Chemical: Drug
darunavir

PharmGKB contains no prescribing info for this . Contact us to report known genotype-based dosing guidelines, or if you are interested in developing guidelines.

last updated 09/17/2014

1. Annotation of EMA Label for darunavir and CYP3A4

Informative PGx

Summary

The EMA European Public Assessment Report (EPAR) for darunavir (PREZISTA) does not contain human pharmacogenetic information, but does contain pharmacogenetic information related to the genotype of the HIV virus. It contains information regarding metabolism of darunavir by CYP3A and gives information regarding the coadministration of drugs that are CYP3A substrates, inhibitors or inducers.

Annotation

The EMA-approved drug darunavir is tagged with CYP3A4 in [Article:24433361].

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

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

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

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 darunavir

Gene ? Variant?
(147) 		Alternate Names ? Chemicals ? Alleles ?
(+ chr strand) 		Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs4294800 NC_000015.10:g.91917464A>G, NC_000015.9:g.92460694A>G, NM_001145044.1:c.646+1006A>G, NM_013272.3:c.646+1006A>G, XM_005254889.1:c.646+1006A>G, XM_005254890.1:c.472+1006A>G, XM_005254891.1:c.301+1006A>G, XM_011521456.1:c.472+1006A>G, XM_011521457.1:c.646+1006A>G, XR_429450.2:n.566+1006A>G, XR_931795.1:n.736+1006A>G, XR_931796.1:n.736+1006A>G, rs17596258
A > G
 SNP
No VIP available No Clinical Annotations available VA
rs8027174 NC_000015.10:g.91941607G>T, NC_000015.9:g.92484837G>T, NM_001145044.1:c.646+25149G>T, NM_013272.3:c.646+25149G>T, XM_005254889.1:c.646+25149G>T, XM_005254890.1:c.472+25149G>T, XM_005254891.1:c.301+25149G>T, XM_011521456.1:c.472+25149G>T, XM_011521457.1:c.646+25149G>T, XR_429450.2:n.566+25149G>T, XR_931795.1:n.736+25149G>T, XR_931796.1:n.736+25149G>T, rs17518122
G > T
 SNP
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • AIDS073035
  • Darunavirum [INN-latin]
  • TMC-114
  • TMC114
  • UIC-94017
Trade Names
  • Prezista
Brand Mixture Names

PharmGKB Accession Id

PA163522472

Type(s):

Drug

Description

Darunavir is a protease inhibitor used to treat HIV. It acts on the HIV aspartyl protease which the virus needs to cleave the HIV polyprotein into its functional fragments.

Source: Drug Bank

Indication

Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Darunavir is a HIV protease inhibitor which prevents HIV replication by binding to the enzyme's active site, thereby preventing the dimerization and the catalytic activity of the HIV-1 protease. Darunavir selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Structual analyses suggests that the close contact that darunavir has with the main chains of the protease active site amino acids (Asp-29 and Asp-30) is an important contributing factor to its potency and wide spectrum of activity against multi-protease inhibitor resistant HIV-1 variants. Darunavir can also adapt to the changing shape of a protease enzyme because of its molecular flexibility. Darunavir is known to bind to two distinct sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer.

Source: Drug Bank

Pharmacology

Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease. In studies, the drug, co-administered with ritonavir in combination therapy, significantly reduced viral load and increased CD4 cell counts in this treatment-experienced patient population (Tibotec, 2006, Product Monograph, Prezista 2006). Darunavir is used as an adjunct therapy with low dose ritonavir, which inhibits cytochrome P450 3A (CYP3A) which increases the bioavailability and half life of darunavir.

Source: Drug Bank

Food Interaction

Take with food - better absorption (+30%).

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A.

Source: Drug Bank

Protein Binding

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

Source: Drug Bank

Absorption

The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively.

Source: Drug Bank

Half-Life

The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.

Source: Drug Bank

Clearance

* 32.8 L/hr [Healthy volunteers receiving intravenous administration of 400 mg of darunavir] * 5.9 L/hr [Healthy volunteers receiving intravenous administrations of 400 mg of darunavir and 100 mg of ritonavir twice daily]

Source: Drug Bank

Route of Elimination

Darunavir is primarily metabolized by CYP3A. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively.

Source: Drug Bank

Chemical Properties

Chemical Formula

C27H37N3O7S

Source: Drug Bank

Isomeric SMILES

CC(C)CN(C[C@H]([C@H](CC1=CC=CC=C1)NC(=O)O[C@H]2CO[C@@H]3[C@H]2CCO3)O)S(=O)(=O)C4=CC=C(C=C4)N

Source: Drug Bank

[H][C@]12OCC[C@@]1([H])[C@H](CO2)OC(=O)N[C@@H](CC1=CC=CC=C1)[C@H](O)CN(CC(C)C)S(=O)(=O)C1=CC=C(N)C=C1

Source: Drug Bank

Canonical SMILES

CC(C)CN(C[C@@H](O)[C@H]

Source: Drug Bank

Average Molecular Weight

547.664

Source: Drug Bank

Monoisotopic Molecular Weight

547.235221243

Source: Drug Bank

SMILES

[H][C@@]12CCO[C@]1([H])OC[C@@H]2OC(=O)N[C@@H](CC1=CC=CC=C1)[C@H](O)CN(CC(C)C)S(=O)(=O)C1=CC=C(N)C=C1

Source: Drug Bank

InChI String

InChI=1S/C27H37N3O7S/c1-18(2)15-30(38(33,34)21-10-8-20(28)9-11-21)16-24(31)23(14-19-6-4-3-5-7-19)29-27(32)37-25-17-36-26-22(25)12-13-35-26/h3-11,18,22-26,31H,12-17,28H2,1-2H3,(H,29,32)/t22-,23-,24+,25-,26+/m0/s1

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 ?

