PGx Passport guidelines
The "PGx Passport" provides pharmacogenomic dosing recommendations to guide drug treatment based on an individual's pharmacogenomic phenotypes. For more information on its origin, the guidelines used, licensing, disclaimer and terms of use, please see the "Disclaimer and further information" section at the bottom of this page.

AMITRIPTYLINE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause an increase in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and decreased 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: use 60% of the standard dose and monitor the plasma concentrations of amitriptyline and nortriptyline
    As side effects are related to nortriptyline plasma concentrations and the efficacy to amitriptyline plus nortriptyline plasma concentrations, which are influenced to a lesser extent by CYP2D6, it is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, but the efficacy is maintained.

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 IM 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 study found a 6-fold increase in the percentage of patients with substantial side effects. The percentage increased 16-fold in the subgroup of patients without co-medication influencing CYP2D6.

Kinetic consequences:
Studies have shown that amitriptyline plus nortriptyline plasma concentrations are 0-70% increased and nortriptyline plasma concentrations 67-165% increased.
One study found an 18% decrease in the amitriptyline/nortriptyline metabolic ratio.

ATOMOXETINE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic variation increases the plasma concentration of atomoxetine and can thereby reduce the dose requirement.

Recommendation:

  1. in the event of side effects occurring and/or a response later than 9 weeks: reduce the dose and check whether the effect is conserved
    The plasma concentration of atomoxetine is a factor of 2-3 times higher for IM than for EM at the same dose.

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 phenotype IM: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2D6).

Clinical consequences:
Results vary from no difference in frequency, severity and nature of the side effects to an increase in the risk of a sleep disorder (OR = 1.7) or a dry mouth (OR = 1.6). IMs were not over-represented in the group of patients who did not finish the treatment and the average dose was comparable for IM and EM/UM.
One study found that 6 out of 10 patients who experienced side effects and/or had a late response at a standard dose were IM. For the two IM who then received a reduced dose (to 1.14 mg/kg per day and 0.42 mg/kg per day), this resulted in conserved efficacy and a reduction of the side effects.

Kinetic consequences:
Atomoxetine or atomoxetine+4-hydroxyatomoxetine: increase in the AUC by 100-232%, a decrease in the oral clearance by 55% and an increase in the half-life by 38%.
4-Hydroxyatomoxetine: One study found that the plasma concentration of 4-hydroxyatomoxetine for all genotypes was less than 1% of the plasma concentration of atomoxetine. Therefore, 4-hydroxyatomoxetine does not contribute significantly to the AUC of atomoxetine+4-hydroxyatomoxetine.

CLOMIPRAMINE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

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

Recommendation:

  1. decrease the dose to 70% 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 IM 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 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:
One study found a 1.9-fold increase in the percentage of patients with side effects.
Side effects include dry mouth, constipation, dizziness, sedation, reduced sexual functioning and sweating.

Kinetic consequences:
One study found an increase in the dose-corrected plasma concentration of clomipramine and desmethylclomipramine by 48%.
The same study found an increase in the dose-corrected plasma concentration of clomipramine by 50%.
In one case, the plasma concentration of clomipramine plus N-desmethylclomipramine was 1215 ng/mL (therapeutic range: 175-400 ng/mL) at a dose of clomipramine 150 mg/day.

CODEINE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic polymorphism reduces the conversion of codeine to morphine. This can result in reduced analgesia.

Recommendation:

  • For COUGH:
    1. no action required
  • For PAIN:
    It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.
    1. be alert to a reduced effectiveness
    2. in the case of inadequate effectiveness:
      1. try a dose increase
      2. if this does not work: choose an alternative
        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.
    3. if no alternative is selected: advise the patient to contact their doctor in the event of inadequate analgesia

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 IM 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:
For the indication of pain: theoretically, the risk of reduced effectiveness increases with a decrease in the plasma concentrations of morphine and morphine-6-glucuronide. In two studies in which a combination preparation containing codeine was used as additional analgesia following a Caesarean section, there was no effect of the CYP2D6 genotype on the analgesia or the total codeine dose used. With use for a maximum of four days, there was also no effect on the percentage of children and mothers with side effects.

