Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIJ35KBZI)
Drug Name			Midazolam		Drug Info		Lonafarnib		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Anxiolytics/Sedatives/Hypnotics				Antineoplastics
Structure

Mechanism of Midazolam-Lonafarnib Interaction (Severity Level: Major)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Midazolam				Lonafarnib
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 3A4				× Structure Sequence MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
		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). Click to Show/Hide
Mechanism Description		Decreased metabolism of Midazolam caused by Lonafarnib mediated inhibition of CYP450 enzyme

Recommended Action
Management		Given the potential for prolonged and/or increased sedation and respiratory depression associated with excessive midazolam blood levels, concomitant use of midazolam with potent CYP450 3A4 inhibitors such as lonafarnib is considered contraindicated. If midazolam is required in patients treated with lonafarnib, the prescribing information recommends temporarily discontinuing lonafarnib for 10 to 14 days before and 2 days after administration of midazolam.

References
1	Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ "The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin." Eur J Clin Pharmacol 54 (1998): 53-8. [PMID: 9591931]
2	Merry C, Mulcahy F, Barry M, Gibbons S, Back D "Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease." AIDS 11 (1997): 268-9. [PMID: 9030388]
3	Michalets EL "Update: clinically significant cytochrome P-450 drug interactions." Pharmacotherapy 18 (1998): 84-112. [PMID: 9469685]
4	Olkkola KT, Backman JT, Neuvonen PJ "Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther 55 (1994): 481-5. [PMID: 8181191]
5	Palkama VJ, Ahonen J, Neuvonen PJ, Olkkola KT "Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam." Clin Pharmacol Ther 66 (1999): 33-9. [PMID: 10430107]
6	Product Information. Versed (midazolam). Roche Laboratories, Nutley, NJ.
7	Product Information. Zokinvy (lonafarnib). Eiger BioPharmaceuticals, Palo Alto, CA.
8	Tsunoda SM, Velez RL, vonMoltke LL, Greenblatt DJ "Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole." Clin Pharmacol Ther 66 (1999): 461-71. [PMID: 10579473]
9	Vonmoltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI "Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents." J Clin Pharmacol 36 (1996): 783-91. [PMID: 8889898]
10	Wrighton SA, Ring BJ "Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine." Pharm Res 11 (1994): 921-4. [PMID: 7937537]