AMITRIPTYLINE

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause a decrease in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and increased plasma concentrations of the active metabolites E-10-OH-amitriptyline and E-10-OH-nortriptyline.

Recommendation:

1. Choose an alternative if possible
   Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
   
2. If an alternative is not an option: increase the dose to 1.25 times the standard dose, monitor the plasma concentrations and be alert to potential therapy failure due to decreased amitriptyline plus nortriptyline plasma concentrations and to increased plasma concentrations of the potentially cardiotoxic, active hydroxy metabolites.

Mechanism:
Amitriptyline is mainly converted by CYP2C19-mediated N-demethylation to the active metabolite nortriptyline. Both amitriptyline and nortriptyline are metabolised by CYP2D6 to 10-hydroxy metabolites, predominantly E-10-hydroxy metabolites. Amitriptyline is approximately three times as potent as E-10-OH-amitriptyline. Nortriptyline is approximately twice as potent as E-10-OH-nortriptyline.
N-oxidation and N-glucuronidation of amitriptyline also take place.
Nortriptyline is converted by CYP2D6 and CYP2C19 to the inactive metabolite didesmethylamitriptyline (desmethylnortriptyline).
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
The therapeutic efficacy of amitriptyline correlates with the sum of the plasma concentrations of amitriptyline and nortriptyline, but side effects correlate with nortriptyline plasma concentrations.
The hydroxy metabolites are potentially cardiotoxic.

Clinical consequences:
One case described therapy failure after an initial short period of improvement.

Kinetic consequences:
A 20% decrease in amitriptyline plus nortriptyline plasma concentrations was found (non-significant).
A positive correlation between CYP2D6 activity and (hydroxyamitriptyline + hydroxynortriptyline)/(amitriptyline + nortriptyline) ratio was also found. This means that there is a relative increase in hydroxy metabolites in UM patients.
A 47% increase in the amitriptyline/nortriptyline metabolic ratio was found (non-significant).

ATOMOXETINE

The genetic variation results in an increased conversion of atomoxetine to the active metabolite 4-hydroxyatomoxetine, which has a much lower plasma concentration. As the plasma concentration of the active ingredients decreases as a result, this gene variation can result in reduced efficacy.

Recommendation:

1. be extra alert to reduced efficacy of the treatment
   
2. advise the patient to contact their doctor in the event of inadequate effect
   
3. an alternative can be selected as a precaution
   Clonidine is not metabolised by CYP2D6.

Mechanism:
Atomoxetine is primarily metabolised by CYP2D6 to 4-hydroxyatomoxetine. This metabolite is equipotent to atomoxetine, but circulates in much lower concentrations in the plasma.
The enzyme CYP2C19 and other iso-enzymes form N-desmethylatomoxetine, which is virtually inactive.
For more information about the UM phenotype, see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for “CYP2D6”).

Clinical consequences:
Theoretically, the risk of a decreased effectiveness of the therapy increases when the sum of the plasma concentrations of atomoxetine and 4-hydroxyatomoxetine decreases.

Kinetic consequences:
Following a single dose, the AUC of atomoxetine decreased by approximately two thirds for 1 UM with gene dose 3. The concentration of 4-hydroxyatomoxetine was less than 1% of the concentration of atomoxetine, meaning that the contribution of 4-hydroxyatomoxetine was negligible.

AZATHIOPRINE

The genetic variation reduces the conversion of azathioprine and mercaptopurine to mainly inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.

Recommendation:

1. Choose an alternative or start with 10% of the standard dose.
   Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
   The frequency of monitoring should be increased.
2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur

Mechanism:
Azathioprine is converted in the body to mercaptopurine. Mercaptopurine is an inactive pro-drug, which is converted to the active metabolites - thioguanine nucleotides - in the body. Two catabolic routes reduce mercaptopurine bio-availability for thioguanine nucleotide formation. Thiopurine methyltransferase (TPMT) catalyses S-methylation of both mercaptopurine and the 6-mercaptopurine ribonucleotides formed in the metabolic pathway. In addition to this, mercaptopurine is oxidised to the inactive 6-thiouric acid by the enzyme xanthine oxidase (XO), which occurs primarily in the liver and intestines. For more information about the PM phenotype: see the general background information about TPMT on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
In eleven out of sixteen cases, the standard dose resulted in termination of treatment due to leukopaenia/myelosuppression. Four patients underwent significant dose reduction due to leukopaenia/myelosuppression and/or high concentrations of the active metabolite. One PM developed only mild toxicity at the standard dose. A meta-analysis involving 43 PM with cancer found that 86% developed severe myelosuppression (in comparison to 7% for all genotypes). In a meta-analysis with 7 PM with auto-immune diseases, the risk of leukopaenia increased (OR = 20.84; 95% CI: 3.42-126.89). In this meta-analysis there was no difference in the risk of other adverse events (myelotoxicity, hepatotoxicity and pancreatitis). The tolerated dose varied for 27 PM from 2.2%-20% of the standard dose (mean 10%). One PM tolerated a dose of 124% of the standard dose. One study found a comparable clinical response (some remaining leukaemia cells) in PM at 10% of the standard dose as for EM at 100%. Another study found a good clinical response (improvement of ulcerative colitis) at 2.2% of the standard dose.

Kinetic consequences:
In one study, the concentration of the active metabolite was 8.5-fold higher in comparison to EM at 14% of the dose. In one patient at 5% of the dose, the concentration of the active metabolite was 4.6-fold higher and in one patient at 20% of the dose, the concentration was 5.0-fold higher. One study found a concentration of the active metabolite within the target range at 2.2% of the standard dose. In two cases at 10% of the standard dose, the concentration of the active metabolite was 3.4-4.3 times the postulated therapeutic lower limit. In one case, the dose-corrected concentration of the active metabolite was increased by a factor of seven.