Kinetic consequences:
The plasma concentration of morphine decreases significantly by approx. 15%.
The AUC of codeine increases by 6%.

DOXEPIN

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic polymorphism in CYP2D6 leads to decreased metabolic capacity of the enzyme, which may cause increased plasma concentrations of doxepin and nordoxepin.

Recommendation:

  1. decrease the dose to 80% 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 IM 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 side effects increases with an increase in the plasma concentrations of doxepin and nordoxepin.

Kinetic consequences:
Following a single dose of 75 mg doxepin, the AUC of doxepin + nordoxepin increased by 19% and the oral clearance of doxepin decreased by 42%.

EFAVIRENZ

Reason: CYP2B6 INTERMEDIATE METABOLIZER

Genetic variations may lead to reduced metabolism of efavirenz. This may increase the efavirenz plasma concentration and therefore the risk of adverse events. However, the efavirenz plasma concentration remains within the therapeutic range for the majority of IM patients.

Recommendation:

  1. Determine the efavirenz plasma concentration if adverse events occur and reduce the dose to 400 or 200 mg/day if needed.
    The therapeutic range established for efavirenz is 1000-4000 ng/ml.

Mechanism:
Efavirenz is mainly converted by CYP2B6 to 8-hydroxyefavirenz. Efavirenz is metabolised to a limited extent by CYP3A4/5 and efavirenz is metabolised by UGT2B7 by direct N-glucuronidation.
For more information about the IM phenotype, see the general background information about CYP2B6 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2B6).

Clinical consequences:
There were no studies that found significant differences between IM and EM patients. There were studies that found significant trends for EM versus IM versus PM patients.
A study showed an increase in the rate of therapy withdrawal (especially due to neuropsychiatric adverse events) with the number of *6 alleles, but the percentage for IM was not higher than that for EM. The increase in the rate of therapy withdrawal with the number of *6 alleles was not confirmed in another study.
Two studies showed an increase in the percentage of patients with drug-induced liver injury that correlated with the number of *6 alleles, but the trend was only significant in 1 study.
In one study including 12 patients (11x PM and 1x IM) with efavirenz plasma concentrations exceeding 6000 ng/ml, the dose was reduced to 400 or 200 mg/day. After dose reduction, HIV remained undetectable in plasma for more than 6 months (longest follow-up 26 months). Neuropsychiatric adverse events improved or resolved.

Kinetic consequences:
None of the studies showed median or mean efavirenz plasma concentrations or median efavirenz AUC above the therapeutic range in the IM group. Concentrations above the therapeutic range were observed for individual IMs. In one study, 7% of the IM patients had efavirenz plasma concentrations 1.5 times the upper limit of normal (ULN) versus 0% of the EM patients.
The median efavirenz plasma concentration increased by 16-39%.
The mean efavirenz plasma concentration increased by 45%.
The median efavirenz AUC increased by 17%.

ELIGLUSTAT

Reason: CYP2D6 INTERMEDIATE METABOLIZER

This gene variation reduces the conversion of eliglustat to inactive metabolites. However, in the absence of CYP2D6 and CYP3A inhibitors, this does not result in a clinically significant increased risk of side effects.

Recommendation:

  • Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR:
    Eliglustat is contra-indicated.
    1. choose an alternative if possible
      Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione.
      Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir.
      Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.
  • Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):
    1. use a dose of 84 mg eliglustat 1x daily
  • Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):
    1. consider a dose of 84 mg eliglustat 1x daily
    2. be alert to side effects
  • Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):
    • choose an alternative if possible
    • if an alternative is not an option:
      • consider a dose of 84 mg eliglustat 1x daily
      • be alert to side effects
  • Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):
    1. choose an alternative
    2. if an alternative is not an option:
      1. consider a dose of 84 mg eliglustat 1x daily
      2. be alert to side effects
  • Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum):
    Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.
    1. choose an alternative if possible
  • NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:
    1. use the standard dose of 84 mg 2x daily

Mechanism:
Eliglustat is converted to inactive metabolites, primarily by CYP2D6 and to a lesser extent by CYP3A.
For more information about the IM 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:
Clinical consequences are not known for IM, only for EM and IM.

