VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions.
(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509, decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxyl-metabolite of VX-509, which is involved in clinically significant TDI-based DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.
Drug Metabolism and Pharmacokinetics (C.Z., L.L., S.L., H.T., A.C., N.H.) and Department of Chemistry (F.M.), Vertex Pharmaceuticals Inc., Boston, Massachusetts.
Craig
C
Zetterberg
Drug Metabolism and Pharmacokinetics (C.Z., L.L., S.L., H.T., A.C., N.H.) and Department of Chemistry (F.M.), Vertex Pharmaceuticals Inc., Boston, Massachusetts.
Francois
F
Maltais
Drug Metabolism and Pharmacokinetics (C.Z., L.L., S.L., H.T., A.C., N.H.) and Department of Chemistry (F.M.), Vertex Pharmaceuticals Inc., Boston, Massachusetts.
Leena
L
Laitinen
Drug Metabolism and Pharmacokinetics (C.Z., L.L., S.L., H.T., A.C., N.H.) and Department of Chemistry (F.M.), Vertex Pharmaceuticals Inc., Boston, Massachusetts.
Shengkai
S
Liao
Drug Metabolism and Pharmacokinetics (C.Z., L.L., S.L., H.T., A.C., N.H.) and Department of Chemistry (F.M.), Vertex Pharmaceuticals Inc., Boston, Massachusetts.
Hong
H
Tsao
Drug Metabolism and Pharmacokinetics (C.Z., L.L., S.L., H.T., A.C., N.H.) and Department of Chemistry (F.M.), Vertex Pharmaceuticals Inc., Boston, Massachusetts.
Ananthsrinivas
A
Chakilam
Drug Metabolism and Pharmacokinetics (C.Z., L.L., S.L., H.T., A.C., N.H.) and Department of Chemistry (F.M.), Vertex Pharmaceuticals Inc., Boston, Massachusetts Niresh_hariparsad@vrtx.com.
Niresh
N
Hariparsad
D000328:Adult; D000368:Aged; D042931:Aldehyde Oxidase / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000201:enzymology; D006574:Heterocyclic Compounds, 2-Ring / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D006900:Hydroxylation; D000075242:Janus Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D018570:Risk Assessment; D014633:Valine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D055815:Young Adult
C000596981:2-((2-(1H-pyrrolo(2,3-b)pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide; D065692:Cytochrome P-450 CYP3A Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D000075242:Janus Kinase Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D042931:Aldehyde Oxidase; D014633:Valine