CITALOPRAM

The gene variation leads to increased citalopram plasma concentrations. This increases the risk of QT prolongation and torsades de pointes.

Recommendation:

1. do not exceed the following daily doses (50% of the standard maximum dose) or choose an alternative:
   • adults to 65 years: 20 mg as tablets or 16 mg as drops
     
   • adults over 65 years: 10 mg as tablets or 8 mg as drops

Mechanism:
Citalopram is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4 to the weakly active N-desmethylcitalopram. Desmethylcitalopram is converted by CYP2D6 to didesmethylcitalopram.
For more information about the PM phenotype: see the general background information about CYP2C19 on the KNMP Knowledge Database or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
The relationship between plasma concentration and efficacy and side effects has not been established. The risk of citalopram-induced QT prolongation and torsades de pointes is dependent on the dose and therefore dependent on the plasma concentration.
The upper limit of the therapeutic range of citalopram is 400 ng/mL. Toxicity has been confirmed at citalopram plasma concentrations from 210 ng/mL. In general, therapeutic plasma concentrations of citalopram range between 30 and 130 ng/mL.

Clinical consequences:
A study of sixteen IM patients and one PM found 3.0% longer QTc interval. For this group, the study found no difference in the median dose and the percentage of patients with a dose higher than 40 mg/day.
Two studies found no difference in the occurrence of side effects. A study involving newborns, with a group of four IM and one PM, found no difference in the severity of serotonergic symptoms following citalopram use by the mother.
There was no difference in tolerance for the PM. For IM+PM, the results for the probability of tolerance varied from no difference in the validation study to a decrease.
For the probability of remission, the effect varied from no difference to an increase by 48%.
There was no significant effect on the set dose.

Kinetic consequences:
Increase in AUC by 19-119%. The increase in AUC is primarily caused by an increase in the active S-enantiomer: an increase in AUC of the racemate by 19% is equivalent to an increase in the AUC of S-citalopram by 57%.
For the plasma concentration, the effect varied from an increase by 64% to a decrease by 6%.
Decrease in oral clearance by 24-76%.
Increase in half-life by 10-40%.

This is NOT a gene-drug interaction.

Mechanism:
Citalopram is converted to N-desmethylcitalopram, primarily by CYP2C19 and to a lesser extent by CYP3A4. N-desmethylcitalopram is converted to didesmethylcitalopram by CYP2D6.
N-desmethylcitalopram has an antidepressant effect. However, the activity is low and clinically non-significant at standard doses of citalopram.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
One study found no effect on tolerance, response and remission.

Kinetic consequences:
Three studies found no significant effect on the plasma concentration of citalopram.

CLOMIPRAMINE

The genetic polymorphism leads to increased metabolic capacity of CYP2D6. This may cause decreased plasma concentrations of clomipramine and the active metabolite and increased concentrations of the potentially cardiotoxic hydroxy metabolites.

Recommendation:

1. choose an alternative
   Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
2. if an alternative is not an option:
   1. increase the dose to 150% of the standard dose
   2. monitor the plasma concentrations of clomipramine and desmethylclomipramine
      Only clomipramine is relevant for the indications of obsessive compulsive disorder and for other anxiety disorders. Both concentrations are relevant for toxicity and for the indication of depression.

Mechanism:
Clomipramine and the active metabolite N-desmethylclomipramine are primarily converted by CYP2D6 to inactive hydroxy metabolites.
Clomipramine is mainly converted by CYP2C19 to N-desmethylclomipramine.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
The inactive hydroxy metabolites are potentially cardiotoxic. More of these hydroxy metabolites are formed in UM and with dose increases, whilst they also accumulate with severe renal function impairment.
The active metabolite desmethylclomipramine lacks serotonin re-uptake activity. Therefore, the metabolite does not appear to contribute to the treatment of obsessive compulsive disorder and other anxiety disorders. However, the metabolite does contribute to toxicity and the treatment of depression.
In the case of depression, a value of 0.2-0.3 mg/L is used for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. In theory, a value of 0.4 mg/L is used for anxiety disorders. In the case of severe anxiety disorders, the dose can be further increased under strict monitoring of the ECG, up to a sum of the plasma concentrations no greater than 0.7 mg/L. If this still has not produced any effect, fluvoxamine is sometimes added at a low dose (initial dose 50 mg) in order to inhibit the conversion of clomipramine to desmethylclomipramine. There is some experience of this and it does increase the ratio of clomipramine/desmethylclomipramine. In other words, treatment is very much tailored to the individual in the case of anxiety disorders.

Clinical consequences:
In two cases with non-response, an increase in the plasma concentrations through dose increase or CYP2D6 inhibition resulted in recovery of the problem. The dose increase involved an increase from 150 to 300 mg/day. Other reports of dose increases for UM are not known.
Theoretically, the risk of side effects due to potentially cardiotoxic hydroxy metabolites increases with an increase in the plasma concentrations.

Kinetic consequences:
One study with 3 UM found a decrease in the dose-corrected plasma concentration of clomipramine and desmethylclomipramine by 33%.
The same study found a decrease in the dose-corrected plasma concentration of clomipramine by 25%.
Unusually low plasma concentrations of clomipramine and desmethylclomipramine were observed in two cases.
Theoretically, the plasma concentrations of the hydroxy metabolites can increase.

CLOPIDOGREL

Genetic variation reduces activation of clopidogrel. This increases the risk of serious cardiovascular events in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention). No negative clinical consequences have been proved in other patients.

Recommendation:

• PERCUTANEOUS CORONARY INTERVENTION:
  1. choose an alternative
     Prasugrel and ticagrelor are not metabolised by CYP2C19 (or to a lesser extent).
• OTHER INDICATIONS:
  1. determine the level of inhibition of platelet aggregation by clopidogrel
     
  2. consider an alternative in poor responders
     Prasugrel and ticagrelor are not metabolised by CYP2C19 (or to a lesser extent).

