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CYP2D6 Metabolizing enzyme

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CYP2D6 Metabolizing enzyme

8.3.2. CYP2D6 influences drug degradation and dopamine synthesis

CYP2D6 metabolizes around 25% of all active pharmaceutical ingredients12 , including the drugs relevant to the treatment of ADHD

  • Vyvanse (AMP)
  • Atomoxetine
  • Nortryptiline
  • Imipramine
  • Desipramine (irrelevant today, strong inhibitor)

In addition, CYP2D6 is also involved in one of the dopamine synthesis pathways in humans by converting tyramine to dopamine.3 In rats, however, this is carried out by CYP2D2, CYP2D4 and CYP2D184
This alternative synthesis pathway appears to be quantitatively modest under normal physiological conditions in rats, but may be more efficient in the human brain and may become particularly important when the main synthesis pathway is impaired (e.g. tyrosine hydroxylase deficiency or aromatic amino acid decarboxylase deficiency). Furthermore, alternative CYP2D6-mediated dopamine synthesis could be relatively important in individuals who possess more than one CYP2D6 gene (e.g. in Mediterranean populations).5

This raises the question for us as to whether people with particularly active CYP2D6 gene variants could therefore have increased dopamine synthesis and increased dopamine degradation and people with particularly low CYP2D6 gene variants could therefore have reduced dopamine synthesis and reduced dopamine degradation. We are not yet aware of any studies on this.

8.3.2.1. CYP2D6 gene variants influence the rate of metabolism

A CYP2D6 gene defect is inherited in an autosomal recessive manner.
Based on the experience with the influence of CYP2D6 on the effect of other drugs, the different CYP2D6 gene variants lead to different types of metabolization2

  • Approx. 90 %6 of Europeans carry the wild type or a heterozygous defect
    • Moderately fast metabolizers - approx. 40 %2
    • Fast metabolizer - approx. 46 %2
    • CYP2D6 is fully efficient
    • Carriers are “extensive metabolizers (EM)”
  • Approx. 7%2 to just under 10%6 of Europeans carry a homozygous enzyme defect
    • CYP2D6 has limited performance
    • Carriers are “poor metabolizers (PM)”
      • Effects amplified
      • Increased risk of side effects
      • Particularly slow dosing is important
      • Particularly low dosage helpful
  • In contrast, around 1.5%7 to 7%2 of Europeans have up to 12 active CYP2D6 copies
    • CYP2D6 is hyper-powerful
    • Carriers are “ultra-fast metabolizers”
      • Accelerated degradation of drugs
        • Can lead to ineffectiveness
        • Especially for drugs with a high first-pass effect
        • Is associated with therapy resistance (non-responders)
        • Increased dose / more frequent dosing can be helpful

A more general distinction between the types of metabolization is as follows:68

  • Slow metabolizer (PM)
    • No wild-type allele present (homozygous mutant); both alleles inactive, no sufficient amount of functional enzyme
  • Intermediate metabolizer (IM)
    • At least 1 wild-type allele retained (heterozygous); 1 allele active and 1 allele inactive or impaired active or both alleles impaired active, reduced functional enzyme
  • Extensive metabolizer (EM)
    • At least 1 wild-type allele (heterozygous); sufficient amount of functional enzyme
  • Ultra-fast metabolizer (UM)
    • Duplication of a wild-type allele; increased amount of functional enzyme

“In such cases, the average doses reported in the literature do not do justice to either fast or slow metabolizers.”9 Depending on the CYP2D6 metabolization type, the dosage of nortryptiline must be varied between 10 mg and 500 mg.10

The large fluctuations in the duration of action of some ADHD drugs broken down by CYP2D6 (in 2/3 of people with ADHD, a single dose of Vyvanse only works for 7 hours or even less) cannot be explained by CYP2D6 gene variants alone.
The effectiveness of CYP2D6 degradation is influenced by gene variants of the POR gene (cytochrome P450 oxidoreductase)1

