmacokinetics or toxicity, and possible or known metabolism by enzymes
associated with other polymorphisms. The fact that adverse reactions have been
seen in over half of patients taking irinotecan (Camptosar), including grade
3/4 late-onset diarrhea in about 30%, suggested that a genetic polymorphism
might be a contributory factor.
Points of Influence
Irinotecan metabolism offers several possible points at which a
genetic polymorphism might exert influence. Dr. Ratain said that plasma
disposition curves following irinotecan infusion show significant individual
variability, particularly with regard to levels of the glucuronide metabolite
SN-38G. In general, patients who maintain higher levels of SN-38G are less
likely to have problems with diarrhea. Those whose metabolisms are slower to
convert SN-38 to the glucuronide form have more diarrhea.
This observation led to construction of a model to explain
irinotecan pharmacokinetics and toxicity (Figure 1). "The major
determinant of diarrhea is the amount of SN-38 in the gut lumen, which in turn
is determined by the rate of glucuronidation of SN-38 and by the amount of
SN-38 transported into the gut," Dr. Ratain said.
The biliary ratio (SN-38/SN-38G) has been used to validate this
model. Dr. Ratain reported that in 26 prospectively studied patients treated
with irinotecan, those with higher biliary ratio or biliary index were
significantly more likely to have grade 3 or grade 4 diarrhea. "There was
a highly significant relationship (P = .003) between biliary index and degree
of diarrhea but not between irinotecan dose and diarrhea," Dr. Ratain
Human UGT-1 Locus
Researchers used rat models to sort out the factors behind this
variability. These studies pointed to the human UGT-1 locus, which encodes
multiple forms of UDP-glucuronosyl transferase (UGT). Not only does this locus
come in several versions, but frequencies of the UGT1A1 promoter region vary
distinctively among ethnic groups.
Dr. Ratain said that in vitro studies have shown that people
who have one or two copies of the UGT1A1 7 allele (ie, genotypes 7/7 or 6/7)
are less able to glucuronate SN-38 than those whose genotypes are alleles 6/6.
"This suggested a relationship between genotype and toxicity in the
clinic," Dr. Ratain said.
Examination of genotypes in patients in clinical studies showed
that patients either heterozygous or homozygous for the 7 allele are
significantly more likely to have grade 2 to 4 diarrhea when treated at 300
mg/m2. Those with 6/7 or 7/7 genotypes are also at greater risk for serious
neutropenia at the 300 mg/m2 dose. Studies at the currently recommended dose of
350 mg/m2 dose are ongoing. "The subset of patients who develop diarrhea
are likely to be genotypes 7/7 or 6/7," Dr. Ratain said.
Japanese researchers have studied frequencies of the Gly71Arg
allele in various populations and in Japanese newborns with hyperbilirubinemia.
Dr. Ratain said that these studies show the allele frequency varies from 0 in
Germans to 0.23 in Koreans and Chinese and 0.32 in infants with
hyperbilirubinemia. "Coding region polymorphisms are very common in Asian
populations," he said.
DNA Sequence Diversity
A related area is DNA sequence diversity in genes affecting the
activity of CYP3A in the cytochrome P450 system. "Twenty percent of the
population has the CYP3A5 allele, and irinotecan is a substrate for
CYP3A5," Dr. Ratain said.
The National Institutes of Health Pharmacogenetics Research
Network and Knowledge Base is expected to provide some of that information. Dr.
Ratain is studying 300 patients in an ongoing Cancer and Leukemia Group B
(CALGB) trial of irinotecan/leucovorin who will have DNA specimens collected
to enable investigators to look back after study completion and determine
whether differences in toxicity correlated with genotype. Other
pharmacogenetics studies underway involve drug metabolizing enzymes, asthma
treatment, tamoxifen (Nolvadex), membrane transport proteins, as well as