EvidenceGene
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CYP3A4
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
SLCO3A1

Drug Interactions

Interaction Description
bromazepam - darunavir Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if darunavir is initiated, discontinued or dose changed. Dosage adjustments may be required. (source: Drug Bank )
clarithromycin - darunavir Increased levels of clarithromycin (source: Drug Bank )
clarithromycin - darunavir Increased levels of clarithromycin (source: Drug Bank )
dantrolene - darunavir Darunavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
darunavir - clarithromycin Increased levels of clarithromycin (source: Drug Bank )
darunavir - clarithromycin Increased levels of clarithromycin (source: Drug Bank )
darunavir - lidocaine Possible increase in lidocaine levels (source: Drug Bank )
darunavir - lidocaine Possible increase in lidocaine levels (source: Drug Bank )
darunavir - lopinavir Decreased levels of darunavir (source: Drug Bank )
darunavir - lopinavir Decreased levels of darunavir (source: Drug Bank )
darunavir - saquinavir Decreased levels of darunavir (source: Drug Bank )
darunavir - saquinavir Decreased levels of darunavir (source: Drug Bank )
lovastatin - darunavir Darunavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated. (source: Drug Bank )
tadalafil - darunavir Darunavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity. (source: Drug Bank )
tamoxifen - darunavir Darunavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen. (source: Drug Bank )
tamoxifen - darunavir Darunavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen. (source: Drug Bank )
tamsulosin - darunavir Darunavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Darunavir is initiated, discontinued, or dose changed. (source: Drug Bank )
tamsulosin - darunavir Darunavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Darunavir is initiated, discontinued, or dose changed. (source: Drug Bank )
telithromycin - darunavir Co-administration may result in altered plasma concentrations of Darunavir and/or Telithromycin. Consider alternate therapy or monitor the therapeutic/adverse effects of both agents. (source: Drug Bank )
teniposide - darunavir The strong CYP3A4 inhibitor, Darunavir, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
tiagabine - darunavir The strong CYP3A4 inhibitor, Darunavir, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
tolterodine - darunavir Darunavir may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity. (source: Drug Bank )
tolterodine - darunavir Darunavir may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity. (source: Drug Bank )
topotecan - darunavir The p-glycoprotein inhibitor, Darunavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank )
tramadol - darunavir Darunavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank )
trazodone - darunavir The protease inhibitor, Darunavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
trazodone - darunavir The protease inhibitor, Darunavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
trimipramine - darunavir The strong CYP3A4 inhibitor, Darunavir, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
vardenafil - darunavir Darunavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil. (source: Drug Bank )
venlafaxine - darunavir Darunavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Darunavir is initiated, discontinued, or dose changed. (source: Drug Bank )
verapamil - darunavir Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
vincristine - darunavir Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
vinorelbine - darunavir Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
voriconazole - darunavir Darunavir may reduce serum concentrations and efficacy of voriconazole. This combination should be avoided unless the potential benefits outweigh the risk of reduced voriconazole efficacy. (source: Drug Bank )
zolpidem - darunavir Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
zonisamide - darunavir Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if darunavir is initiated, discontinued or dose changed. (source: Drug Bank )
zopiclone - darunavir Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if darunavir is initiated, discontinued or dose changed. (source: Drug Bank )

Curated Information ?

EvidenceDisease
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
HIV

Publications related to darunavir: 7

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
EMA Initiatives and Perspectives on Pharmacogenomics. British journal of clinical pharmacology. 2014. Ehmann Falk, 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
Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz. European journal of clinical pharmacology. 2014. Naidoo Panjasaram, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients. Clinical pharmacokinetics. 2013. Moltó José, 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
Cost-effectiveness analysis of UGT1A1 genetic testing to inform antiretroviral prescribing in HIV disease. Antiviral therapy. 2013. Schackman Bruce R, 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
The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition. Pharmacological reviews. 2012. Michaud Veronique, 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
HIV-1 antiretroviral drug therapy. Cold Spring Harbor perspectives in medicine. 2012. Arts Eric 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
Nuclear receptor-mediated induction of CYP450 by antiretrovirals: functional consequences of NR1I2 (PXR) polymorphisms and differential prevalence in whites and sub-Saharan Africans. Journal of acquired immune deficiency syndromes (1999). 2010. Svärd Jenny, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
59676-563-01
DrugBank:
DB01264
ChEBI:
367163
KEGG Drug:
D03656
PubChem Compound:
213039
PubChem Substance:
17397753
46506908
Drugs Product Database (DPD):
2284057
BindingDB:
8125
ChemSpider:
184733
Therapeutic Targets Database:
DAP001086
FDA Drug Label at DailyMed:
814301f9-c990-46a5-b481-2879a521a16f

Clinical Trials

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

No trials loaded.

NURSA Datasets

provided by nursa.org

No NURSA datasets available.

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

Sources for PharmGKB drug information: DrugBank, PubChem.