Chemical: Drug
modafinil

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last updated 10/25/2013

1. FDA Label for modafinil and CYP2D6

Actionable PGx

Summary

Modafinil, used to improve wakefulness, is metabolized by many cytochrome P450s. Patients that are poor metabolizers for CYP2D6 may need dose modifications for medications that have ancillary metabolism via CYP2C19, such as tricyclic antidepressants (TCAs).

Annotation

PGx information can be found in the Drug Interactions label section.

Excerpts from the modafinil label:

In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when PROVIGIL is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result.

In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with PROVIGIL and may require dosage reduction and monitoring for toxicity.

CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the modafinil drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Narcolepsy
    • Indications & usage section, Adverse reactions section, Precautions section
    • source: PHONT
  • CYP2C19
    • dosage, metabolism/PK, Dosage & administration section, Drug interactions section, Clinical pharmacology section, Precautions section
    • source: U.S. Food and Drug Administration
  • CYP2C9
    • dosage, metabolism/PK, Dosage & administration section, Drug interactions section, Clinical pharmacology section, Precautions section
    • source: U.S. Food and Drug Administration
  • CYP2D6
    • dosage, metabolism/PK, Drug interactions section, Clinical pharmacology section, Precautions section
    • source: U.S. Food and Drug Administration
  • CYP3A4
    • dosage, metabolism/PK, Dosage & administration section, Drug interactions section, Clinical pharmacology section, Precautions section
    • source: U.S. Food and Drug Administration

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all variant annotations for modafinil

Gene ? Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA
rs1045642 NC_000007.13:g.87138645A>G, NC_000007.14:g.87509329A>G, NG_011513.1:g.208920T>C, NM_000927.4:c.3435T>C, NP_000918.2:p.Ile1145=, rs10239679, rs11568726, rs117328163, rs17210003, rs2229108, rs386513066, rs60023214, rs9690664
A > G
SNP
I1145I
No VIP available CA VA
rs1128503 NC_000007.13:g.87179601A>G, NC_000007.14:g.87550285A>G, NG_011513.1:g.167964T>C, NM_000927.4:c.1236T>C, NP_000918.2:p.Gly412=, rs116989428, rs17276907, rs2032587, rs2229105, rs28365046, rs386518005, rs58257317
A > G
SNP
G412G
No VIP available CA VA
rs2032582 NC_000007.13:g.87160618A>C, NC_000007.13:g.87160618A>T, NC_000007.14:g.87531302A>C, NC_000007.14:g.87531302A>T, NG_011513.1:g.186947T>A, NG_011513.1:g.186947T>G, NM_000927.4:c.2677T>A, NM_000927.4:c.2677T>G, NP_000918.2:p.Ser893Ala, NP_000918.2:p.Ser893Thr, rs10228331, rs2229106, rs386553610, rs57135550, rs9641018
A > C
SNP
S893A
VIP No Clinical Annotations available No Variant Annotations available
rs4680 NC_000022.10:g.19951271G>A, NC_000022.11:g.19963748G>A, NG_011526.1:g.27009G>A, NM_000754.3:c.472G>A, NM_001135161.1:c.472G>A, NM_001135162.1:c.472G>A, NM_007310.2:c.322G>A, NP_000745.1:p.Val158Met, NP_001128633.1:p.Val158Met, NP_001128634.1:p.Val158Met, NP_009294.1:p.Val108Met, NR_039918.1:n.-5G>A, XM_005261229.1:c.472G>A, XM_011529885.1:c.586G>A, XM_011529886.1:c.586G>A, XM_011529887.1:c.472G>A, XM_011529888.1:c.472G>A, XM_011529889.1:c.472G>A, XM_011529890.1:c.472G>A, XM_011529891.1:c.472G>A, XP_005261286.1:p.Val158Met, XP_011528187.1:p.Val196Met, XP_011528188.1:p.Val196Met, XP_011528189.1:p.Val158Met, XP_011528190.1:p.Val158Met, XP_011528191.1:p.Val158Met, XP_011528192.1:p.Val158Met, XP_011528193.1:p.Val158Met, rs1131157, rs11544671, rs165688, rs17295216, rs17349704, rs17818178, rs17849308, rs17850006, rs2070104, rs3177905, rs3190784, rs3747070, rs58002978
G > A
SNP
V158M
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Generic Names
  • modafinil
Trade Names
  • Dea No. 1680
  • Modafinil [Usan:Inn]
  • Modafinilo [Spanish]
  • Modafinilum [Latin]
  • Moderateafinil
  • Modiodal
  • Provigil
  • Sparlon
Brand Mixture Names

PharmGKB Accession Id

PA450530

Type(s):

Drug

Description

Modafinil is a stimulant drug marketed as a 'wakefulness promoting agent' and is one of the stimulants used in the treatment of narcolepsy. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins, whose neurons are activated by modafinil. The prexin neuron activation is associated with psychoactivation and euphoria. The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA.

Source: Drug Bank

Indication

To improve wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors.

Source: Drug Bank

Pharmacology

Modafinil is a stimulant drug marketed as a 'wakefulness promoting agent' and is one of the stimulants used in the treatment of narcolepsy. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins, whose neurons are activated by modafinil. The prexin neuron activation is associated with psychoactivation and euphoria. Modafinil is not indicated for complaints of lack of energy or fatigue; but it appears to be very helpful for some patients. Also, it has been used in the treatment of hypersomnia, a disorder in which patients lack the capacity for meaningful sleep and may require ten or more hours per day. Recent studies have have found that modafinil may help recovering cocaine addicts fight their addiction.