Mechanism:
Clopidogrel is a pro-drug, of which 85% is converted by esterases to an inactive metabolite. The remaining 15% is primarily converted by CYP2C19 and CYP3A4 to 2-oxoclopidogrel and subsequently to the active metabolite H4, an unstable thiol compound that inhibits platelet aggregation by formation of a disulphide bridge with a cysteine residue on the platelet ADP receptor (P2Y12).
For more information about the PM phenotype: see the general background information about CYP2C19 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2C19).

Clinical consequences:
Increased incidence of stent thrombosis by 267-425% or OR 3.78. Results ranged from no difference to an increased risk of serious cardiovascular events (HRcorr = 1.98 for all patients; HRcorr = 3.58 for patients undergoing percutaneous coronary intervention; OR = 1.59-1.75; RR = non-significant -3.64). The RR was non-significant in a meta-analysis of Caucasian patients, but was significant after exclusion of a large study in which the percentage of patients undergoing percutaneous coronary intervention was 18.7% (RR = 1.57). The RR was also non-significant in a meta-analysis including mainly Caucasian patients (122 PM) not undergoing percutaneous coronary intervention. The RR among Caucasian patients undergoing percutaneous coronary intervention (278 PM) was 1.67. The RR was higher among East-Asian populations (studies involving percutaneous coronary intervention only): 3.04-3.64.
Results ranged from no difference in major bleeding to a decreased risk of all bleeding (OR = 0.36; RR = 0.56).
Genotype-guided therapy after percutaneous coronary intervention involving IM patients receiving a double clopidogrel dose and PM patients receiving an alternative (ticagrelor or clopidogrel in combination with cilostazol), led to a reduced incidence of serious cardiovascular events (OR = 0.42 and decrease by 71% respectively) compared to therapy involving all patients receiving clopidogrel 75 mg/day. Genotype-guided therapy in the study using ticagrelor as an alternative did not lead to significant differences in serious cardiovascular events and bleeding between PM, IM and EM patients, while the incidence of death decreased by 89%, of myocardial infarction by 86% and stent thrombosis by 78% in the study using clopidogrel in combination with cilostazol as an alternative.
Treatment of PM patients with double dosed clopidogrel for 1 month led to more minor bleeding than treatment with ticagrelor (HR = 2.88). Residual platelet aggregation was higher among the clopidogrel group.
Platelet reactivity at the 225 mg/day dose was higher than that of EM+UM patients at the 75 mg/day dose. Non-response defined by platelet reactivity at the 900 mg loading dose was higher than that at the 300 mg loading dose for EM+UM patients. The above applies to patients. The dose response was higher among healthy volunteers.

Kinetic consequences:
The AUC of the active metabolite H4 decreased by 49-72%.
The AUC increased by 194%.
The AUC of 2-oxoclopidogrel decreased by 43-65%.

CODEINE

The genetic polymorphism increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children.

Recommendation:

Codeine is contra-indicated for CYP2D6 UM.

1. if possible, select an alternative
   For PAIN: do not select tramadol, as this is also metabolised by CYP2D6.
   Oyxcodone is also metabolised by CYP2D6, but generally the dose can be titrated so that adequate analgesia is achieved without side effects.

Mechanism:
Codeine is primarily metabolised by CYP3A4, CYP2D6 and by glucuronidation. Conversion by CYP2D6 results in formation of the active metabolite morphine, which has a 200x higher affinity for the µ-opioid receptor than codeine itself. Morphine is further converted to morphine-3-glucuronide and the active morphine-6-glucuronide.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank.

Other considerations:
The analgesic effect of codeine is caused by the active metabolites morphine and morphine-6-glucuronide. Both codeine and the metabolite morphine result in suppression of the cough reflex.

Clinical consequences:
Five out of six adult UMs experienced codeine-induced side effects. In one case, this resulted in coma. Out of two neonates who received breast milk from mothers (UM) who used codeine, one died. The other exhibited extreme drowsiness and poor feeding behaviour, but recovered after switching completely to formula milk. In two cases, young children died of codeine-induced side effects following tonsillectomy due to obstructive sleep apnoea.
UMs experience more side effects. The percentage of people with sedation increased by 82%. In the case of breastfeeding mothers, the risk of central nervous system depression in mother and child increased with decreasing gene dose. This was not the case in a study in which codeine was used for a maximum of four days.

Kinetic consequences:
Morphine: increase in the AUC by 45% for UM + EM (gene dose ≥ 2.5). Increase in the plasma concentration to toxic levels in young children.
Codeine: no change in the AUC.
Theoretically, the plasma concentration of codeine is reduced.

DOXEPIN

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause decreased plasma concentrations of doxepin and nordoxepin and an increase in the plasma concentration of the hydroxy metabolites.

Recommendation:

1. choose an alternative
   Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline.
   
2. if an alternative is not an option: increase the dose to 200% of the standard dose and monitor the plasma concentrations of doxepin and nordoxepin before setting the maintenance dose

Mechanism:
Doxepin and the active metabolite N-desmethyldoxepin (nordoxepin) are primarily converted by CYP2D6 to inactive hydroxy metabolites. Doxepin is mainly converted by CYP2C19 to nordoxepin.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
The reliability of calculation of the dose adjustment is currently limited by the fact that it is not known which isomer is the active form, whilst it has been found that the metabolism of the E-isomer in particular is influenced by CYP2D6.

Clinical consequences:
Theoretically, the risk of reduced effectiveness of the therapy increases with a decrease in the plasma concentrations of doxepin and nordoxepin.

Kinetic consequences:
The AUC of doxepin + nordoxepin is reduced by 55%.

