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

206 Applying Pharmacogenomics in Therapeutics
TABLE 8.1 (Continued)
FDA Product Labeling for CNS Medications
Drug Name
Pharmacogenetic
Biomarker
Label Information
Thioridazine CYP2D6 • Reduced CYP2D6 activity: Would be expected to augment
the prolongation of the QTc interval associated with
thioridazine and may increase the risk of serious,
potentially fatal cardiac arrhythmias.
• Thioridazine is contraindicated in individuals with a known
genetic defect leading to reduced levels of activity of
CYP2D6.
Trimipramine CYP2D6 • PMs: Higher than expected plasma concentrations of TCAs
when given usual doses. Depending on the fraction of drug
metabolized by CYP2D6, the increase in plasma
concentration may be small, or quite large (eightfold
increase in plasma AUC of the TCAs).
Valproic acid UCD • Contraindicated in patients with known urea cycle
disorders.
• Prior to the initiation of valproate therapy, evaluation for
UCD should be considered for patients with:
• a history of unexplained encephalopathy or coma,
encephalopathy associated with a protein load,
pregnancy-related or postpartum encephalopathy,
unexplained mental retardation, or history of elevated
plasma ammonia or glutamine;
• cyclical vomiting and lethargy, episodic extreme
irritability, ataxia, low BUN, or protein avoidance;
• a family history of UCD or a family history of
unexplained infant deaths (particularly males); or
• other signs or symptoms of UCD.
Venlafaxine CYP2D6 • Total concentrations of active metabolites were similar
between PMs and EMs.
• No dosage adjustment is required when venlafaxine is
coadministered with a CYP2D6 inhibitor.
Note: AUC, area under the curve; C max , maximum drug plasma concentration; CYP, cytochrome 450;
EM, extensive metabolizers; PM, poor metabolizers; SJS, Steven–Johnson syndrome; t ½ , half-life;
TCA, tricyclic antidepressant; TEN, toxic epidermal necrolysis; UCD, urea cycle disorder.
neuropsychiatric drug efficacy. Using pharmacogenomics in determining the pharmacokinetics
of medications has been useful in the potential prediction of adverse
effects, demonstrated by the development of clinical guidelines for dosing of medications
based on CYP genotypes. 7
A final approach to the study of pharmacogenomics in neurologic and psychiatric
research is the utilization of genome-wide association studies (GWASs).
A major limitation to the use of GWASs is the large sample sizes assumed to be