Source: Drug Bank

Food Interaction

Take without regard to meals.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic

Source: Drug Bank

Protein Binding

60%

Source: Drug Bank

Absorption

Rapid following oral administration.

Source: Drug Bank

Half-Life

23-215 hours

Source: Drug Bank

Route of Elimination

The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites.

Source: Drug Bank

Volume of Distribution

  • 0.9 L/kg

Source: Drug Bank

Chemical Properties

Chemical Formula

C15H15NO2S

Source: Drug Bank

Isomeric SMILES

C1=CC=C(C=C1)C(C2=CC=CC=C2)[S@](=O)CC(=O)N

Source: Drug Bank

NC(=O)CS(=O)C(C1=CC=CC=C1)C1=CC=CC=C1

Source: Drug Bank

Canonical SMILES

NC(=O)CS(=O)C(C1=CC=CC=C1)C1=CC=CC=C1

Source: Drug Bank

Average Molecular Weight

273.35

Source: Drug Bank

Monoisotopic Molecular Weight

273.082349419

Source: Drug Bank

SMILES

NC(=O)CS(=O)C(C1=CC=CC=C1)C1=CC=CC=C1

Source: Drug Bank

InChI String

InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17)

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
ADRA1B (source: Drug Bank)
SLC6A3 (source: Drug Bank)

Drug Interactions

Interaction Description
clozapine - modafinil Modafinil increases the effect and toxicity of clozapine (source: Drug Bank)
clozapine - modafinil Modafinil increases the effect and toxicity of clozapine (source: Drug Bank)
cyclosporine - modafinil Modafinil decreases the effect of cyclosporine (source: Drug Bank)
cyclosporine - modafinil Modafinil decreases the effect of cyclosporine (source: Drug Bank)
ethinyl estradiol - modafinil Modafinil decreases the effect of contraceptive (source: Drug Bank)
ethinyl estradiol - modafinil Modafinil decreases the effect of contraceptive (source: Drug Bank)
modafinil - clozapine Modafinil increases the effect and toxicity of clozapine (source: Drug Bank)
modafinil - clozapine Modafinil increases the effect and toxicity of clozapine (source: Drug Bank)
modafinil - cyclosporine Modafinil decreases the effect of cyclosporine (source: Drug Bank)
modafinil - cyclosporine Modafinil decreases the effect of cyclosporine (source: Drug Bank)
modafinil - ethinyl estradiol Modafinil decreases the effect of the contraceptive (source: Drug Bank)
modafinil - mestranol Modafinil decreases the effect of the contraceptive (source: Drug Bank)
modafinil - mestranol Modafinil decreases the effect of the contraceptive (source: Drug Bank)
modafinil - triazolam Modafinil decreases the effect of triazolam (source: Drug Bank)
modafinil - triazolam Modafinil decreases the effect of triazolam (source: Drug Bank)
telithromycin - modafinil Telithromycin may reduce clearance of Modafinil. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Modafinil if Telithromycin is initiated, discontinued or dose changed. (source: Drug Bank)
triazolam - modafinil Modafinil decreases the effect of triazolam (source: Drug Bank)
triazolam - modafinil Modafinil decreases the effect of triazolam (source: Drug Bank)
trimipramine - modafinil The strong CYP2C19 inhibitor, Modafinil, may decrease the metabolism and clearance of Trimipramine, a CYP2D6 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Modafinil is initiated, discontinued or dose changed. (source: Drug Bank)
voriconazole - modafinil Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of modafinil by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of modafinil if voriconazole is initiated, discontinued or dose changed. (source: Drug Bank)

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to modafinil: 10

No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Pharmacogenetics and Treatment Response in Narcolepsy Type 1: Relevance of the Polymorphisms of the Drug Transporter Gene ABCB1. Clinical neuropharmacology. 2016. Moresco Monica, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
An efficient early phase 2 procedure to screen medications for efficacy in smoking cessation. Psychopharmacology. 2013. Perkins Kenneth A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sensitivity and Specificity of A Procedure for Early Human Screening of Novel Smoking Cessation Medications. Addiction (Abingdon, England). 2013. Perkins Kenneth A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19. Pharmacogenetics and genomics. 2011. Scott Stuart A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI. Science (New York, N.Y.). 2008. Minzenberg Michael J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical chemistry. 2008. Zanger Ulrich M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. Clinical pharmacology and therapeutics. 2002. Robertson Philmore, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. The pharmacogenomics journal. 2002. Dauvilliers Y, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug metabolism and disposition: the biological fate of chemicals. 2000. Robertson P, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0339-4168-11
DrugBank:
DB00745
KEGG Drug:
D01832
PubChem Compound:
4236
PubChem Substance:
188735
46504648
Drugs Product Database (DPD):
2239665
BindingDB:
50156055
ChemSpider:
4088
FDA Drug Label at DailyMed:
def2a743-ec37-452e-8e6b-b15f72ad2215

Clinical Trials

These are trials that mention modafinil and are related to either pharmacogenetics or pharmacogenomics.

No trials found.

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Sources for PharmGKB drug information: DrugBank, PubChem.