ELIGLUSTAT

This gene variation increases the conversion of eliglustat to inactive metabolites. As a result, a normal dose is not effective. There is not enough scientific substantiation to suggest an effective dose for all UM.

Recommendation:

Eliglustat is contra-indicated.
1. choose an alternative if possible

Mechanism:
Eliglustat is converted to inactive metabolites, primarily by CYP2D6 and to a lesser extent by CYP3A.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
Eliglustat is an inhibitor of CYP2D6 and P-gp. Eliglustat therefore inhibits its own metabolism by inhibiting CYP2D6. This results in a non-linear relationship between dose and concentration.

Clinical consequences:
All four UM who received a dose of 127 mg 2x daily (254 mg/day) had an adequate clinical response. One UM who received a dose of 84 mg 2x daily did not have an adequate clinical response.

Kinetic consequences:
No kinetic consequences have been published. The Dutch SmPC states that a dose recommendation cannot be made for UM.

ESCITALOPRAM

The gene variation leads to increased escitalopram plasma concentrations. This increases the risk of QT prolongation and torsades de pointes.

Recommendation:

1. Do not exceed the following doses (50% of the standard maximum dose) or choose an alternative: adults <65 years 10 mg/day, ≥65 years 5 mg/day

Mechanism:
Escitalopram is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4 to the weakly active N-desmethylescitalopram. Desmethylescitalopram is converted by CYP2D6 to didesmethylescitalopram.
For more information about the PM phenotype: see the general background information about CYP2C19 on the KNMP Knowledge Database or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
The relationship between plasma concentration and efficacy and side effects has not been established. The risk of escitalopram-induced QT prolongation and torsades de pointes is dose and therefore plasma concentration dependent.
The upper limit of the therapeutic range of escitalopram is 250 ng/mL.

Clinical consequences:
One study showed that the QTc-interval did not increase in a group of one PM and 21 IM patients. The IM+PM group and the EM group were however not comparable, because the percentage of women was significantly lower among IM+PM patients than among EM patients. Women had a 3.7% longer QTc-interval than men. The percentage of patients using CYP2C19 substrates, inhibitors or inducers was significantly higher among IM+PM patients. There was a trend towards a 2.8% longer QTc-interval among patients using this co-medication.
A study including six PM patients found no difference between the genotypes in terms of side effects and in the percentage of patients who withdrew from the study. Another study found no differences in neurological, psychological and ‘other’ side effects for a group of 23 IM+PM patients after one week. The score for autonomous side effects, e.g. sweating and gastrointestinal symptoms at one week was lower, but this is probably not clinically relevant.
There was no difference in the dose guided by side effects and effect.
Three studies found no difference in response in patients with depression (one including 16 PMs, one including nine PMs and one including 23 IM+PMs). A study including one PM with peripheral neuropathy did not find a difference in response. A study including a group of 22 IM and one PM with autism spectrum disorder did not find a difference in response.

Kinetic consequences:
The plasma concentration increased by 67-470%.
The AUC0-24h increased by 86%.

FLECAINIDE

The genetic variation increases conversion of flecainide to inactive metabolites. A higher dose is possibly required as a result.

Recommendation:

There are no data about the pharmacokinetics and/or the effects of flecainide in UM.

1. monitor the plasma concentration as a precaution and record an ECG or select an alternative
   Examples of anti-arrhythmic drugs that are not metabolised via CYP2D6 (or to a lesser extent) include sotalol, disopyramide, quinidine and amiodarone.

Mechanism:
The R-enantiomer of flecainide is metabolised by CYP2D6, the S-enantiomer is metabolised via other routes. This results in the formation of the pharmacologically inactive metabolites meta-O-desalkyl flecainide and meta-O-desalkyl lactam flecainide.
The therapeutic range encompasses plasma concentrations of flecainide of 200-1000 ng/mL.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2D6).

Clinical consequences:
Theoretically, the risk of reduced effectiveness increases with a decrease in the plasma concentration of flecainide.

Kinetic consequences:
Theoretically, the plasma concentration of flecainide is reduced when the metabolic activity of CYP2D6 increases.

HALOPERIDOL

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause decreased plasma concentrations of haloperidol and the active metabolite reduced haloperidol.

Recommendation:
It is not possible to offer substantiated advice for dose adjustment due to the limited amount of available literature.

1. Advise the prescriber to:
   1. be alert to possible reduced plasma concentrations of haloperidol and reduced haloperidol and increase the dose based on results of therapeutic drug monitoring,
      
   2. or prescribe an alternative according to the current guidelines.
      Anti-psychotics that are not metabolised via CYP2D6 - or to a much lesser extent - include, for example, flupentixol, fluphenazine, quetiapine, olanzapine or clozapine.

Mechanism:
Haloperidol is primarily metabolised via glucuronidation and to a lesser extent by CYP3A4, CYP2D6 and carbonyl reduction. The active metabolite, reduced haloperidol, can be oxidised back to haloperidol by CYP2D6 and CYP3A4.
An elevated ratio of reduced haloperidol/haloperidol is associated with the occurrence of side effects.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word "pharmacogenetics").

Clinical consequences:
The improvement of the symptoms is smaller than for the other phenotypes.
Theoretically, the risk of reduced effectiveness of the therapy increases with a decrease in the plasma concentrations of haloperidol and the active metabolite. The risk of side effects increases when the ratio of reduced haloperidol/haloperidol increases.

Kinetic consequences:
Haloperidol: decrease in plasma concentration by 4% following oral administration and by 35% following administration as an intra-muscular depot, increase in oral clearance by 18%.
Reduced haloperidol: increase in plasma concentration by 260%.
Ratio of plasma concentration of reduced haloperidol/haloperidol: increase by 367%.

IMIPRAMINE

The genetic polymorphism leads to decreased metabolic capacity of CYP2C19, which may cause increased imipramine plasma concentrations.

