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Aprepitant
drug data and news
Aprepitant drug data, resources, and news articles (when available). Onconews.org provides news on cancer research. This section, which includes profiles on medicines that may or not be cancer-related is in beta form. If things run smoothly we will be releasing a new format late in the summer of 2006.
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| Generic name | Aprepitant | ||
| Brand Names/Synonyms | Aprepitant; Aprepitant [Usan]; Emend; MK 0869; MK 869 | ||
| Indication | For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents). | ||
| Sponsored links | Description | Not Available | |
| Pharmacology | Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). | ||
| Mechanism Of Action | Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. | ||
| Aprepitant News (When available) |
Chemo-induced nausea reduced by aprepitant Jan 24, 2006 FDA Approves EMEND(R) (aprepitant), in Combination with Other ... Jan 11, 2006 FDA Approves EMEND® (aprepitant), in Combination with Other ... Jan 11, 2006 HUGIN NEWS/ANGUS MACLEOD NAMED DIRECTOR OF MEDICINAL CHEMISTRY AT ... Jan 10, 2006 Meck OK'd for wider use of nausea drug Jan 11, 2006 Emend® Approved for Prevention of Moderate Chemotherapy ... Jan 12, 2006 NEWS RELEASE Jan 17, 2006 New Class Of Drug Reduces Post-operative Vomiting Oct 26, 2005 Merck Announces New Unisured Discount Program Targeted to More ... Oct 7, 2005 Emend® Controls Vomiting Over Multiple Cycles of Chemotherapy Oct 4, 2005 Merck Announces New Unisured Discount Program Targeted to More ... Oct 7, 2005 Emend® Controls Vomiting Over Multiple Cycles of Chemotherapy Oct 4, 2005 Delayed Nausea After Chemotherapy Poses Treatment Challenge Sep 20, 2005 Emend® Reduces Chemotherapy-Induced Nausea and Vomiting Aug 30, 2005 The Painful History of Substance P Aug 25, 2005 The Lance effect Jul 10, 2005 The Lance effect Jul 10, 2005 Awards Given For Green Innovations Jun 21, 2005 ADM, Merck, BASF Headline EPA Green Chemistry Awards Jun 20, 2005 EPA Recognizes Projects for Environmentally Friendly Technologies Jun 21, 2005 Pharmacokinetics of Palonosetron in Combination With Aprepitant in ... Jun 8, 2005 Awards Given For Green Innovations Jun 21, 2005 ADM, Merck, BASF Headline EPA Green Chemistry Awards Jun 20, 2005 EPA Recognizes Projects for Environmentally Friendly Technologies Jun 21, 2005 Nanotech Meets the FDA: A Success Story About the First ... May 27, 2005 EMEND® (aprepitant) Helps Prevent Nausea/Vomiting for Breast ... Apr 19, 2005 MEDICARE TO EXPAND COVERAGE FOR HEARING LOSS AND COVER APREPITANT ... Apr 7, 2005 News For Your Web Site Apr 19, 2005 Merck Announces New Unisured Discount Program Targeted to More ... Apr 19, 2005 Governor Tom Vilsack Supports New Merck Uninsured Discount Program ... Apr 20, 2005 Study of Breast Cancer Patients Showed Regimen Including EMEND-R ... Apr 18, 2005 Medicare to Cover Merck Drug to Treat Nausea Apr 5, 2005 Medicare to Cover Merck Nausea Drug Apr 5, 2005 MEDICARE TO EXPAND COVERAGE FOR HEARING LOSS AND COVER APREPITANT ... Apr 7, 2005 Medicare to Cover Merck Drug to Treat Nausea Apr 5, 2005 | ||
| Dosage Forms | CAPSULE | ||
| Drug_Category | Antiemetics; ATC:A04AD12 | ||
| Absorption | The mean absolute oral bioavailability of aprepitant is approximately 60 to 65%. | ||
| Interactions | Interactions for Aprepitant: Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Effect of aprepitant on the pharmacokinetics of other agents As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4. Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of Aprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs. Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of Aprepitant with digoxin in a clinical drug interaction study. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron or granisetron. No clinical or drug interaction study was conducted with dolasetron. Corticosteroids: Dexamethasone: Aprepitant, when given as a regimen of 125mg with dexamethasone coadministered orally as 20 mg on Day 1, and Aprepitant when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate by 2.2-fold, on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with Aprepitant, to achieve exposures of dexamethasone similar to those obtained when it is given without Aprepitant. The daily dose of dexamethasone administered in clinical studies with Aprepitant reflects an approximate 50% reduction of the dose of dexamethasone. Methylprednisolone Aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with Aprepitant to achieve exposures of methylprednisolone similar to those obtained when it is given without Aprepitant. Warfarin: A single 125-mg dose of Aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of Aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-)warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with Aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Aprepitant with each chemotherapy cycle. Tolbutamide: Aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was admini,stered orally prior to the administration of the 3-day regimen of Aprepitant and on Days 4,8, and 15. Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%; therefore, the efficacy of oral contraceptives during administration of Aprepitant may be reduced. Although a 3-day regimen of Aprepitant given concomitantly with oral contraceptives has not been studied, alternative or back-up methods of contraception should be used. Midazolam: Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of Aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with Aprepitant. In another study with intravenous administration of midazolam, Aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of Aprepitant and on Days 4, 8, and 15. Aprepitant increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of Aprepitant on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline. Effect of other agents on the pharmacokinefics of aprepitant Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of Aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of Aprepitant. Ketoconazole: When a single 125-mg dose of Aprepitant was administered on Day5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of Aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of Aprepitant was administered on Day9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of Aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of Aprepitant. Additional interactions Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax, by approximately 20% of both aprepitant and paroxetine. | ||
| Toxicity | Not Available | ||
| Organisms Affected | Humans and other mammals | ||
| Chemical IUPAC Name | 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one | ||
| Chemical Formula | C23H21F7N4O3 | ||
| Molecular Weight | 534.427 g/mol | ||
| Smiles String | CC(C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)OC2C(N(CCO2)CC3=NC(=O)NN3)C4=CC=C(C=C4)F | ||
| Melting Point | Not Available | ||
| Water Solubility | Practically insoluble | ||
| State | Solid | ||
| LogP/Hphobicity | 5.535 | ||
| Isoelectric Point | Not Available | ||
| Biotransformation | Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. | ||
| Half Life | 9-13 hours | ||
| Protein Binding [%] | >95% | ||
| RxList Link | RXlist | ||
| Sponsored links | |||
| Drug Reference |
http://www.drugs.com/cons/Aprepitant.html http://www.rxlist.com/cgi/generic3/emend.htm | ||
| Drug Type | Approved Drug | ||
| Accession No | APRD00100 | ||
| CAS Registry Number | 170729-80-3 | ||
| KEGG Compound ID | Not Available | ||
| PubChem ID | SID:728707 | ||
| PharmGKB ID | PA10025 | ||
| SwissProt ID | Not Available | ||
| GenBank ID | Not Available | ||
| Drug ID Number [DIN] | Not Available |
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