Page 115 - Hematology_ Basic Principles and Practice ( PDFDrive )

86 Part I Molecular and Cellular Basis of Hematology

TABLE CPIC Recommendations on Medications Whose Adverse Effects Have Been Associated With Variability in Candidate Genes
8.2 and Manifest Predominantly as Hematologic Abnormalities (see Table 8.1, CPIC website)
Adverse Drug Reaction Drug(s) That Cause ADR Important Genetic Variant(s) CPIC Recommendation
Myelosuppression 6-Mercaptopurine TPMT*2 (rs1800426), *3A Start with reduced doses for patients with one
6-Thioguanine (rs1800460 + rs1142345), nonfunctional TPMT allele, or drastically reduced
azathioprine *3C (rs1142345) doses for patients with malignancy and two
nonfunctional alleles; adjust dose based on degree of
myelosuppression and disease-specific guidelines.
Consider alternative nonthiopurine immunosuppressant
therapy for patients with nonmalignant conditions and
two nonfunctional alleles
Bleeding risk Clopidogrel CYP2C19*17 (rs12248560) Recommends an alternative antiplatelet therapy (e.g.,
prasugrel, ticagrelor) for poor or intermediate CYP2C19
metabolizers if there is no contraindication
Myelosuppression 5-Fluorouracil (5-FU) Dihydropyrimidine For fluoropyrimidines (i.e., 5-FU, capecitabine, or tegafur)
(mucositis, dehydrogenase: DPYD*2A recommends an alternative drug for patients who are
neurotoxicity) (rs3918290), *13 homozygous for DPYD nonfunctional variants, as these
(rs55886062), DPYD patients are typically DPD deficient. Consider a 50%
rs67376798 A (on the reduction in starting dose for heterozygous patients
positive chromosomal strand) (intermediate activity)
Bleeding risk Warfarin and other CYP2C9*2 (rs1799853), The best way to estimate the anticipated stable dose of
coumarin derivatives CYP2C9*3 (rs1057910), warfarin is to use the algorithms available on http://
VCORC1 (rs9923231) www.warfarindosing.org
Acute hemolytic Rasburicase and other Deficient or deficient with Rasburicase is contraindicated in G6PD-deficient patients
anemia drugs (see Ref. 20 and chronic nonspherocytic with or without CNSHA. In patients with a negative or
21 for a full list of hemolytic anemia (CNSHA). inconclusive genetic test results an enzyme activity
drugs) A male carrying a class I, II, test is recommended prior to rasburicase treatment to
or III allele, a female determine whether a patient is G6PD deficient
carrying two deficient class
I–III alleles (see text for
more details)

that pharmacogenetic-guided warfarin dosing is more accurate and comprehensive drug transporter databases are available else-
than standard fixed, but not algorithm-guided, dosing. Neither the where (see Table 8.1). There is also a growing body of data on the
EU-PACT nor the COAG trial were powered for clinically relevant endogenous functions (e.g., transport of metabolites, antioxidants,
endpoints, such as bleeding and thromboembolic events, and the signaling molecules, and hormones) of ATP and SLC transporters,
currently ongoing randomized Genetics Informatics Trial (GIFT) of and a number of hematologic diseases were identified to be caused by
Warfarin to Prevent Deep Venous Thrombosis will assess the clinical variants in these transporters (e.g., variants in SLC19A2 in thiamine-
outcome benefit of pharmacogenetic-guided warfarin dosing. 15 responsive megaloblastic anemia, variants in SLC11A2 in sideroblastic
Alternative anticoagulants (e.g., dabigatran, apixaban, rivaroxa- anemia, variants in SLC4A1 in hereditary spherocytosis type 4 and
ban, and edoxaban) have been developed; for example, the dosing southeast Asian ovalocytosis, and variants in ABCG5 and ABCG8 in
of dabigatran, which acts as a direct thrombin inhibitor, is not mitochondriopathies with large platelets and ovalocytes). Herein we
influenced by these genetic polymorphisms, which makes this drug provide one selected example on how variants in a drug transporter
a potential alternative for patients in whom heredity is associated with (i.e., SLCO1B1) have been identified to influence the disposition and
extreme variations in warfarin effects. toxicity of the antileukemic drug methotrexate (MTX).

DRUG TRANSPORTERS SLCO1B1 and Methotrexate

Although passive diffusion is thought to account for tissue distribu- The solute carrier organic anion-transporter family member 1B1
tion of some drugs and their metabolites, there is a growing body of (SLCO1B1) gene, for example, encodes an organic anion transporter
evidence that membrane transporters play an important role in drug 1B1 (OATP1B1) that is located primarily on the sinusoidal face
disposition and effects. Membrane transporters are highly expressed of human hepatocytes. OATP1B1 mediates the hepatic uptake of
in epithelial cells, and move drugs and other xenobiotics across the many endogenous compounds (e.g., bilirubin) and xenobiotics such
gastrointestinal (GI) tract into systemic circulation and across hepatic as HMG-CoA reductase inhibitors (e.g., simvastatin) from sinusoi-
and renal tissue into the bile and urine, respectively, for excretion. dal blood, resulting in their net excretion from blood, likely via
They also distribute drugs into and out of “therapeutic sanctuaries” biliary excretion. A common sequence variant in the coding region
such as the brain and testes, and transport them into and out of sites of SLCO1B1 (rs4149056) decreases the transport activity of the
of action, such as leukemia cells. encoded protein and results in markedly increased plasma concentra-
The two multi-specific drug transporter superfamilies encompass tions of drugs that are eliminated from the blood via hepatic uptake.
the adenosine triphosphate (ATP)-binding cassette (ABC) and the Using GWAS, correlations have been established between variants
16
solute carrier (SLC) transporters. Whereas SLC transporters largely, in SLCO1B1 and myopathy after treatment with the HMG-CoA
but not exclusively, mediate cellular uptake, the ABC drug trans- reductase inhibitor simvastin. 9
porters mainly efflux substrates from cells. The function, substrate In the field of hematology, a GWAS identified the rs4149056
specificity, and organ distribution among different transporters vary variant to be significantly associated with MTX clearance and GI