DMD # 60673 1 Impact on creatinine renal clearance by the interplay of multiple renal transporters – A Case Study with INCB 039110

This article has not been copyedited and formatted. The final version may differ from this version. Abstract Serum creatinine is commonly used as a marker of renal function but increases in serum creatinine may not represent changes in glomerular filtration rate (GFR). INCB039110 is an inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a Phase I study, a modest and reversible increase in serum creatinine was observed following treatment with INCB039110. However, a dedicated renal function study with INCB039110 conducted in healthy volunteers indicated no change in GFR, assessed by iohexol plasma clearance. 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 and in that system, INCB039110 caused a dose-dependent decrease in transcellular transport of creatinine with weaker net inhibition compared to 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. This article has not been copyedited and formatted. The final version may differ from this version.