Recommendation:

1. Reduce the dose to 70% of the standard dose and monitor imipramine and desipramine plasma concentrations, or choose an alternative.
   Antidepressants that are not or to a lesser extent metabolised via CYP2C19 include, for example, fluvoxamine and mirtazapine.

Mechanism:
The primary metabolic routes for imipramine are N-methylation mainly by CYP2C19 to the active metabolite desipramine and hydroxylation by CYP2D6 to 2-hydroxy-imipramine. Desipramine is metabolised by CYP2D6 to 2-hydroxydesipramine.
The PM phenotype leads to absence of CYP2C19 activity.
For more information about the PM phenotype: see the general background information about CYP2C19 on the KNMP Knowledge Bank or on www.knmp.nl (search for keyword “pharmacogenetics”).

Other considerations:
The therapeutic effectiveness and side effects of imipramine are associated with the plasma concentration of the sum of imipramine and desipramine.

Clinical consequences:
One study showed non-significant increases in therapeutic effect (by 10%) and in side effects (by 42%).

Kinetic consequences:
Increased imipramine plus desipramine plasma concentrations by 17-85%.
Increased imipramine plus desipramine AUC by 36%.

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause decreased plasma concentrations of imipramine and desipramine and an increase in the plasma concentration of the hydroxy metabolites.

Recommendation:

1. choose an alternative
   Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. if an alternative is not an option: increase the dose to 170% of the standard dose and monitor the plasma concentrations of imipramine and desipramine before setting the maintenance dose

Mechanism:
Imipramine and the active metabolite desipramine are primarily converted by CYP2D6 to inactive hydroxy metabolites. Imipramine is mainly converted by CYP2C19 to desipramine.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
Theoretically, the risk of reduced effectiveness of the therapy increases with a decrease in the plasma concentrations of imipramine and desipramine.

Kinetic consequences:
Plasma concentration of imipramine + desipramine: decrease by 41%.

IMIPRAMINE

The genetic polymorphism leads to decreased metabolic capacity of CYP2C19, which may cause increased imipramine plasma concentrations.

Recommendation:

1. Reduce the dose to 70% of the standard dose and monitor imipramine and desipramine plasma concentrations, or choose an alternative.
   Antidepressants that are not or to a lesser extent metabolised via CYP2C19 include, for example, fluvoxamine and mirtazapine.

Mechanism:
The primary metabolic routes for imipramine are N-methylation mainly by CYP2C19 to the active metabolite desipramine and hydroxylation by CYP2D6 to 2-hydroxy-imipramine. Desipramine is metabolised by CYP2D6 to 2-hydroxydesipramine.
The PM phenotype leads to absence of CYP2C19 activity.
For more information about the PM phenotype: see the general background information about CYP2C19 on the KNMP Knowledge Bank or on www.knmp.nl (search for keyword “pharmacogenetics”).

Other considerations:
The therapeutic effectiveness and side effects of imipramine are associated with the plasma concentration of the sum of imipramine and desipramine.

Clinical consequences:
One study showed non-significant increases in therapeutic effect (by 10%) and in side effects (by 42%).

Kinetic consequences:
Increased imipramine plus desipramine plasma concentrations by 17-85%.
Increased imipramine plus desipramine AUC by 36%.

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause decreased plasma concentrations of imipramine and desipramine and an increase in the plasma concentration of the hydroxy metabolites.

Recommendation:

1. choose an alternative
   Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. if an alternative is not an option: increase the dose to 170% of the standard dose and monitor the plasma concentrations of imipramine and desipramine before setting the maintenance dose

Mechanism:
Imipramine and the active metabolite desipramine are primarily converted by CYP2D6 to inactive hydroxy metabolites. Imipramine is mainly converted by CYP2C19 to desipramine.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
Theoretically, the risk of reduced effectiveness of the therapy increases with a decrease in the plasma concentrations of imipramine and desipramine.

Kinetic consequences:
Plasma concentration of imipramine + desipramine: decrease by 41%.

MERCAPTOPURINE

METOPROLOL

The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate.

Recommendation:

1. use the maximum dose for the relevant indication as a target dose
   

2. if the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative
   Possible alternatives include:

   • HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolised by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolised (to a lesser extent than metoprolol) by CYP2D6.
   • OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolised by CYP2D6.

Mechanism:
Metoprolol is primarily metabolised by CYP2D6 to O-desmethylmetoprolol and further to α-hydroxymetoprolol. The active S-enantiomer of metoprolol is metabolised by CYP2D6 to a lesser extent than the less active R-enantiomer of metoprolol.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Database or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
Blood pressure: Two studies (hypertension patients and healthy study subjects) found no effect on systolic and diastolic blood pressure.
Heart rate: One study involving hypertension patients and with a target dose of 200 mg/day found a decrease in heart rate by 2%. One study involving patients with a recent acute myocardial infarction and a low dose of 0.9 mg/kg per day found almost no therapeutic effect (heart rate reduction from 78 to 69 beats per minute). The prevalence of disruption of the ventricular rhythm was increased by a factor 11 to 22%. In a study involving study subjects who received a single dose of 100 mg, the heart rate during exertion did not differ for EM, but the drop in heart rate at rest decreased by 14%.

Kinetic consequences:
Decrease in plasma concentration by 70-79%.
Decrease in AUC by 40-49%, decrease in AUC S-metoprolol by 48%.

NORTRIPTYLINE

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the active metabolite E-10-OH-nortriptyline.

