title: Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110.
abstract: Serum creatinine is commonly used as a marker of renal function, but increases in serum creatinine might not represent changes in glomerular filtration rate (GFR). INCB039110 (2-(3-(4-(7H-pyrrolo[2,3-day]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile) is an inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a phase 1 study, a modest and reversible increase in serum creatinine was observed after treatment with INCB039110. However, a dedicated renal function study with INCB039110, assessed by iohexol plasma clearance, conducted in healthy volunteers indicated no change in GFR. In vitro studies were therefore conducted to investigate the interaction of INCB039110 with five transporters that are likely involved in the renal clearance of creatinine. Cell systems expressing individual or multiple transporters were used, including a novel quintuple-transporter model OAT2/OCT2/OCT3/MATE1/MATE2-K. INCB039110 potently inhibited OCT2-mediated uptake of creatinine as well as MATE1-/MATE2-K-mediated efflux of creatinine. Given the interactions of INCB039110 with multiple transporters affecting creatinine uptake and efflux, an integrated system expressing all five transporters was sought; in that system, INCB039110 caused a dose-dependent decrease in transcellular transport of creatinine with weaker net inhibition compared with the effects on individual transporters. In summary, a molecular mechanism for the increase in serum creatinine by INCB039110 has been established. These studies also underline the limitations of using serum creatinine as a marker of renal function.
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.) yzhang@incyte.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Mark S
authors.initials: MS
authors.lastname: Warren
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Xuexiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Bill
authors.initials: B
authors.lastname: Williams
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Naresh
authors.initials: N
authors.lastname: Punwani
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Jane
authors.initials: J
authors.lastname: Huang
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.).
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D003404:Creatinine / Q000097:blood*; D018592:Cross-Over Studies; D004285:Dogs; D005919:Glomerular Filtration Rate; D064368:Healthy Volunteers; D006801:Humans; D007539:Isonicotinic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015394:Molecular Structure; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001384:Azetidines; D015415:Biomarkers; C000603457:INCB039110; D007539:Isonicotinic Acids; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D047428:Protein Kinase Inhibitors; D003404:Creatinine; C507904:JAK1 protein, human; D053613:Janus Kinase 1