Kinetic consequences:
For one IM the AUC was 2-4 times higher than the AUCs of the EMs with the highest and lowest AUC respectively.
The recommended dose of 84 mg 2x daily is based on modelling according to the pharmacokinetic/pharmacodynamic data from the dose titration schedules that were used in the clinical studies for IM and EM.

FLECAINIDE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic variation reduces conversion of flecainide to inactive metabolites. This may increase the risk of side effects.

Recommendation:

  • Indications other than diagnosis of Brugada syndrome:
    1. reduce the dose to 75% of the standard dose and record an ECG and monitor the plasma concentration
  • Provocation test for diagnosis of Brugada syndrome:
    No action required.
    At a dose of 2.0 mg/kg body weight to a maximum of 150 mg, the response is better for patients with alleles that result in reduced activity.
    All 5 patients with these alleles and 20% of the patients with two fully active alleles exhibited a response within 30 minutes.

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 IM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2D6).

Clinical consequences:
Reduction in late responses to the provocation test for diagnosis of Brugada syndrome. All 5 patients with alleles that result in reduced activity and 20% of the patients with two fully active alleles exhibited a response within 30 minutes.
In a study involving 7 IM, there was no difference in the corrected QT interval, the QRS duration and the JTc interval (=QTc-QRS) following a single dose.
Theoretically, the risk of side effects increases with an increase in the flecainide plasma concentration.

Kinetic consequences:
Increase in the AUC by 7-23%, increase in the plasma concentration by 72%.

IMIPRAMINE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

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

Recommendation:

  1. decrease the dose to 70% 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 IM 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 side effects increases with an increase in the plasma concentrations of imipramine and desipramine.

Kinetic consequences:
Plasma concentration of imipramine + desipramine: increase by 48%.

METOPROLOL

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The gene variation reduces the conversion of metoprolol to inactive metabolites. However, the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia.

Recommendation:

  • If a GRADUAL REDUCTION in HEART RATE is desired, or in the event of SYMPTOMATIC BRADYCARDIA:
    1. increase the dose in smaller steps and/or prescribe no more than 50% of the standard dose
  • OTHER CASES:
    1. no action required

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 IM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Database or on www.knmp.nl (search for key word “pharmacogenetics”).

Other considerations:
Patients with heart failure are a vulnerable patient group to develop side effects.
The literature reveals that an increase in the AUC of the active enantiomer does not result in a difference in blood pressure change compared to EM.

Clinical consequences:
Heart rate: For asymptomatic bradycardia, the study results varied from no difference in patients with hypertension and mixed indications to an increase in the risk for patients with heart failure (OR = 1.72). There is no evidence to support an increase in symptomatic bradycardia. For the reduction in heart rate, the study results varied from no difference to an increase by a factor 1.14-1.63. A study involving heart failure patients, with measurements at various time points, found a difference during and shortly after the titration phase, but not thereafter.
Side effects did not occur more often.
Blood pressure: Six studies with patients found no difference in the decrease in systolic blood pressure. Four out of six studies with patients found no difference in the decrease in diastolic blood pressure. The other two found a decrease that was greater by a factor 1.17-1.34 for at least one time point. One study with hypertension patients demonstrated no significant difference in the prevalence of effective blood pressure reduction.

Kinetic consequences:
Increase in the plasma concentration of S-metoprolol by 48-110% and of R+S-metoprolol by 5-587%.
Increase in AUC of S-metoprolol by 218%, increase in AUC of R+S-metoprolol by 62-244%.