Recommendation:

1. choose an alternative
   Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option:
   1. increase the dose to 160% of the standard dose and monitor the plasma concentration of nortriptyline
   2. be alert to an expected increase in the plasma concentration of the possibly cardiotoxic, active metabolite E-10-hydroxynortriptyline

Mechanism:
Nortriptyline is mainly metabolised by CYP2D6 to the active metabolite E-10-hydroxynortriptyline. This metabolite is approximately half as potent as nortriptyline itself. Nortriptyline is converted via CYP2D6 and CYP2C19 to the inactive metabolite desmethylnortriptyline.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
E-10-hydroxynortriptyline is approximately half as potent as the mother substance in the inhibition of norepinephrine uptake. It has a much lower anticholinergic activity than nortriptyline and is associated with cardiotoxicity.

Clinical consequences:
For one patient, the nortriptyline dose had to be increased to 500 mg/day (3-5x the standard dose) in order to achieve therapeutic plasma concentrations and a response.
Theoretically, the risk of cardiotoxic metabolites increases with an increase in plasma concentration of E-10-hydroxynortriptyline and the risk of a reduced effectiveness of the therapy increases with a decrease in plasma concentration of nortriptyline.

Kinetic consequences:
In studies, the AUC of nortriptyline was decreased by 23-41% and the oral clearance was increased by 85%.
With 3 functional alleles: for nortriptyline, increase in clearance by 62%-315% and a decrease in half-life by 12%.
With 13 functional alleles: for nortriptyline, increase in clearance by 325% and a decrease in half-life by 8%.

OXYCODONE

The genetic polymorphism increases the conversion of oxycodone to the more active metabolite oxymorphone. Pain relief without increased side effects is however generally achieved when dosing is guided by pain.

Recommendation:

1. be alert to side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention) and/or
2. advise the patient to contact their doctor in the event of side effects.

Mechanism:
Oxycodone is partially converted by CYP3A4 to noroxycodone and by CYP2D6 to oxymorphone. Oxymorphone has approximately 14x the analgesic activity of oxycodone, for noroxycodone this is approximately 0.01x.
For more information about the UM phenotype: see the general background information about CYP2D6 in the KNMP Knowledge Bank.

Clinical consequences:
One patient developed insomnia, anxiety and increased alertness on using oxycodone 10 mg twice.
There are no clinical studies that make a direct comparison between UM and EM (there are only comparisons of more than 2 groups). One study in cancer patients showed no effect of CYP2D6 genotype on fatigue, nausea, cognitive function and depression. One study including healthy volunteers who were given a single dose showed increased sedation and decreased functioning in a psychomotor test (replacing numerical digits) with increasing gene dose.
A postoperative study showed a decrease in cumulative oxycodone consumption until 12 hours after surgery and equi-analgesic dose compared to piritramide with increasing gene dose. In the study involving a single dose per kg body weight, the pain threshold on exposure to ice water and on electrical nerve stimulation increased with increasing gene dose.

Kinetic consequences:
A 6.7% decrease in dose led to a non-significant increase in median oxymorphone serum concentration by 44% compared to EM+IM. The increase in serum concentration was significant for the PM, EM+IM, UM trend.
There was no significant decrease in median oxycodone serum concentration with increasing gene dose.

PAROXETINE

The conversion of paroxetine by the enzyme CYP2D6 increases as a result of a genetic variation. This can reduce the effectiveness.

Recommendation:
It is not possible to offer substantiated advice for dose adjustment based on the literature.

1. if possible, select an alternative
   Anti-depressants that are not metabolised by CYP2D6, or to a lesser extent, include for example citalopram or sertraline.

Mechanism:
Paroxetine is primarily metabolised by CYP2D6 to inactive metabolites.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2D6).

Clinical consequences:
There was no therapeutic effectiveness in 100% of the UMs for who the therapeutic effectiveness was determined (n=6).

Kinetic consequences:
The plasma concentration decreased by ≥ 91%. For 71% of the UMs, where the plasma concentration was determined (n=7), this value was below the detection limit following standard doses of paroxetine.
Increase in maximum metabolisation rate (Vm) by 708%.
Increase in oral clearance with increase in gene dose, particularly at low doses.

PROPAFENONE

Genetic variation decreases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This increases the risk of reduced or no efficacy.

Recommendation:

It is not possible to offer adequately substantiated recommendations for dose adjustment based on the literature.

1. Either monitor plasma concentrations, perform an ECG and be alert to reduced efficacy of the therapy.
   
2. Or choose an alternative
   Antiarrhythmic drugs that are hardly if at all metabolised by CYP2D6 include, for example, sotalol, disopyramide, quinidine and amiodarone.

Mechanism:
Propafenone is metabolised by CYP2D6 to the equipotent metabolite 5-hydroxypropafenone. It is converted by CYP1A2 and CYP3A4 to N-depropylpropafenone, which is less active.
Propafenone is a CYP2D6 inhibitor. Propafenone pharmacokinetics are therefore non-linear.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
A study including 5 UM patients showed that propafenone was ineffective as prophylactic therapy for paroxysmal atrial fibrillation; a study including 3 UM patients found no effect on the efficacy of prophylactic therapy for atrial tachyarrhythmia (67% in UM patients versus 69% in EM patients).
Theoretically, the risk of reduced efficacy increases with a decrease in the sum of the propafenone and 5-hydroxypropafenone plasma concentrations.

Kinetic consequences:
Propafenone plasma concentration decreased by 61%.
The 5-hydroxypropafenone plasma concentration theoretically increases.

SERTRALINE

The gene variation leads to increased plasma concentrations of sertraline and the active metabolite desmethylsertraline. This increases the risk of side effects.

Recommendation:

1. Do not give doses exceeding 50 mg/day
   
2. Guide the dose by response and side effects and/or sertraline plus desmethylsertraline plasma concentrations.

Mechanism:
Sertraline is primarily converted by CYP2C19 to the active metabolite desmethylsertraline, which is also converted predominantly by CYP2C19.
For more information about the PM phenotype: see the general background information about CYP2C19 on the KNMP Knowledge Database or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
Although desmethylsertraline is less active than sertraline, the sum of the sertraline and desmethylsertraline concentrations is used for therapeutic drug monitoring (therapeutic range: 50-250 ng/L).

