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Table 7 Genotype-phenotype drug response interpretations of Pharmacogenomics Advisory Group-approved drug-gene pair: Codeine and CYP2D6 a

From: The Coriell personalized medicine collaborative pharmacogenomics appraisal, evidence scoring and interpretation system

Common diplotypesb

Expected population frequency, %c

PK/PD phenotype

Clinical phenotype

FDA guidelines

Caucasian

ancestry

African ancestry

East Asian ancestry

CYP2D6*1/*1, CYP2D6*1/*3, CYP2D6*1/*4, CYP2D6*1/*5, CYP2D6*1/*6, CYP2D6*1/*7, CYP2D6*1/*9, CYP2D6*1/*10, and other rare diplotypes (see Additional file 1: Table S21)d

80

69

45

EM: normal enzymatic function and normal conversion of codeine to morphine

Normal analgesic response to standard dose of codeine

–

CYP2D6*4/*41, CYP2D6*4/*9, CYP2D6*4/*10, CYP2D6*41/*41, CYP2D6*5/*41, CYP2D6*9/*41, CYP2D6*10/*41, and other rare diplotypes (see Additional file 1: Table S21)

12

26

26

IM; reduced enzymatic function, leading to reduced conversion of codeine to morphine

Reduced analgesic response (pain relief). May require an increased dose to obtain an analgesic effect or should consider alternative pain medication

–

CYP2D6*3/*4, CYP2D6*4/*4, CYP2D6*4/*5, CYP2D6*4/*7 and other rare diplotypes (see Additional file 1: Table S21)

8

3

14

PM: greatly reduced or abolished enzymatic function, leading to greatly reduced conversion of codeine to morphine

Little or no analgesic response (pain relief). Should consider alternative pain medication

–

Rare in Caucasians. The following are common in East Asians: CYP2D6*1/*1 × N, CYP2D6*1 × N/*1 × N, CYP2D6*1 × N/*4, CYP2D6*1 × N/*5, CYP2D6*1 × N/*10, CYP2D6*1 × N/*10C(*36)

<0.1

2

15

UM: enhanced enzymatic function, leading to greater conversion of codeine to morphine and higher drug exposure

Increased risk of drug toxicity and ADRs. Should consider alternative pain medication

CYP2D6 PMs and UMs may experience different efficacy. Even at labeled dosage regimens, UMs may experience overdose symptoms. Use of codeine by UM mothers can potentially lead to serious ADRs, including death, in nursing infants

  1. Abbreviations: ADR adverse drug reaction, EM Extensive metabolizer, FDA Food and Drugs Administration, IM intermediate metabolizer, PD pharmacodynamic, PK pharmacokinetic, PM poor metabolizer, UM Ultra-rapid metabolizer.
  2. aSupporting evidence may be found in Additional file 2: Section S5.0 to 5.7 and Additional file 1: Tables S19 to S21. These include summaries of the PhAESIS evaluation and referenced publications supporting the drug-gene clinical phenotypes.
  3. bDiplotypes with frequencies of less than 0.4% in Caucasians are included above. Other rare diplotypes that fall under the same phenotype category can be found in the genotype-phenotype Punnett table (see Additional file 1: Table S21). Diplotypes above and in the genotype-phenotype Punnett table include both clinically validated genetic results (those that include variants with evidence code 1) and results that include variants with evidence scores 2 to 7 (potentially clinically relevant). The latter require further validation to support their inclusion for clinical reporting.
  4. cPopulation frequencies are estimated based on reported gene variant allele frequencies (see Additional file 1: Table S20) and Hardy-Weinberg principles.
  5. dCYP2D6*1 denoted in the above table represents either the *1 or *2 allele with normal CYP2D6 activity.