NORTRIPTYLINE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

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

Recommendation:

  1. decrease the dose to 60% of the standard dose and monitor the plasma concentrations of nortriptyline before setting the maintenance dose

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 IM 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:
Anticholinergic side effects were reported in 1 case, disappeared with dose reduction.
Nervousness and tinnitus were reported as side effects in another case.

Kinetic consequences:
The plasma concentration and AUC of nortriptyline increase by 35-123% and 86-179% respectively. The clearance decreases by 31%-57%. The dose decreases by 70% of the dose for EM.

OXYCODONE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic polymorphism reduces conversion of oxycodone to the more active metabolite oxymorphone. Adequate pain relief is however generally achieved when dosing is guided by pain.

Recommendation:

  1. be alert to reduced pain relief

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 IM phenotype: see the general background information about CYP2D6 in the KNMP Knowledge Bank.

Clinical consequences:
There are no clinical studies that make a direct comparison between IM and EM (there are only comparisons of more than 2 groups).
One study showed no effect of CYP2D6 genotype on postoperative pain scores. This study showed an increase in cumulative oxycodone consumption until 12 hours after surgery and the equi-analgesic dose compared to piritramide with decreasing gene dose.

Kinetic consequences:
Oxycodone: plasma concentration increased by 54%.
Oxymorphone: plasma concentration decreased by 53% compared to (EM + gene dose 1-0).

PHENYTOIN

Reason: CYP2C9 *1/*3

Genetic variation reduces conversion of phenytoin to inactive metabolites. This increases the risk of side effects. The life-threatening cutaneous side effects Stevens-Johnson Syndrome and toxic epidermal necrolysis may occur, especially in Asian patients.

Recommendation:

  1. The loading dose does not need to be adjusted.
  2. For the other doses, use 75% of the standard dose and assess the dose based on effect and serum concentration after 7-10 days.
  3. Advise the patient to get in touch if side effects (such as ataxia, nystagmus, slurred speech, sedation or, especially in Asian patients, rash) occur.

Mechanism:
Phenytoin is predominantly metabolised by CYP2C9 (90%) and also by CYP2C19 (10%), to the metabolite para-hydroxyphenytoin (5-(para-hydroxyphenyl)-5-phenylhydantoin).
For more information about the CYP2C9*1/*3 genotype: see the general background information about CYP2C9 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2C9).

Other considerations:
The therapeutic phenytoin concentration should ideally be between 8 and 20 mg/L (total), which is generally equivalent to 0.5-2 mg/L (free). Toxicity occurs at > 20 mg/L (total), > 2 mg/L (free).

Clinical consequences:
One study found an increased risk of neurotoxicity (OR = 15.3).
There was no significant relationship between CYP2C9 genotype and severity of the side effect gingival hyperplasia.
Non-significant increase in the risk of hospital admission due to phenytoin toxicity.
Another study found a 2.1-fold increase in the percentage of patients with side effects for *1/*3+*1/*2.
A meta-analysis and two case-control studies found an increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis for *1/*3+*3/*3 (OR = 4.3-30). A case-control study found no increased risk of the cutaneous side effect DRESS (which is also life-threatening), while two other analyses did (OR = 8.8-19). A case-control study that used two control groups found an increased risk of the mild cutaneous side effect maculopapular exanthema (OR = 2.6-5.5).
Two cases have been reported of patients with toxic plasma concentrations and symptoms of phenytoin intoxication. One report was on a patient who used phenytoin 187.5 mg/day and who also had a CYP2C19 polymorphism. The other report was on a patient who used phenytoin 300 mg/day and who did not have a CYP2C19 polymorphism.
Dose reduction by 16-42%.

Kinetic consequences:
AUC increases by 48%, oral clearance decreases by 57%, half-life increases by 55%, the (dose-corrected) plasma concentration increases by 29-95%.

