13

Genotype concordance with predicted phenotype has also been found to be lower in

pediatric patients.

20 Additionally, ethnic variation among study results also suggests

that testing may be more beneficial in certain groups, namely those with Asian

ancestry. As is the case when using ethnicity to determine whether or not to complete

any genetic test, self-reported ancestry is not always a reliable means of predicting

someone’s actual genetic lineage. With the generation of promising preliminary

studies, a continued focus on NAT2 genotype effects on isoniazid safety has the

potential to result in institutions and organizations adopting policies to proactively

test NAT2 in the context of isoniazid treatment to both prevent adverse drug events

and increase treatment success in the future.

PHARMACODYNAMIC IMPLICATIONS

CASE 4-2

QUESTION 1: E.F. is a 51-year-old male status post ST elevation myocardial infarction (STEMI) and atrial

fibrillation with a residual left ventricular thrombus. Despite aggressive dose escalations of warfarin, his

international normalized ratio (INR) will not budge above 1.7. His current dose of warfarin is 10 mg daily and

he reports no dietary changes or excessive vitamin K intake. There are no drug–drug interactions identified in

his regimen. The cardiology team asks about pharmacogenomic testing. What are the known genes involved in

warfarin metabolism that would impact E.F.’s INR?

Table 4-1

NAT2 Genotypes and Phenotypes

NAT2 Allele Activity

Slow *5-7, *10, *12D, *14, *17, *19

Rapid *4 (wild type), *11, *12A-C, *13, *18

NAT2 Phenotype Summary

Genotype Acetylator Rate Clinical Manifestation with Isoniazid Therapy

Homozygous slow Slow Increased risk of adverse drug events

Heterozygous Intermediate

Homozygous rapid Fast/rapid Possible increased risk of treatment

aShown in a small number of studies.

13

p. 53

p. 54

Table 4-2

Summary of NAT2 Genotypes and Hepatotoxicity Risk with Isoniazid Studies

Study Study Type Population Metric Result

Sun et al.

14 Meta-analysis

N = 5 case–control

studies

133 cases

(hepatotoxicity)

492 controls

Chinese

Japanese

East Indian

Caucasian

Prevalence of SA

status in

hepatotoxicity cases

vs. control

Overall: no significant finding

Asian subgroup analysis:

↑ risk hepatotoxicity for SAs

OR 2.52 (CI 1.5–4.3)

Wang et al.

15 Meta-analysis

N = 14 case–

controlstudies

11 Asian, 3 nonAsian

474 cases

(hepatotoxicity)

1,446 controls

Japan

China

Taiwan

India

Korea

Turkey

Switzerland

USA (8%)

SA hepatotoxicity

risk vs. RA

↑ risk hepatotoxicity for SAs

OR_Asian: 4.9 (CI 3.3–7.1)

OR_non-Asian: 3.7 (CI 1.3–

10.5)

↑ risk hepatotoxicity in

combination regimen

Ben Mahmoud

et al.

16

Observational Case–

control

N = 65

Tunisian SA hepatotoxicity

risk vs. RA and IAs

↑ risk hepatotoxicity for SAs

OR 4.3; (CI 1.5–18)

Du et al.

17 Meta-analysis

N = 26 studies

1,198 cases

2,921 controls

Asian

Caucasian

M.Eastern

Brazilian

Prevalence of SA

status in

hepatotoxicity cases

vs. control

Overall:

↑ risk hepatotoxicity for SAs

OR 3.1 (CI 2.5–3.9)

Caucasian: no significant finding

Huang et al.

18 Observational Case–

control

N = 224

Taiwan SA hepatotoxicity

risk vs. RA

↑ risk hepatotoxicity for SAs

OR 2.8 (CI 1.3–6.2)

Pasipanodya et

al.

13

Meta-analysis

N = 3,471

UK

Asia

East Africa

RA treatment failure

risk vs. SA

↑ risk of treatment failure for

RAs

RR 2 (CI 1.5–2.7)

USA

Prague

SA, slow acetylator; RA, rapid acetylator; IA, intermediate acetylator; OR, odds ratio; CI, confidence interval.

Table 4-3

NAT2 Genotype-Based Dosing Recommendations for Isoniazid

Summary of Results from Azuma et al.

19

Genotype-Based

Dosing

Recommendation AE

Standard (5

mg/kg)

Genotype-Based

Dosing p

Slow 50% dose decrease (˜2.5

mg/kg)

DILI 78% 0% 0.003

TF 22.9%a 0% NR

Intermediate Standard (5 mg/kg) DILI 4.7% NR

TF 26.8% NR

Rapid 50% dose increase (˜7.5

mg/kg)

DILI 4.2% 4.6% NS

TF 38% 15% 0.013

DILI,drug-induced liver disease;TF,treatment failure; NR: no result; NS: nonsignificant.

Warfarin’s mechanism of action is to inhibit the Vitamin K Epoxide Reductase

Complex subunit 1 (VKORC1), a key enzymatic component in the vitamin K clotting

pathway.

21 By inhibiting VKORC1, synthesis of the vitamin K–dependent clotting

factors II, VII, IX, and X is reduced and anticoagulation is achieved in conditions

where thrombosis is a concern, such as atrial fibrillation. The amount of VKORC1

present in a person is linked to the VKORC1 gene, a key pharmacodynamic

consideration. Patients with the GG genotype at VKORC1 rs9923231 are considered

warfarin insensitive, meaning they are likely to require larger doses of medication to

effectively inhibit the VKORC1 pathway. The AA genotype has been associated with

lesser amounts of VKORC1, and therefore, these patients are considered to be

warfarin sensitive and may require lower doses of medication for inhibition and

anticoagulation.

22

Another significant factor affecting warfarin dosing and response is the effect of

genetic variants on warfarin metabolism. Warfarin is taken orally as a racemic

mixture of R- and S-enantiomers, and its subsequent metabolism is complex,

involving multiple genes and pathways. The primary pathway of the S-enantiomer,

the active form of the drug, is via the CYP2C9 enzyme.

22 CYP2C9 is the predominant

enzyme pathway responsible for more than 25% of the variation in warfarin

metabolism. CYP2C9 is highly polymorphic, with several known variants within the

population linked to reduced metabolic rates, including CYP2C9 *2 and *3 alleles.

Reduced warfarin metabolism leads to increased concentrations of the active form of

the drug. These patients may require lower warfarin doses, and thus may be at

increased risk of bleeding using standard dosing algorithms.

22

p. 54

p. 55

A more recent gene of focus with limited evidence relating to warfarin sensitivity

is CYP4F2.

23 CYP4F2 affects the metabolism and therefore physiologic levels of

vitamin K. Patients with the TT genotype for CYP4F2 rs2108622 are thought to

maintain higher concentrations of vitamin K, and therefore require approximately 1

mg/day more warfarin than patients with the CC genotype.

23 Although current dosing

models focus strictly on genotype for CYP2C9 and VKORC1 for warfarin initiation,

CYP4F2 has shown early promise as a potential factor for strengthening the

effectiveness of dose prediction algorithms in some ethnicities.