Clinical consequences:
One of two PM patients in a study developed relevant side effects.
Two of six PM patients in another study involving single administration of sertraline developed serious gastrointestinal disorders and side effects involving the central nervous system.
A study including 2 PM patients did not show an association between genotype-predicted CYP2C19 activity and side effects. If the sum of the sertraline and desmethylsertraline plasma concentrations also affects side effects, this association is however complicated by the fact that the sertraline plasma concentration decreases while that of desmethylsertraline increases in patients with the UM genotype (increased activity), contrary to PM and IM patients, in whom both increase.
This same study found a non-significant trend towards an association between genotype-predicted CYP2C19 activity and response.

Kinetic consequences:
A study including 5 PM patients showed a 277% increase in dose-corrected sertraline plus desmethylsertraline plasma concentrations, driven by a 193% increase in sertraline and a 315% increase in desmethylsertraline.
Another study reported a 112% increase in sertraline plasma concentration versus EM+IM and the SPC states an increase by 50%.
A study including 1 PM patient did not show an association between genotype-predicted CYP2C19 activity and dose-corrected sertraline and desmethylsertraline plasma concentrations.

This is NOT a gene-drug interaction.

Mechanism:
Sertraline is mainly converted by CYP2C19 to the inactive metabolite desmethylsertraline. For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
-

Kinetic consequences:
There are no studies into the kinetic consequences for UM.
However, one study with PM and EM found no effect of the CYP2D6 activity on the AUC and half-life.

TIOGUANINE

Genetic variation reduces conversion of thioguanine to inactive metabolites. This increases the risk of serious, life-threatening adverse events such as myelosuppression.

Recommendation:

1. Choose an alternative or start with 6-7% of the standard dose
   Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
   The frequency of monitoring should be increased.
2. If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore  throat in combination with fever, regular nosebleeds and tendency to bruising) develop

Mechanism:
Thioguanine is an inactive prodrug, which is converted into the active metabolites (thioguanine nucleotides) by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Two catabolic routes reduce thioguanine bioavailability for thioguanine nucleotide formation. Thiopurine methyltransferase (TPMT) catalyses S-methylation of thioguanine. Thioguanine is converted to the inactive metabolites 6-thioxanthine and then 6-thiouric acid by the enzymes guanase and xanthine oxidase (XO) respectively. For more information about the PM phenotype: see the general background information about TPMT on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
Disease remission was achieved in one PM patient with Crohn’s disease without myelosuppression developing using 7.14% of the standard dose (20 mg/2 weeks; 0.018 mg/kg/day). Inpatient initiation of thioguanine in one PM patient with acute lymphoblastic leukaemia led to 6.25% of the standard dose (2.5 mg/m2). One case report describes a patient who developed severe and prolonged pancytopenia and myelosuppression at the standard thioguanine dose. One study found that TPMT gene variants were not associated with altered risk of thioguanine-related hepatic sinusoidal obstruction syndrome.

Kinetic consequences:
Compared to EM, one case found a similar concentration of the active metabolite (variation over time 0.5-1 times the mean EM concentration) at 7.14% of the standard dose (20 mg/2 weeks instead of 20 mg/day). The dose-corrected concentration of the active metabolite was 19-fold higher in one PM patient.

TRAMADOL

The genetic polymorphism reduces the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in side effects.

Recommendation:

As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

1. decrease the dose to 20-40% of the standard dose
   
2. if a dose reduction does not have the desired effect: select an alternative
   Do not choose codeine, as it is contra-indicated for CYP2D6 UM.
   Oyxcodone is also metabolised by CYP2D6, but generally the dose can be titrated so that adequate analgesia is achieved without side effects.
   
3. if an alternative is not selected: advise the patient to contact their doctor in the event of side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).

Mechanism:
Tramadol is metabolised by CYP2D6, CYP3A4 and by glucuronidation. Conversion by CYP2D6 results in formation of the active metabolite O-desmethyltramadol, of which the (+)-enantiomer has a 300x higher affinity for the µ-opioid receptor than the mother substance. Tramadol itself primarily inhibits the re-uptake of norepinephrine and serotonin. (+)-O-desmethyltramadol appears to play a dominant role in both the analgesia and the side effects.
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank.

Clinical consequences:
One case in which transient side effects occurred: ataxia, pupil dilation, stiffness in arms and legs, trembling and dysphoria.
One case in which respiratory depression and loss of consciousness occurred in patient-controlled analgesia with tramadol.
A study with 11 UM found an increase in the pain threshold and pain tolerance. In addition, the percentage of individuals with nausea increased by 411% and one person experienced vomiting whilst another experienced palpitations. The significance of these effects was not reported.

Kinetic consequences:
(+)-O-desmethyltramadol: increase in AUC by 225-490%.

VENLAFAXINE

The genetic polymorphism leads to increased metabolic capacity of CYP2D6. This can cause a decrease in the plasma concentration of venlafaxine and an increase in the plasma concentration of the active metabolite O-desmethylvenlafaxine.

Recommendation:

1. be alert to a possible decrease in the sum of the plasma concentrations of venlafaxine and the active metabolite O-desmethylvenlafaxine
   
2. if necessary, increase the dose to 150% of the standard dose
   
3. if dose adjustment based on therapeutic drug monitoring is not possible, an alternative should be selected
   Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.

Mechanism:
Venlafaxine is mainly converted by CYP2D6 to the active metabolite O-desmethylvenlafaxine.
Venlafaxine and O-desmethylvenlafaxine are primarily converted by CYP3A4 and CYP2C19 to inactive metabolites (N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine respectively).
For more information about the UM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “pharmacogenetics”).

