Table 1.

Examples of the successful application of pharmacogenomics.

Drug	Disease	Phenotype	Type of impact (PK, toxicity, efficacy)	Percentage of patients that could benefit	Notes
Thiopurine Therapy	Examples include acute lymphoblastic leukemia and ulcerative colitis	TPMT intermediate activity	Toxicity (myelo- suppression)	3–14% - those homozygous or heterozygous TPMT [28]	Homozygous IP/WI-deficient patients (less than 0.5% of ndividuals) usually experience life- threatening myelosuppression
Codeine (but applies to many drugs)	Pain	CYP2D6 conversion of codeine to morphine, the active metabolite	PK (metabolism) and consequent efficacy, toxicity	0–10% poor metabolizers; 1–2% ultrarapid metabolizers [83]	Poor metabolizers have no analgesia; ultrarapid metabolizers risk morphine toxicity
Warfarin	Hypercoagulable states (e.g., thromboembolism)	CYP2C9 metabolism of S-warfarin, the potent enantiomer [10] VKORC1 inhibition by warfarin (VKORC1 gene encodes the target enzyme of warfarin)	PK (metabolism) and consequent efficacy (anticoagulation), as well as toxicity (lower chance of major hemorrhage) [10,33]	Asian (86%) and Caucasian (55%) incidence of ‘low dose’ individuals from either VKORC1 or CYP2C9 variants (from at least one VKORC1 haplotype A or CYP2C9 variant allele) [91]	Narrow therapeutic range Major bleeding in 10–16% [10] PGx findings led to US label updates in 2007 and 2010
Clopidogrel	Hypercoagulable states (e.g., thromboembolism)	LOF allele of CYP2C19	PK(CYP2C19 metabolism to active drug)	Up to 30% of study population [92]; 2–14% of the general population are poor CYP2C19 metabolizers [85]	PGx findings led to US label updates in 2009 and 2010
Gefitinib	NSCLC	EGFR	Efficacy	12–18% [29]	PGx findings made during drug development; first EGFR-targeted category approved for NSCLC [29]
Trastuzumab	Breast cancer	HER2-positive tumors	Efficacy (overal survival and disease- free survival)	20% of breast cancer patients	Cardiac toxicity an important consideration in benefit:risk analysis [93]
Abacavir	HIV	HLA-B*5701	Safety (identifying serious adverse event: hypersensitivity reaction)	5–8% of clinical trial patients [10,94]	Postmarketing - leading to US label update in 2008 100% negative-predictive value for mmunologically confirmed hypersensitivity reaction
Ivacaftor (Kalydeco)	Cystic fibrosis	G551D mutation in the CFTR gene	Efficacy [95]	The mutation exists in 4% of cystic fibrosis patients	Development of the drug guided by PGx principles [37]
Irinotecan	Colorectal cancer	Lower capacity to metabolize SN-38 (active metabolite of irinotecan) in patients homozygous for the UGT1A1*28 allele	Toxicity [96]	UGT1A1*28 mutation in 26–31% of Caucasians, 42–56% of Africans and 9–16% of Asians, but may be higher in ndians [97]	One of the first drugs to receive pharmagenomically guided labeling requirements by the US FDA in 2005

LOF: Loss of function; NSCLC: Non-small-cell lung cancer; PGx: Pharmacogenomics; PK: Pharmacokinetics; SN-38: 7-ethyl-10-hydroxy-camptothecin (the active metabolite of irinotecan).