The CPIC Dosing Guideline update for nortriptyline recommends a 25% dose reduction for CYP2D6 intermediate metabolizers. For CYP2D6 ultrarapid or poor metabolizers, an alternative drug should be considered. If nortriptyline is warranted, consider a 50% dose reduction in CYP2D6 poor metabolizers.
This annotation is based on the CPIC® guideline for tricyclic antidepressants and CYP2D6 and CYP2C19.
December 2016 Update
Advance online publication December 2016.
- The 2016 update of CPIC guidelines regarding the use of pharmacogenomic tests in dosing of tricyclic antidepressants (TCAs) have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Literature up to July 2016 was reviewed, recommendations and supplemental information were updated.
- Excerpt from the 2016 dosing guideline update:
- "There is substantial evidence linking CYP2D6 genotypes to phenotypic variability in tricyclic side-effect and pharmacokinetic profiles. Modifying pharmacotherapy for patients who have CYP2D6 genomic variants that affect drug efficacy and safety could potentially improve clinical outcomes and reduce the failure rate of initial treatment."
- " There are scarce studies focusing solely on CYP2D6 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."
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Table 1: Dosing recommendations for nortriptyline based on CYP2D6 phenotype:
Adapted from Tables 1 and 2 of the 2016 guideline update.
|Likely phenotype||Activity score||Genotypes||Examples of diplotypes||Implications||Therapeutic Recommendationsb||Classification of recommendation for amitriptyline and nortriptylinec|
|CYP2D6 Ultrarapid metabolizer (~1-20% of patients)d||>2.0||An individual carrying more than two copies of functional alleles||*1/*1xN, *1/*2xN||Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure.||Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6.|
If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments.e
|CYP2D6 Normal metabolizer (~72-88% of patients)d||1.0-2.0f||An individual carrying two normal function alleles or two decreased function alleles or one normal and no function allele or one normal and decreased function allele or combinations of duplicated alleles that result in an activity score of 1.0-2.0||*1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5||Normal metabolism of TCAs.||Initiate therapy with recommended starting dose.g||Strong|
|CYP2D6 Intermediate metabolizer (~1-13% of patients)d||0.5||An individual carrying one decreased and one no function allele||*4/*41, *5/*9, *4/*10||Reduced metabolism of TCAs to less active compounds when compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.||Consider 25% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.e||Moderate|
|CYP2D6 Poor metabolizer (~1-10% of patients)d||0||An individual carrying only no function alleles||*4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6||Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.||Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6.|
If a TCA is warranted, consider 50% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.e
b Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations in the guideline for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.
c The rating scheme for the recommendation of classification is described in the Supplement.
d CYP2D6 metabolizer status frequencies are based on average multi-ethnic frequencies. See the CYP2D6 Frequency Tables for population-specific allele and phenotype frequencies.
e Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.
f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.
g Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.
Advance online publication January 2013.
- Guidelines regarding the use of pharmacogenomic tests in dosing of amitriptyline and nortriptyline have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
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