Clinical consequences:
One study found no difference in effectiveness. Another study with 2 UM had 1 responder and 1 non-responder. Theoretically, the risk of reduced effectiveness increases with lower plasma concentrations of venlafaxine + active metabolite.
In one study, the number of side effects decreased non-significantly by 39%. Another study found no effect on the sodium concentration.

Kinetic consequences:
The plasma concentration of venlafaxine + O-desmethylvenlafaxine decreases by 24-41%.
The ratio of the plasma concentrations O-desmethylvenlafaxine/ venlafaxine increases by 139-199%. The increase in the ratio is primarily caused by a decrease in the plasma concentration of venlafaxine.

VORICONAZOLE

The gene variation can reduce the conversion of voriconazole and consequently increase the plasma concentration. This could result in improved efficacy or an increase in the risk of side effects.

Recommendation:

• Monitor the plasma concentration

Mechanism:
Voriconazole is predominantly metabolised by CYP2C19 and otherwise by CYP2C9 and CYP3A4. The most important metabolite, voriconazole-N-oxide, is inactive.
For more information about the PM phenotype: see the general background information about CYP2C19 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “CYP2C19”).

Other considerations:
Several studies indicate a higher risk of hepatotoxicity at higher plasma concentrations of voriconazole.
The kinetics of voriconazole are non-linear at therapeutic doses.

Clinical consequences:
Efficacy
A meta-analysis of 10 studies including a total of 67 PM found an increase in the treatment success (RR = 1.31). A study not included in the meta-analysis with 7 PM found no effect for PM versus IM versus EM in the response after 6 weeks and in death during treatment with standard intravenous doses, an oral dose of 300 mg 2x daily (or 150 mg 2x daily for patients < 40 kg) and permitted dose adjustment based on response, side effects or trough concentrations.
Side effects
A meta-analysis of 10 studies including a total of 67 PM found no difference in all side effects. A study not included in the meta-analysis with 2 PM also found no difference in side effects.
A meta-analysis of 10 studies including a total of 67 PM found no difference in neurotoxicity. A study not included in the meta-analysis with 5 PM found no effect for PM versus IM versus EM in the effect on psychiatric side effects with standard intravenous doses, an oral dose of 300 mg 2x daily (or 150 mg 2x daily for patients < 40 kg) and permitted dose adjustment based on response, side effects or trough concentrations.
A meta-analysis of 10 studies including a total of 67 PM found no difference in hepatotoxicity. A study not included in the meta-analysis with 8 PM and dose according to the SmPC found no significant increase – after correction for confounding factors – in the risk of hepatotoxicity for PM versus IM versus EM. A study not included in the meta-analysis with 7 PM found no effect for PM versus IM versus EM in the effect on hepatic side effects with standard intravenous doses, an oral dose of 300 mg 2x daily (or 150 mg 2x daily for patients < 40 kg) and permitted dose adjustment based on response, side effects or trough concentrations. The liver function test results were elevated in 1 patient receiving voriconazole 600 mg/day.
Trough concentrations
A study involving 15 PM and standard initial dose followed by therapeutic drug monitoring found an increase in the percentage of first trough concentrations in the therapeutic range (1-5.5 µg/mL) and in the incidence of therapeutic trough concentrations and a reduction in the percentage of sub-therapeutic first trough concentrations (< 1 µg/mL) for PM versus IM versus EM. All PM in this study had a therapeutic first trough concentration. In a study involving 42 IM and 14 PM and a dose of 200-250 mg 2x daily, the distribution over the trough concentration groups (< 1 µg/mL, 1-4 µg/mL and > 4 µg/mL) was different for IM+PM (fewer low and more high trough concentrations) than for EM.

Kinetic consequences:
A meta-analysis of 10 studies including a total of 67 PM found a significant increase in the trough concentration by 1.22 µg/mL. A study not included in the meta-analysis with 8 PM with a dose according to the SmPC found a significant increase in the trough concentration. Two studies not included in the meta-analysis found a significant increase in the median trough concentration (1 study with 4 PM and a dose of 200 mg 2x daily and 1 study with 1 paediatric PM and dose-corrected trough concentrations).
The trough concentration increased by 39-90%.
The trough concentration in children increased by 330%.
The median trough concentration increased by 29-80%.
The median trough concentration in children increased by 933%. The initial dose in this study was lower for most of the patients than the dose in the “Kinderformularium” (paediatric formulary).
The dose required to achieve therapeutic trough concentrations (1-5 µg/mL) decreased by 46%.
The median dose required to achieve therapeutic trough concentrations (1-5.5 µg/mL) in children/adolescents increased by 7%.
The AUC in children increased by 240%.
The median AUC in children increased by 140%.
In healthy volunteers, the AUC for voriconazole increased by 159-480%, the oral clearance decreased by 65-75% and the half-life increased by 69-244%.

ZUCLOPENTHIXOL

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause decreased zuclopentixol plasma concentrations.

Recommendation:

No data have been published from studies into the pharmacokinetics and effects of zuclopentixol for this phenotype.

1. As a precaution, the prescriber should advised to be alert to a decreased zuclopentixol plasma concentration and - if necessary - the dose should be increased on the basis of the clinical effect, or an alternative should be prescribed according to the current guidelines.
   Antipsychotics that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, flupentixol, quetiapine, olanzapine and clozapine.

Mechanism:
Zuclopentixol is primarily metabolised by CYP2D6 to inactive metabolites.
For more information about the UM phenotype, see the general background information about CYP2D6 on the KNMP Knowledge Bank.

Clinical consequences:
Theoretically, the risk of reduced effectiveness of the therapy increases with a decrease in the zuclopentixol plasma concentration.

Kinetic consequences:
Theoretically, the zuclopentixol plasma concentration is reduced.