Imipramine response

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary.

FDA Table of Pharmacogenetic Associations, Section 3: Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only

Please review the complete therapeutic recommendations that are located here: (1, 44).

CYP2D6 IM: imipramine - The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and desipramine.

• use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

CYP2D6 PM: imipramine - The risk of side effects may be increased, because the gene variation leads to increased plasma concentrations of imipramine and the active metabolite desipramine.

• use 30% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose The therapeutic range is 150-300 ng/mL for the sum of the imipramine and desipramine plasma concentrations. Values exceeding 500 ng/mL are considered toxic.

CYP2D6 UM: imipramine - The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of imipramine and the active metabolite desipramine and to increased plasma concentrations of the potentially cardiotoxic hydroxy metabolites.

• use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine in order to set the maintenance dose
• if a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid imipramine.Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

CYP2C19 IM: imipramine - NO action is required for this gene-drug interaction.

The genetic variation increases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects.

CYP2C19 PM: imipramine - The risk of side effects is increased. The gene variation results in an increase in the plasma concentration of imipramine+desipramine.

• use 70% of the standard dose and monitor the effect and side effects, or the imipramine and desipramine plasma concentrations to determine the maintenance dose.
• or avoid imipramine.Antidepressants that are not or to a lesser extent metabolised by CYP2C19 include, for example, nortriptyline, fluvoxamine and mirtazapine.

CYP2C19 UM: imipramine - NO action is required for this gene-drug interaction.

The genetic variation decreases imipramine plasma concentrations, but not imipramine+desipramine plasma concentrations, which govern effectiveness and side effects.

Please review the complete therapeutic recommendations that are located here: (2).

Because the TCAs have comparable pharmacokinetic properties, it may be reasonable to extrapolate this guideline to other TCAs including clomipramine, desipramine, doxepin, imipramine, and trimipramine, with the acknowledgement that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline. […]

CYP2D6 dosing recommendations.

[…]. The recommended starting dose of amitriptyline or nortriptyline does not need adjustment for those with genotypes predictive of CYP2D6 normal metabolism. A 25% reduction of the recommended dose may be considered for CYP2D6 intermediate metabolizers. The strength of this recommendation is classified as “moderate” because patients with a CYP2D6 activity score of 1.0 are inconsistently categorized as intermediate or normal metabolizers in the literature, making these studies difficult to evaluate.

CYP2D6 ultrarapid metabolizers have a higher probability of failing amitriptyline or nortriptyline pharmacotherapy due to subtherapeutic plasma concentrations, and alternate agents are preferred. There are documented cases of CYP2D6 ultrarapid metabolizers receiving large doses of nortriptyline in order to achieve therapeutic concentrations. However, very high plasma concentrations of the nortriptyline hydroxy-metabolite were present, which may increase the risk for cardiotoxicity. If a tricyclic is warranted, there are insufficient data in the literature to calculate a starting dose for a patient with CYP2D6 ultrarapid metabolizer status, and therapeutic drug monitoring is strongly recommended. Adverse effects are more likely in CYP2D6 poor metabolizers due to elevated tricyclic plasma concentrations; therefore, alternate agents are preferred. If a tricyclic is warranted, consider a 50% reduction of the usual dose, and therapeutic drug monitoring is strongly recommended.

CYP2C19 dosing recommendations.

[…]. The usual starting dose of amitriptyline may be used in CYP2C19 normal and intermediate metabolizers. Although CYP2C19 intermediate metabolizers would be expected to have a modest increase in the ratio of amitriptyline to nortriptyline plasma concentrations, the evidence does not indicate that CYP2C19 intermediate metabolizers should receive an alternate dose.

Patients taking amitriptyline who are CYP2C19 rapid or ultrarapid metabolizers may be at risk for having low plasma concentrations and an imbalance between parent drug and metabolites causing treatment failure and/or adverse events. Although the CYP2C19*17 allele did not alter the sum of amitriptyline plus nortriptyline plasma concentrations, it was associated with higher nortriptyline plasma concentrations, possibly increasing the risk of adverse events. For patients taking amitriptyline, extrapolated pharmacokinetic data suggest that CYP2C19 rapid or ultrarapid metabolizers may need a dose increase. Due to the need for further studies investigating the clinical importance of CYP2C19*17 regarding tricyclic metabolism and the possibility of altered concentrations, we recommend to consider an alternative tricyclic or other drug not affected by CYP2C19. This recommendation is classified as optional due to limited available data. If amitriptyline is administered to a CYP2C19 rapid or ultrarapid metabolizer, therapeutic drug monitoring is recommended.

CYP2C19 poor metabolizers are expected to have a greater ratio of amitriptyline to nortriptyline plasma concentrations. The elevated amitriptyline plasma concentrations may increase the chance of a patient experiencing side effects. Use an alternative agent not metabolized by CYP2C19 (e.g., nortriptyline and desipramine) or consider a 50% reduction of the usual amitriptyline starting dose along with therapeutic drug monitoring.

Other TCAs.

Because the TCAs have comparable pharmacokinetic properties, it may be reasonable to extrapolate this guideline to

other TCAs, including clomipramine, desipramine, doxepin, imipramine, and trimipramine … with the acknowledgment that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline.

CYP2D6 and CYP2C19 combined dosing recommendations.

Although specific combinations of CYP2D6 and CYP2C19 alleles are likely to result in additive effects on the pharmacokinetic properties of TCAs, little information is available on how to adjust initial doses based on combined genotype information. Patients carrying at least one CYP2D6 no function allele and two CYP2C19 normal function alleles had an increased risk of experiencing side effects when administered amitriptyline, while patients with at least one CYP2C19 no function allele and two CYP2D6 normal function alleles had a lower risk of experiencing side effects.

Combinatorial gene-based recommendations are provided in Table 4. Therapeutic drug monitoring may be advised if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, rapid, intermediate, or poor metabolism. There are sparse data in patients with a combinatorial CYP2C19 ultrarapid/rapid/intermediate/poor metabolizer phenotype and CYP2D6 ultrarapid/intermediate/poor phenotype. Because there are limited clinical or pharmacokinetic data regarding these combinatorial phenotypes, pharmacotherapy recommendations are classified as optional.

Please review the complete therapeutic recommendations that are located here: (3).