Details of Drug-Drug Interaction
| Drug General Information (ID: DDIDSNKGQI) | |||||||||
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| Drug Name | Ruxolitinib | Drug Info | Tucatinib | Drug Info | |||||
| Drug Type | Small molecule | Small molecule | |||||||
| Therapeutic Class | Multikinase Inhibitors | Antineoplastics/Her2 Inhibitors | |||||||
| Structure | |||||||||
| Mechanism of Ruxolitinib-Tucatinib Interaction (Severity Level: Major) | |||||||||
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| CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph | |||||||||
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| Drug Name | Ruxolitinib | Tucatinib | |||||||
| Mechanism | CYP450 3A4 substrate | CYP450 3A4 inhibitor | |||||||
| Key Mechanism Factor 1 | |||||||||
| Factor Name | Cytochrome P450 3A4 |
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Structure
Sequence
MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
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| Gene Name | CYP3A4 | ||||||||
| Uniprot ID | CP3A4_HUMAN | ||||||||
| KEGG Pathway | hsa:1576 | ||||||||
| Protein Family | Cytochrome P450 family | ||||||||
| Protein Function |
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981).
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| Mechanism Description |
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| Recommended Action | |||||||||
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| Management | Indication specific dose modifications should be made when ruxolitinib is coadministered with strong CYP450 3A4 inhibitors. The recommended starting dose for patients with Polycythemia vera (PV) coadministered potent CYP450 3A4 inhibitors is ruxolitinib 5 mg twice a day. For patients with MF or PV who are stabilized on ruxolitinib 10 mg twice a day or greater and starting a potent CYP450 3A4 inhibitor, the ruxolitinib dose should be reduced by 50% (rounded up to the closest available tablet strength). For patients with MF or PV stabilized on a dose of 5 mg twice a day and starting fluconazole (at a dose of 200 mg per day or less), the ruxolitinib dose should be reduced to 5 mg once a day. For patients with MF or PV stabilized on ruxolitinib 5 mg once a day, concomitant use of strong CYP450 3A4 inhibitors should be avoided or ruxolitinib therapy interrupted for the duration of strong CYP450 3A4 inhibitor use. For patients with for acute graft versus host disease (GVHD) coadministered strong CYP450 3A4 inhibitors, the ruxolitinib dose should be reduced to 5 mg once a day with concomitant ketoconazole use however, no dose adjustments are necessary with other potent CYP450 3A4 inhibitors. | ||||||||
| References | |||||||||||||||||||
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| 1 | Product Information. Jakafi (ruxolitinib). Incyte Corporation, Wilmington, DE. | ||||||||||||||||||