The excretion of AMP depends strongly on the pH value of the urinary tract and the flow rates. The excretion of AMP in the urine is between 1 % and 75 %, the rest is metabolized via the liver. At normal urinary pH levels, 30% to 40% of the dose is excreted as unchanged parent compound and approximately 50% of the dose is excreted as alpha-hydroxyamphetamine or its downstream inactive metabolite, hippuric acid. Since AMP is a weak base with a pKa value of 9.9, it is excreted quickly; if the urine is acidic (pH <6,0). Ist der Urin alkalisch (pH >7.5), excretion is delayed. Accordingly, the relative amounts of AMP and the excreted metabolites differ depending on the pH conditions in the urine. The t1/2 of AMP should increase by about 7 hours for each unit of increase in urine pH. Large deviations from normal physiological values may occur, especially when taking acidifying or alkalizing agents11

Comedication with CYP2D6 substrates, inhibitors or inducers also influences the AMP duration of action.

Berberine, quinine, bupropion as Vyvanse duration of action extenders

Berberine is a very long-lasting, “quasi-irreversible” inhibitor of CYP2D6.

We have received several individual case reports from people with ADHD who were able to prolong the effect of a single dose of Vyvanse, which was clearly too short, by taking Berberine as an augmentation.

  • One person with ADHD reported that 300 mg was sufficient for this, but 150 mg was not. He thus achieved a duration of action of around 8 to 10 hours from a single dose of Vyvanse instead of the previous 4 to 6 hours, and also felt that the effect was more constant.
  • Another reported that he was able to reduce his previous three-dose Vyvanse intake of 50/20/20 (which was accompanied by crashes and drug fluctuations) to 40/0/0 with 1000 mg berberine, which worked consistently and evenly throughout the day. A later further (second) Vyvanse dose led to sleep problems with berberine, presumably due to the now much longer effect.
  • A third person with ADHD reported an optimal dose for him of 500 mg berberine in order to adequately prolong the duration of action of Vyvanse, which had previously been too short for him.

There are also indications of a corresponding effect of quinine (tonic, bitter lemon) or bupropion.
One person with ADHD reported a significantly stronger and longer effect of Vyvanse from augmented bupropion than from augmented berberine or quinine.

7 - 8 % of people with ADHD in Europe have reduced or absent CYP2D6 activity and therefore need to take much lower doses of AMP, ATX or other drugs metabolized by CYP2D6, in the case of AMP even at normal urine pH levels.

Enzyme variant Enzyme activity in vivo Enzyme activity in vitro
CYP2D6.1 normal normal
CYP2D6.3 inactive inactive
CYP2D6.4 inactive
CYP2D6.5 inactive
CYP2D6.6 inactive
CYP2D6.7 inactive
CYP2D6.9 decreased decreased
CYP2D6.10 reduced
CYP2D6.15 inactive
CYP2D6.16 inactive
Source: Kein, Grau (2001).6
Enzyme variant Activity Score (AS) Enzyme activity
*1/*1x2 3 UM
*1/*2x2 3 UM
*1x2/*10 2.25 NM
*1/*1 2 NM
*1/*2 2 NM
*2/*35 2 NM
*1/*17 1.5 NM
*1/*10x2 1.5 NM
*2/*29 1.5 NM
*35/*41 1.5 NM
*1/*10 1.25 NM
*10/*17x2 1.25 NM
*1/*4 1 IM
*2/*5 1 IM
*7/*35 1 IM
*9/*41 1 IM
*17/*41 1 IM
*10/17 0.75 IM
*10/*41 0.75 IM
*4/*9 0.5 IM
*5/*29 0.5 IM
*6/*17 0.5 IM
*4/*10 0.25 IM
*5/*10 0.25 IM
*4/*5 0 PM
*4x2/*6 0 PM
*5/*40 0 PMv
*1/*1062 N/A IM or NM
*4/*1273 N/A PM or IM
*106/*1274 N/A indeterminate
Source: Nofziger et al. (2020).12

A much more comprehensive description of the different CYP2D6 variants can be found at Pharmavar.org (formerly www.cypalleles.ki.se).