PIMOZIDE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic variation results in an increase in the plasma concentration of pimozide. This increases the risk of possibly life-threatening QT-prolongation.

Recommendation:

  1. prescribe no more than the following doses (60-65% of the standard maximum dose): adults 12 mg/day, children 0.065 mg/kg per day to a maximum of 2.6 mg/day

Mechanism:
Pimozide is primarily metabolised by CYP2D6 and CYP3A4. In addition, pimozide is also metabolised by CYP1A2.
For more information about the IM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2D6).

Clinical consequences:
There are no studies in which the clinical effects were studied.

Kinetic consequences:
Following a single dose administration, the oral clearance decreased by 35%.

PROPAFENONE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

Genetic variation increases the sum of the plasma concentrations of propafenone and the active metabolite 5-hydroxypropafenone. This may increase the risk of side effects.

Recommendation:

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

  1. Either guide the dose by therapeutic drug monitoring, perform an ECG and be alert to side effects
  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 IM 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:
Premature ventricular contractions decreased by 66%, heart rate, PR and QRS intervals were non-significantly different.
Theoretically, the risk of side effects increases with an increase in the sum of the propafenone and 5-hydroxypropafenone plasma concentrations.

Kinetic consequences:
For propafenone: AUC increased by 74-100%, plasma concentration increased by 1324%.
The 5-hydroxypropafenone plasma concentration theoretically decreases.

TAMOXIFEN

Reason: CYP2D6 INTERMEDIATE METABOLIZER

This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness.

Recommendation:

  1. select an alternative or measure the endoxifen concentration and increase the dose if necessary by a factor of 1.5-2
    Aromatase inhibitors are a possible alternative for post-menopausal women.
  2. if TAMOXIFEN is selected: avoid co-medication with CYP2D6 inhibitors such as paroxetine and fluoxetine

Mechanism:
The main conversion route of tamoxifen is by CYP3A4/5 to the relatively inactive N-desmethyltamoxifen. This is converted by CYP2D6 to endoxifen (hydroxy-N-desmethyltamoxifen), which has an anti-oestrogenic effect that is 30-100x stronger than tamoxifen. Tamoxifen is further converted by CYP2D6 to the active metabolite 4-hydroxytamoxifen. This metabolite is as potent as endoxifen, but occurs at much lower concentrations. CYP3A4/5 converts 4-hydroxytamoxifen further to endoxifen.
For more information about the PM 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:
There is no consensus about the clinical relevance of the reduced plasma concentration of the active metabolites endoxifen and 4-hydroxytamoxifen.

Clinical consequences:
- Meta-analyses of studies (particularly) into adjuvant treatment, effect of gene variants with reduced or present activity
Four of the six meta-analyses demonstrated that gene variants with reduced or no activity resulted in a significantly worse clinical outcome. One meta-analysis found a significant effect for a well-defined sub-group (post-menopausal patients with surgically removed, non-metastatic, invasive, oestrogen receptor-positive breast cancer, who received adjuvant monotherapy with tamoxifen 20 mg/day for an intented period of five years), but not for all patients combined. One meta-analysis found no difference.
In the meta-analyses that did find a difference, the HR varied from 1.22 to 1.38.
None of the meta-analyses determined the effect for IM alone.
- Treatment of metastatic breast cancer (tamoxifen 40 mg/day)
There was no significant difference in the time to death and in the time to disease progression.
- Adjuvant treatment (tamoxifen 20 mg/day)
The results for the risk of recurrence of breast cancer varied from no significant effect to an increase with an HR of 1.4 to 2.57 or with an OR of 2.37. For a group of IM + PM, which consisted of 96% IM, the HR was 9.52.
No significant effect was found in separate studies for the following risks:
the risk of disease progression
1. the risk of recurrence of breast cancer or death
2. the risk of recurrence of breast cancer, occurrence of another cancer or death
3. the risk of death as a result of breast cancer
4. the risk of death
For a group of IM + PM, which consisted of 89% IM, the risk of recurrence of breast cancer or death was elevated with an HR of 1.33. The HR for the risk of recurrence of breast cancer, occurrence of another cancer or death was 1.29.
The risk of hot flushes was elevated with an HR of 1.23.

