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

160 Applying Pharmacogenomics in Therapeutics
TABLE 6.6
Clinical Recommendation of 5-FU Dosing Based on DPD Phenotype
Phenotype Implications Dosing Recommendations
Homozygous for wild-type allele
(normal DPD activity)
Heterozygote (intermediate DPD
activity)
Homozygous for variant or mutant
(deficiency of DPD activity)
Normal DPD activity, less or
no risk of 5-FU toxicity
Decreased DPD activity,
increased risk for severe or
fatal 5-FU toxicities
No DPD activity, high risk for
severe or fatal 5-FU toxicities
Use standard dose
Start with at least 50%
reduction of starting dose
May titrate up the dose
based on toxicities
Use alternative drugs
Source: Adapted from Caudle KE, et al., Clin Pharmacol Ther, 94(6), 640, 2013.
Approximately 30% of patients with reduced mean DPD activity could experience
grade 3 or 4 toxicities from 5-FU. Screening for DPYD*2A is commercially available
but accounts for approximately 45% of all DPD deficiency cases (Table 6.2).
In addition, patients with partial or complete DPD activity can be identified by blood
lymphocytes, which can also determine whether patients would be at increased risk
for developing 5-FU-related toxicity. 10,11,16,28,29
Although the manufacturer recommends that 5-FU and capecitabine should
not be prescribed for patients with DPD deficiency, preemptive genetic testing is
not currently recommended by the US FDA because the frequency of the DPDdeficient
variant alleles is relatively low, and patients not carrying these deficient
variants may still have grade 3 and 4 toxicities from 5-FU. Clinical guidelines
regarding the dose of 5-FU for carriers of the DPD variants have been published and
summarized in Table 6.6. 57
CYP PGx
PGx of cytochrome P450 (CYP) plays a critical role in regulating the activation and
inactivation of many cancer therapeutic agents (Table 6.1). Several chemotherapeutic
agents are prodrugs that need to be activated by CYPs. CYP2B6 is one of the key
enzymes involved in the activation of cyclophosphamide, ifosfamide, procarbazine,
and thiotepa, and thus, CYP2B6 polymorphism could affect the plasma levels of
their active metabolites, drug efficacy, and toxicities.
Although 50 polymorphisms of CYP2B6 have been identified, the most common
functional variants are CYP2B6*5 and CYP2B6*6 with decreased gene expression
and enzyme activity. Takada and colleagues reported higher rates of nephrotoxicity
associated with CYP2B6*5 in lupus patients treated with pulse cyclophosphamide.
However, the role of CYP2B6*5 is still not clearly defined. 14–16,35,50,58
Constituting only 2–4% of total CYP enzymes in the human liver, CYP2D6 metabolizes
25–30% of all clinically used drugs. Currently, there are four known phenotypes
of the CYP2D6: extensive metabolizer (EM), intermediate metabolizer (IM),