Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

158 Applying Pharmacogenomics in Therapeutics
TABLE 6.5
Clinical Recommendation of 6-MP Based on TPMT Phenotype
Phenotype Implications Dosing Recommendations
Homozygous wild-type (normal
TPMT activity, or EMs)
Heterozygous (intermediate
TPMT activity, or IMs)
Homozygous mutant or variant
type (low or deficient TPMT
activity, or PMs)
Lower concentrations of
toxic metabolites of 6-MP
Moderate concentrations of
toxic metabolites of 6-MP
High concentrations of
toxic metabolites of 6-MP
Start with 6-MP normal dose
Allow 2 weeks to reach steady state
before adjusting doses
Start with reduced dose of 6-MP
(30–70% of full dose) and adjust
doses based on toxic events
Allow 2–4 weeks to reach steady
state before adjusting doses
Start with 1/10 standard dose and
adjust doses based on toxic events
Allow 4–6 weeks to reach steady
state before adjusting doses
Source: Adapted from Relling MV, et al., Clin Pharmacol Ther, 93(4), 324–5, 2013. With permission.
the enzyme activity (PMs). 22 At the steady state, the dosages of 6-MP vary up to
10-fold between PMs and EMs. IMs have up to threefold differences in 6-MP concentrations
compared to EMs. Clinical evidence indicates that a 10- to 15-fold less
dose than conventional in TPMT PM patients enables successful treatment without
substantial toxicity. 3,12,30,31,50
Although this polymorphism is relatively rare, PMs would have severe, lifethreatening
hepatic toxicity, gastrointestinal toxicity, and myelosuppression due to
excessive levels of 6-thioguanine when exposed to standard doses of 6-MP. TPMT
deficiency also increases risk of secondary cancers associated with 6-MP standard
dose treatment. Based on this, the US FDA recommends genotype testing for TPMT
for patients with leukopenia and frequent monitoring of liver function.
Measurement of TPMT activity or genotyping of TPMT before administration of
6-MP may be useful to minimize or avoid toxicity associated with use of 6-MP. The
US FDA recommends TPMT testing to be considered when a patient has clinical or
laboratory evidence of severe meylosuppression after the use of 6-MP. 51 Although it
is shown that TPMT genotyping is clinically beneficial, currently there is no general
correlation regarding TPMT genotyping and the cost-effectiveness of such a test. 52
Current dosing recommendations with different TPMT phenotype and 6-MP can
be found in the CPIC Guidelines, whose summary can be found in Table 6.5. 53
TPMT Polymorphisms and Cisplatin
Cisplatin is a platinum-containing compound that acts as an alkylating agent.
Cisplatin is a widely used chemotherapeutic agent but has been associated with a high
incidence of ototoxicity. Cisplatin ototoxicity may lead to dose reduction and also
termination of therapy. Genetic variants of TPMT and COMT have been identified
to be highly associated with cisplatin-induced ototoxicity in several cohort studies.