The CYP2D6 gene is highly polymorphic. In Central Europe, the following alleles are particularly relevant2

  • CYP2D6.3
  • CYP2D6.4
  • CYP2D6.5
  • CYP2D6.6
  • CYP2D6.9
  • CYP2D6.41

Poor metabolizers may require lower doses of AMP and ultra-rapid metabolizers may require higher doses of AMP. A meta-analysis found that ultra-rapid metabolizers (UM) may require up to 3 times the usual dose of medication, while slow metabolizers (PM) may require up to 20%. The deviations are drug-dependent and do not appear to be generalizable.13 However, the effects of CYP2D6 polymorphisms on AMP metabolism are still unclear.11
In extensive CYP2D6 metabolizers, CYP2D6 inhibitors were used to increase the response to atomoxetine.14

CYP2D6 is also involved in dopamine synthesis via the alternative dopamine synthesis pathway via P-tyrosine and in serotonin synthesis via 5-methoxytryptamine.153

Unexpectedly high hepatic exposure to atomoxetine has been reported in patients with intermediate metabolism who have CYP2D610 or 2D636 alleles.16

8.3.2.2. POR gene variants influence CYP2D6 metabolism rate

The effectiveness of CYP2D6 degradation is influenced by gene variants of the POR gene (cytochrome P450 oxidoreductase, NADPH P450 oxidoreductase, CPR) in addition to the CYP2D6 gene variants.117 The enzyme encoded by POR is required for electron transfer from NADP to cytochrome P450 in microsomes and provides electron transfer to heme oxygenase and cytochrome B5.18 Each POR gene variant affects each CYP differently. The effect on CYP2D6 can therefore not be transferred to other CYPs.
POR (CPR) decreases with age and was 27% lower in men over 45 than in men under 45. As CYP levels also decreased, the ratio remains approximately the same.19

The different gene variants have different influences on CYP2D6 metabolization:1

  • Q153R
    • rare variant
    • increased CYP2D6 activity in
      • Bufuralol: 153 %
      • EOMCC: 128 %
      • Dextromethorphan: 198 %
  • A287P
    • no detectable CYP2D6 activity
      • EOMCC (2H-1-benzopyran-3-carbonitrile,7-(ethoxy-methoxy)-2-oxo-(9Cl)): 0 %
    • reduced CYP2D6 activity in
      • Bufuralol: 25 %
      • Dextromethorphan: 25%
  • R457H
    • no detectable CYP2D6 activity
      • EOMCC: 0 %
  • A503V
    • is found in 28 % of people
      • 19% of people of color in the USA20
      • 37% of people of Asian descent in the USA20
    • reduced CYP2D6 activity in
      • Bufuralol: 53 %
      • EOMCC: 85 %
      • Dextromethorphan: 62 %

There are no studies to date on the effect on ADHD drugs metabolized by CYP2D6. Estimates can therefore only be made on the basis of the effect on other drugs metabolized by CYP2D6.

Other studies, in particular by the research group of Flück et al, investigated the effect of different gene variants on CYP3A421 CYP17A122 and CYP19A123
As the work of Flück et al. shows, the influences of the POR gene variants on the activity of various CYP 450 enzymes are not identical, but roughly comparable. Only Q153R differs massively in relation to CYP17A1. From this it is possible to deduce approximately what influence the POR gene variants could have on CYP 450 enzymes that have not been investigated.

Gene variant in % of the wild type of CYP2D6 in % of the wild type of CYP3A4 in % of the wild type of CYP17A1 in % of the wild type of CYP19A1
Wild type 100 % 100 % 100 % 100 %
A115V 85 % 63 %
T142A 85 % 49 %
Q153R 128 % to 198 % 119 % 9 % 189 %
Y181D 0 % 0 % 0 %
P228L 101 % 75 % 60 %
M263V 76 %
A287P 0 % to 25 % 26 % 9 %
R316W 110 % 61 % 97 %
G413S 100 % 76 % 105 %
R457H 0 % 0 % 0.7 %
Y459H 0 % 0.4 %
V492E 0 % 0.3 %
A503V 53 % to 85 % 107 % 69 %
G504R 93 % 53 % 72 %
G539R 9 % 12 %
L565P 14 %
C569Y 32 % 6 %
Y607C 9 %
V608F 16 % 8 %
R616X 0 % 0 % 0 %
V631I 89 % 74 % 47 %
F646del 88 % 36 % 23 %

The POR gene variant can be determined by a laboratory test.

