Pharmacogenomics Lecture 5: Oncology/Transplant

Tamoxifen (Nolvadex)

SERM approved for both treatment and prevention of ER+ breast cancer in premenopausal women

- only agent FDA approved to prevent breast cancer in high risk patients

5 years

____ years of treatment with Tamoxifen (Nolvadex) halves the recurrence for ER+ breast cancer patients who have had surgical removal

CYP2D6

which enzyme is responsible for the metabolism of Tamoxifen (Nolvadex)?

Anastrozole and Letrozole

[Aromatase Inhibitors]

what are some alternatives to Tamoxifen (Nolvadex)?

ERBB2/HER2

30% of metastatic breast cancer involves ______ gene amplification and protein overexpression

Trastuzumab

monoclonal antibody that targets ERBB2/HER2 breast cancer

Taxol (Paclitaxol)

Primary resistance occurs with monotherapy with Trastuzumab in 66-88% of ERBB2-over expressing breast cancer, so it is combined with ______.

Trastuzumab emtansine (T-DM1)

Trastuzumab deruxtecan (T-Dxd): targeting HER2

Sacituzumab govitecan (SG): targeting Trop-2

list the antibody drug conjugates (ADCs) approved for breast cancer treatment.

Tacrolimus (TAC, Prograf)

calcineurin inhibitor that inhibits interleukin‐2 production and T‐lymphocyteactivation.

- Immunosuppressant following solid organ and hematopoietic stem cell transplantation.

- Other uses: Crohn's disease, glomerulonephritis, GVHD, psoriasis.

- Narrow therapeutic index and substantial individual variability in PK

CYP3A5

Tacrolimus undergoes substantial first pass metabolism in the intestine and liver via CYP______ and to a lesser extent CYP3A4

CYP3A5✶3 (rs776746)

Intronic SNP that results in a splicing defect, leading to a premature stop codon and nonfunctional CYP3A5 protein.

CYP3A5✶6 (rs10264272)

CYP3A5 allele that has no activity due to a splicing defect

CYP3A5✶7 (rs41303343)

CYP3A5 allele that has no activity due to a frameshift

CYP3A5✶3

which CYP3A5 allele is most common in Caucasians (92.1%), resulting in decreased clearance of Tacrolimus?

80-85%

______% of Caucasians are CYP3A5 nonexpressers.

1.5‐2

In kidney, heart, and lung transplant recipients, over 50 studies have shown that CYP3A5✶1 carriers (i.e., ✶1/✶1 or ✶1/✶3) have lower dose‐adjusted TAC trough concentrations than patients with the CYP3A5✶3/✶3genotype. CYP3A5✶1 carriers require _____ times standard TAC doses to achieve similar blood concentrations as CYP3A5✶3/✶3.

0.2 mg/kg/day

what is the standard weight-based TAC dosing?

0.3 mg/kg/day

what is the weight-based dosing for TAC in CYP3A5 expressers?

0.15 mg/kg/day

what is the weight-based dosing for TAC in CYP3A5 nonexpressers?

10-15 ng/ml

what is the target TAC trough levels after 6 oral doses?

0.05

what p value is statistically significant

increase the starting dose 1.5-2 times the recommended starting dose.

- the total starting dose should NOT exceed 0.3 mg/kg/day

what is the therapeutic recommendation for TAC with extensive metabolizers [CYP3A5 expresser]?

increase the starting dose 1.5-2 times the recommended starting dose.

- the total starting dose should NOT exceed 0.3 mg/kg/day

what is the therapeutic recommendation for TAC with intermediate metabolizers [CYP3A5 expresser]?

initiate therapy with standard recommended dose

- use TDM to guide adjustments

what is the therapeutic recommendation for TAC with poor metabolizers [CYP3A5 nonexpresser]?

true

T/F: CPIC guidelines are only applicable to liver transplant

recipients in which the donor and recipient CYP3A5 genotypes are identical.

CYP3A5✶1

For pediatric patients, CPIC guidelines recommend a 1.5-2 fold increase in TAC dose for _____ carriers

true

T/F: even after genotype testing, TDM remains indicated during treatment of TAC

true

CYP3A5 genotype‐guided TAC dosing allows for more rapid attainment of target TAC trough concentrations.

Abacavir (ABC, Ziagen)

Nucleoside reverse transcriptase inhibitor used in

combination with other antiretroviral agents for the treatment of HIV.

5-8%

what percent of patients experience Abacavir hypersensitivity reactions?

- includes at least 2 of the following: fever, rash, GI, fatigue cough, dyspnea

- requires immediate discontinuation of the drug

- rechallenge is contraindicated

6 weeks

- median onset = 10 days

A hypersensitivity reaction to Abacavir occurs within the first ____ weeks of treatment

false; rechallenge contraindicated because immediate and life-threatening reactions, including anaphylaxis can occur.

T/F: If a patient has a hypersensitivity reaction to Abacavir, the drug can be rechallenged in 4 weeks.

Human leukocyte antigens (HLA)

group of genes that code for cell surface protein that are responsible for immune system regulation.

major histocompatibility complex (MHC)

HLA is the human version of _____, a gene family that occurs in many species.

MHC Class I: HLA‐A, HLA‐B, and HLA‐C

•Present peptides from proteins that break down inside the cell.

•Foreign antigens presented by MHC I attract cytotoxic T‐cells (CD8+) that destroy cells.

MHC Class II: HLA‐DR, HLA‐DP, and HLA‐DQ

•Present antigens encountered outside the cell.

•Stimulate the multiplication of T‐helper cells (CD4+)

MHC Class III

Encode components of the complement system, tumor necrosis factor alpha, and heat shock proteins.

hapten

a small molecule elicits an immune response only when attached to a large molecule, such as a protein

hapten synthesis

the drug acts like a hapten and covalently binds to proteins or MNC-bound peptides which are then recognized by T cells

pharmacological interaction hypothesis

drugs interact with immune receptors; drug binds directly and noncovalently to a T-cell receptor, leading to T-cell activation

altered peptide binding hypothesis

drugs interact with a specific HLA allele, which alters that allele's specificity for peptide binding and results in T-cell activation

- drug alters peptide binding profile

type = B57

Regarding HLA genetic nomenclature, what pair of digits describes the type?

HLA-B 57:01

01

Regarding HLA genetic nomenclature, what pair of digits describes the subtype?

HLA-B 57:01

very low risk of hypersensitivity (94% of people)

what is the likely phenotype if the genotype shows absence of 57:01 alleles (reported as "negative") when testing for Abacavir?

high risk of hypersensitivity (6% of people)

what is the likely phenotype if the genotype shows presence of at least on 57:01 allele (reported as "positive") when testing for Abacavir?

Southwest Asian (11-20%)

which population has the highest HLA-B 57:01 allele frequency?

PREDICT-1 Study

one of the first studies to show that prospective pharmacogenomic testing can be used to prevent serious ADRs