Annotation of CPIC Guideline for acebutolol, betaxolol, bisoprolol, carvedilol, nebivolol, propranolol and CYP2D6

This annotation is based on the CPIC® guideline for beta-blocker therapy and CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4 and GRK5.

July 2024

The authors of the CPIC® guideline for beta-blocker therapy and CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4 and GRK5 evaluated the available evidence for the use of acebutolol, betaxolol, bisoprolol, carvedilol, nebivolol and propranolol in patients carrying CYP2D6 variants. They conclude that there is insufficient evidence to guide clinical practice at this time.

These guidelines are applicable to:

• adult patients
• pediatric patients

Excerpts from the guideline:

Carvedilol. While there is considerable evidence that CYP2D6 intermediate and poor metabolizers experience increased carvedilol exposure, there are far fewer reports in the literature [...] assessing whether this translates to clinical differences in heart rate or blood pressure response. This may, in part, be due to the fact that carvedilol is predominantly used in heart failure and is therefore slowly up-titrated, preventing many poor metabolizers from ever receiving a dose that could cause significant bradycardia. In addition, CYP2D6 metabolizes carvedilol to both pharmacologically inactive and active metabolites, which may explain why significant differences in carvedilol exposure by CYP2D6 phenotype do not seem to consistently translate into significant differences in clinical response. The committee acknowledged the assessment from the U.S. Food and Drug Administration that CYP2D6 poor metabolizers may be at a higher risk of dizziness when given carvedilol, which may be based upon unpublished data. However, considering only published results, the writing committee felt there was insufficient evidence to support carvedilol dosing recommendations based on predicted CYP2D6 phenotype (CPIC level C - no recommendation).

CYP2D6 poor metabolizers can experience several-fold higher plasma metoprolol, carvedilol, and nebivolol concentrations following oral administration, compared to those who are not CYP2D6 poor metabolizers. Insufficient evidence exists to indicate whether propranolol systemic exposure is similarly increased in CYP2D6 poor metabolizers.

Of note, beta-blockers exhibit a sigmoid dose-response relationship. Thus, increasing beta-blocker plasma concentrations beyond a certain threshold does not result in further increases in drug response

Download and read:

• Guideline publication
• Guideline supplement

Table 1: Recommended therapeutic use of carvedilol in relation to CYP2D6 phenotype

Adapted from Tables 1 & S8 of the guideline

^a See the CYP2D6 Allele Frequency Table on the CYP2D6 Gene-Specific Information Tables page for ancestry-specific allele and phenotype frequencies.
^b Assignment of allele function and allele activity values, including citations for allele function, can be found in the CYP2D6 Allele Definition Table and the CYP2D6 Allele Functionality Table on the CYP2D6 Gene-Specific Information Tables page. For a complete list of CYP2D6 diplotypes and predicted phenotypes, see the CYP2D6 Diplotype to Phenotype Table on the CYP2D6 Gene-Specific Information Tables page.
^c Where xN represents the number of CYP2D6 gene copies.
^d CYP2D6 metabolizes carvedilol to both pharmacologically inactive and active metabolites.
^e Rating scheme described in the Strength of Recommendations section in the guideline supplement.

Table 2: Recommended therapeutic use of acebutolol, betaxolol, bisoprolol and propranolol in relation to CYP2D6 phenotype

Adapted from Tables 1 & S9 of the guideline

^a See the CYP2D6 Allele Frequency Table on the CYP2D6 Gene-Specific Information Tables page for ancestry-specific allele and phenotype frequencies.
^b Assignment of allele function and allele activity values, including citations for allele function, can be found in the CYP2D6 Allele Definition Table and the CYP2D6 Allele Functionality Table on the CYP2D6 Gene-Specific Information Tables page. For a complete list of CYP2D6 diplotypes and predicted phenotypes, see the CYP2D6 Diplotype to Phenotype Table on the CYP2D6 Gene-Specific Information Tables page.
^c Where xN represents the number of CYP2D6 gene copies.
^d Rating scheme described in the Strength of Recommendations section in the guideline supplement.

Table 3: Recommended therapeutic use of nebivolol in relation to CYP2D6 phenotype

Adapted from Tables 1 & S10 of the guideline

^a See the CYP2D6 Allele Frequency Table on the CYP2D6 Gene-Specific Information Tables page for ancestry-specific allele and phenotype frequencies.
^b Assignment of allele function and allele activity values, including citations for allele function, can be found in the CYP2D6 Allele Definition Table and the CYP2D6 Allele Functionality Table on the CYP2D6 Gene-Specific Information Tables page. For a complete list of CYP2D6 diplotypes and predicted phenotypes, see the CYP2D6 Diplotype to Phenotype Table on the CYP2D6 Gene-Specific Information Tables page.
^c Where xN represents the number of CYP2D6 gene copies.
^d Rating scheme described in the Strength of Recommendations section in the guideline supplement.