8.3.2.3. HNF4α gene variants influence CYP2D6 metabolism rate

HNF4α gene variants regulate the activity of CYP2D6.2425

8.3.2.4. CYP2D6: substrates/inhibitors/inducers

The presentation is largely based on the compilation by Maucher (2019).26

This list - like all information from ADxS.org - is not intended for personal therapeutic use. Although we endeavor to collect all information, the list is nevertheless incomplete. Errors cannot be ruled out. Please ask your doctor or pharmacist.

8.3.2.4.1. CYP2D6 substrates

Substrates that are metabolized by CYP2D6 include272

  • 5-Methoxytryptamine
    • CYP2D6 is a step in serotonin synthesis via the alternative dopamine synthesis pathway via 5-methoxytryptamine15
  • Ajmaline
    • N-propylajmaline (an ajmaline derivative):10
      • 20 mg / day for slow-release tablets
      • 200 mg / day for ultrafast metabolizers
  • Alprenolol (beta blocker)
  • Amiflamin
  • Amitriptyline (tricyclic AD)28
  • Amoxapine
  • Amphetamine291428
    • AMP is broken down in various ways:
      • Hydroxylation by CYP2D6:2730
        • 4-Hydroxyamphetamine
        • Noradrenaline (alpha-hydroxyamphetamine, norepinephrine)
        • both are subject to a further metabolism
        • One study found:31
          • Are CYP2D6 substrates and have been metabolized by CYP2D6
            • 4-methoxyamphetamine
            • 4-methoxy-nethylamphetamine
            • 4-methoxy-N-butylamphetamine
          • not against it
            • Amphetamine
            • N-ethylamphetamine
            • N-butylamphetami
        • One study found little evidence of metabolization of amphetamine drugs by CYP2D632
    • oxidative deamination
    • CYP3A4 metabolized to33
      • l-phenylpropan-2-one
        • is subsequently excreted as inactive benzoic acid
  • Aprinidine28
  • Aripiprazole (dopamine D2 partial agonist, neuroleptic)28
  • Atomoxetine28
    • Degradation mainly by CYP2D6 to 4-OH-atomoxetine (an active metabolite)
    • Low also by CYP2C19 to N-desmethylatomoxetine14
  • Betaxolol (beta blocker)
  • Brexpiprazole
  • Bufuralol (beta blocker)28
  • Bupranolol (beta blocker)
  • Captopril
  • Cariprazine
  • Carvedilol (beta blocker)28
  • Chloroquine
  • Chlorphenamine
  • Chlorpromazine28
  • Chlorpropamide
  • Cinnarizine
  • Citalopram(weak)
  • Clomiphene28
  • Clomipramine (tricyclic AD)
  • Clonidine
  • Clozapine (neuroleptic)
  • Codeine28
    • No analgesic effect in slow metabolizers because too little morphine is produced10
  • Debrisoquine28
  • Delavirdin
  • Desipramine (tricyclic AD)28
  • Dexfenfluramine
  • Dexamphetamine / Dextroamphetamine / D-Amphetamine / D-Amfetamine
    • According to most sources, d-amphetamine is metabolized by CYP2D63435 , at least weakly36
    • Another source describes CYP3A4 as a further and secondary metabolization pathway37
    • According to other sources, d-amphetamine is metabolized without CYP involvement38
  • Dexfenfluramine (Fenfluramine)