Kinetic consequences:
Endoxifen: decrease in the plasma concentration by 5-54%.
4-hydroxytamoxifen: results varied from no significant difference to a decrease in the plasma concentration by 2-45%.
Tamoxifen: results varied from no significant difference to a decrease in the plasma concentration by 5%.
The plasma concentration of endoxifen differed non-significantly between IM on 40 mg/day and EM on 20 mg/day (27 IM), or was numerically higher for IM on 40 mg/day (12 IM). None of the studies found an increase in adverse drug reactions as a result of a dose increase.
The plasma concentration of endoxifen was numerically higher for 14 IM on 30 mg/day than for EM on 20 mg/day.

TRAMADOL

Reason: CYP2D6 INTERMEDIATE METABOLIZER

The genetic polymorphism reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia.

Recommendation:
It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

  1. be alert to a reduced effectiveness
  2. in the case of inadequate effectiveness:
    1. try a dose increase
    2. if this does not work: choose an alternative
      Do not select codeine, 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.
  3. if no alternative is selected: advise the patient to contact their doctor in the event of inadequate analgesia

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 IM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank.

Clinical consequences:
A study of patient-controlled analgesia found an increase in the total consumption of tramadol by 13.2%. There was no difference in pain scores and the incidence of side effects.
One study found a decrease in the pupil constricting effect of tramadol (a measure of the opioid effect).
One study found a reduced risk of nausea and vomiting (OR = 0.29).

Kinetic consequences:
(+)-O-desmethyltramadol: change in AUC varied from a decrease by 50% to an increase by 7%.
Tramadol: increase in AUC by 15-150%, decrease in clearance by 34%-59%.

VENLAFAXINE

Reason: CYP2D6 INTERMEDIATE METABOLIZER

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

Recommendation:

It is not possible to offer adequately substantiated advice for dose reduction based on the literature.

  1. Choose an alternative
    Antidepressants that are not metabolised by CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
  2. If an alternative is not an option and side effects occur:
    1. reduce the dose
    2. check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine
      It is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, while the effectiveness is maintained. In general, it is assumed that the effectiveness is determined by the sum of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. However, the side effects do not appear to be related to this sum.

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 IM 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:
Venlafaxine is potentially cardiotoxic.
In general, the sum of the plasma concentration of venlafaxine and O-desmethylvenlafaxine is used to determine whether the plasma concentration lies within the therapeutic range. However, the side effects do not appear to be related to this sum.
One study found a reduced effectiveness for depression in patients with an increased ratio of venlafaxine/active metabolite (PM).

Clinical consequences:
In one study, 5 patients experienced side effects at a low dose of venlafaxine. The treatment had to be stopped in 4 of these 5 patients.
One study found no difference in the effectiveness for obsessive compulsive disorder for IM+PM. For IM, there are no studies into the effectiveness for depression.

Kinetic consequences:
For venlafaxine + O-desmethylvenlafaxine, the AUC increases by 14-17% and the plasma concentration increases by 1-22%.
The ratio of the plasma concentrations O-desmethylvenlafaxine/venlafaxine decreases by 52-66%. The decrease in the ratio is primarily caused by an increase in the plasma concentration of venlafaxine.

WARFARINE

Reason: CYP2C9 *1/*3

This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.

Recommendation:

  1. use 65% of the standard initial dose

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica.
From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

Mechanism:
Warfarin consists of a racemic mixture. S-warfarin is a stronger inhibitor of blood clotting than R-warfarin. S-warfarin is primarily metabolised by CYP2C9, whilst R-warfarin is primarily metabolised by other enzymes.
For more information about the *1/*3 genotype: see the general background information about CYP2C9 on the KNMP Knowledge Bank or on www.knmp.nl (search for CYP2C9).

Clinical consequences:
- Risk of bleeding
One meta-analysis found an increase in the risk of severe bleeding (HR = 2.43) and the risk of all bleeding events (HR = 2.05). Another meta-analysis found no effect on the risk of all bleeding events.
- Risk of over-anticoagulation
The risk of over-anticoagulation was not determined separately for *1/*3.
One meta-analysis found an increased risk of INR > 4 for *1/*3 + *2/*3 + *3/*3 (HR = 2.37).
- Maintenance dose
The maintenance dose decreased by 33-41%.
Decrease in the maintenance dose by 1.61-1.79 mg/day (all studies and studies involving Caucasian patients) and 1.13-1.47 mg/day (Asian studies).

Kinetic consequences:
Kinetic studies are not included in the risk analysis.

ZUCLOPENTHIXOL

Reason: CYP2D6 INTERMEDIATE METABOLIZER

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

Recommendation:

  1. Advise the prescriber to start with 75% of the standard dose or to choose an alternative 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 IM phenotype: see the general background information about CYP2D6 on the KNMP Knowledge Bank.

Clinical consequences:
Decrease in the daily dose by 39%, number of changes in dose increased by 160%.
Theoretically, the risk of side effects increases with an increase in the zuclopentixol plasma concentration.

Kinetic consequences:
Increase in plasma concentration by 36%, decrease in clearance by 32%.
Zuclopentixol decanoate: increase in maximum concentration by 75%, increase in concentration after 14 days by 36%.

Disclaimer and further information

Guidelines and inference of recommendations

The pharmacogenomic dosing recommendations are based on the guidelines developed by the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association (KNMP). The Dutch Pharmacogenetics Working Group formulates the optimal recommendations for each phenotype group based on the available scientific evidence. If this optimal recommendation cannot be followed due to practical restrictions, e.g. therapeutic drug monitoring or a lower dose is not available, the health care professional should consider the next best option. The recommendations do not take into account any other factors that can influence a patient's phenotype and drug response, such as drug-drug interactions, various health conditions or environmental factors. The absence of a recommendation for a specific drug is not to be equated with the general absence of variants that might influence an individual's response to this drug since the patient might have a rarer variant that is currently not covered by the U-PGx genotyping test. The present tool matches phenotypes with therapeutic recommendations. The responsibility for inferring the correct pharmacogenomic phenotypes from raw genetic data lies solely with the user.

The database that contains the annotations and recommendations to generate this report are continuously be updated as new scientific evidence becomes available. Therefore, the information included in this report is dependent on the report generation date.

Additional information on the recommendations for oral / vaginal contraceptives with estrogens

The recommendation refers to all estrogen containing hormonal contraceptives for systemic use. This includes, but is not limited to, combination preparations of estrogens (e.g. ethinylestradiol, estradiol) with the following progestogens: Cyproteron, Desogestrel, Dienogest, Drospirenon, Etonogestrel, Gestodeen, Levonorgestrel, Nomegestrol, Norelgestromine, Norethisteron, Norgestimaat.

Origin and development of the PGx passport

The PGx Passport was developed with the intention to allow the continuation of evidence-based pharmacogenomics-guided drug dosing beyond the U-PGx Project. In the U-PGx project (http://www.upgx.eu) pre-emptive pharmacogenomic testing to guide drug and dose selection was implemented within a clinical study in seven European countries to provide evidence on the effect of pharmacogenomics-based prescribing on patient outcomes. In line with the projects goal – to make make effective treatment optimization accessible to every European citizen – this open-source tool was developed.

Show pharmacogenomic data

Gene/Phenotype
Gene/PhenotypeCYP2B6 INTERMEDIATE METABOLIZER
Gene/PhenotypeCYP2D6 INTERMEDIATE METABOLIZER
Gene/PhenotypeCYP2C9 *1/*3
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