  • Dextromethorphan28
  • Dihydrocodeine28
  • Diphenhydramine28
  • Dolasetron (HT3 receptor antagonist)28
  • Donepezil28
  • Doxepin (tricyclic AD)
  • Doxorubicin
  • Duloxetine28
  • Ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine)28
  • Eliglustat
  • Vyvanse (lisdexamfetamine)
  • Encainide (antiarrhythmic drug)
  • Escitalopram(weak)
  • Flecainide (antiarrhythmic drug)28
  • Fluoxetine (SSRI)
  • Flupentixol (neuroleptic)
  • Fluphenazine (neuroleptic)
  • Fluvoxamine39
  • Galantamine28
  • Guanoxone
  • Haloperidol (neuroleptic, dopamine antagonist)
  • Hydrocodone28
  • Ibrutinib
  • Indoramin
  • Imipramine (tricyclic AD) 28
  • Labetalol
  • Levomepromazine
  • Lidocaine
  • Lisdexamfetamine (amphetamine prodrum)
    • Lisdexamfetamine is absorbed in the small intestine via the PEPT1 transporter (possibly also via PEPT2) and then metabolized in the red blood cells to d-amphetamine and L-lysine. Lisdexamfetamine itself does not inhibit or induce CYP2D6, CYP2C19 or CYP3A4.40 This metabolization to d-amphetamine does not occur via CYP2D6.
    • Lisdexamfetamine thus becomes D-amphetamine (dextroamphetamine). This is probably metabolized by CYP2D6. See above under amphetamine
  • Lomustine
  • Loratadine28
  • Maprotiline (tetracyclic antidepressant)
  • MDMA (N-methyl-3,4-methylenedioxyamphetamine, ecstasy)28
  • Methamphetamine
  • Methoxyamphetamine
  • Methoxyphenamine
  • Metoclopramide4128
  • Metoprolol (beta blocker)28
  • Mexiletine (antiarrhythmic drug)28
  • Mianserin (tetracyclic antidepressant)28
  • Minaprin28
  • Mirtazapine28
  • Moclobemide
  • N-methyl-3,4-methylenedioxyamphetamine (MDMA, ecstasy)28
  • Nebivolol
  • Nefazodon
  • Nicergoline
  • Nortriptyline (tricyclic AD 2nd gen.)28
  • N-propylajmaline (antiarrhythmic drug)
  • Ondansetron (HT3 receptor antagonist)28
  • Oxycodone28
  • Palonosetron (HT3 receptor antagonist)
  • Paroxetine (SSRI)28
  • Perazine (neuroleptic)
  • Perhexiline28
  • Perphenazine (neuroleptic)
  • Phenacetin
  • Phenformin
  • Pindolol
  • Pimavanserin
  • Procainamide28
  • Progesterone
  • Promethazine28
  • Propafenone / propaphenone (antiarrhythmic drug)28
  • Propranolol (beta blocker)28
  • Protriptyline
  • Ramosetron (HT3 receptor antagonist)
  • Remoxipride (neuroleptic)
  • Risperidone (neuroleptic)28
  • Rucaparib
  • Salbutamol39
  • Sertindol
  • Sertraline
  • Spartein (antiarrhythmic drug)28
  • Tamoxifen28
  • Tamsulosin
  • Thioridazine (neuroleptic)28
  • Timolol (beta blocker)28
  • Tolterodine
  • Tramadol (opioid)28
  • Trifluperidol (neuroleptic)
  • Trimipramine (tricyclic antidepressant)
  • Tropisetron (HT3 receptor antagonist, serotonin antagonist)28
  • P-Tyrosine
    • CYP2D6 is a step in dopamine synthesis via the alternative dopamine synthesis pathway via P-tyrosine153
  • Valbenazine
  • Venlafaxine (SNRI)28
  • Viloxazine42 43
  • Zuclopenthixol (neuroleptic)28
8.3.2.4.2. CYP2D6 inhibitors

Strong CYP2D6 inhibitors can cause:
up to over 5-fold increase in plasma AUC values
up to over 80 percent decrease in clearance

  • Amiodarone
  • Berberine (very strong and quasi-irreversible = very long-lasting)(KI: 4.29 µM; kinact: 0.025 min-1)4445
  • Bupropion (strong due to genetic downregulation)464728
  • Quinine, quinidine (strong) (tonic water, bitter lemon)
  • Celecoxib28
  • Chlorphenamine
  • Chlorpromazine
  • Cinacalcet (strong)
  • Cimetidine
  • Citalopram (in vivo) (weak)
  • Clemastine
  • Clomipramine
  • Codeine
  • Cocaine
  • Desipramine (strong)
  • Diltiazem (quasi-irreversible)44
  • Diphenhydramine
  • Doxepin
  • Doxorubicin
  • Duloxetine (strong) (SSRI)47
  • Escitalopram (in vivo)(weak)
  • Efavirenz (HIV medication)48
  • Flecainide28
  • Fluoxetine (strong) /SSRI)472728
    • Inhibiting in the nucleus accumbens and striatum, inducing in the cerebellum15
  • Grapefruit
  • Ginseng (unclear)
  • Halofantrine
  • Haloperidol (strong)28
  • Hydroxyzine
  • Imipramine (strong)
  • Cavapyrone
    • Individual cases of liver damage with CYP2D6 deficiency10
  • Garlic
  • Cocaine (strong)
  • Levomepromazine
  • Methadone28
  • Methylphenidate (weak)36
  • Metoclopramide41
  • Mibefradil
  • Midodrine
  • Mifepristone (irreversible inhibitor)44
  • Moclobemide
  • Norfluoxetine (active metabolite of fluoxetine)
  • Nortryptiline (in vitro)
  • Olanzapine
  • Panobinostat
  • Papaverine (in vitro)
  • Paroxetine (strong) (SSRI)472728
  • Pergolide (strong)
  • Perphenazine
  • Promethazine
  • Quetiapine
  • Quinidine28
  • Ranitidine
  • Reboxetine
  • Risperidone
  • Ritonavir
  • Rolapitant
  • Ropinirole
  • Rucaparib
  • Selegiline
  • Sertraline (strong)27 ; doubtful49
  • Sidenafil (in vitro, presumably practically negligible influence)
  • Division
    • Was used to diagnose the CYP2D6 metabolization type10
    • Toxic in case of CYP2D6 deficiency with multiple doses
  • Terbinafine
  • Thioridazine
    • Inhibiting in nucleus accumbens and substantia nigra, inducing in striatum and cerebellum15
  • Ticlopidine
  • Trazodone (strong)
  • Triple amine
  • Valproate
  • Venlaflaxine (in vivo)
  • Yohimbine
  • Vitamin D / Colecalciferol
8.3.2.4.3. CYP2D6 inducers

CYP2D6 induction is rarely observed.

  • Clozapine
    • Inducing in the cerebellum, brain stem, olfactory bulb, other brain regions, inhibiting in the nucleus accumbens, substantia nigra15
  • Dexamethasone (weak)
  • Efavirenz (HIV medication)48
  • Fluoxetine (SSRI)
    • Inducing in cerebellum, inhibiting in nucleus accumbens and striatum15
  • Nefazodon
    • Inducing in the brain stem15
  • Nicotine50
    • The increased rate of smokers with ADHD could be due not only to the receptor effects of nicotine, but also to increased dopamine synthesis (via the alternative dopamine synthesis pathway via P-tyrosine) and the detoxification of neurotoxins via CYP2D6 induction by nicotine15
  • Rifampin51
  • Thioridazine
    • Inducing in the striatum and cerebellum, inhibiting in the nucleus accumbens and substantia nigra15

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  5. Haduch A, Bromek E, Daniel WA (2013): Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol Rep. 2013;65(6):1519-28. doi: 10.1016/s1734-1140(13)71513-5. PMID: 24553000.

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  8. Busse: Cytochrom P450 2D6 (CYP2D6), MVZ Martinsried GmbH, abgerufen 11.02,23

  9. Genetischer Polymorphismus: Biotransformationsenzyme; DAZ 1997, Nr. 40

  10. Hänsel R. (2010): Abnorme Phytopharmakawirkungen durch genetische Ursachen. In: Hänsel, Sticher (Herausgeber): Pharmakognosie – Phytopharmazie. 9. Aufl. S. 284 - 292

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  12. Nofziger C, Turner AJ, Sangkuhl K, Whirl-Carrillo M, Agúndez JAG, Black JL, Dunnenberger HM, Ruano G, Kennedy MA, Phillips MS, Hachad H, Klein TE, Gaedigk A (2020): PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther. 2020 Jan;107(1):154-170. doi: 10.1002/cpt.1643. PMID: 31544239; PMCID: PMC6925641.

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  14. Schoretsanitis G, de Leon J, Eap CB, Kane JM, Paulzen M (2019): Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder. CNS Drugs. 2019 Dec;33(12):1201-1222. doi: 10.1007/s40263-019-00683-7. PMID: 31776871.

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