Prediction of Transporter-Mediated Drug-Drug Interactions for Baricitinib.

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Posada MM, Cannady EA, Payne CD, Zhang X, Bacon JA, Pak YA, Higgins JW, Shahri N, Hall SD, Hillgren KM

Prediction of Transporter-Mediated Drug-Drug Interactions for Baricitinib.

Clin Transl Sci. 2017 Nov;10(6):509-519. doi: 10.1111/cts.12486. Epub 2017 Jul 27.

PubMed ID

28749581 [ View in PubMed

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Abstract

Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC50 ). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Probenecid, a strong OAT3 inhibitor, increased the area under the concentration-time curve from time zero to infinity (AUC[0-infinity] ) of baricitinib by twofold and decreased renal clearance to 69% of control in healthy subjects. Physiologically based pharmacokinetic (PBPK) modeling reproduced the renal clearance of baricitinib and the inhibitory effect of probenecid using the in vitro IC50 value of 4.4 muM. Using ibuprofen and diclofenac in vitro IC50 values of 4.4 and 3.8 muM toward OAT3, 1.2 and 1.0 AUC(0-infinity) ratios of baricitinib were predicted. These predictions suggest clinically relevant drug-drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Baricitinib	Multidrug and toxin extrusion protein 2	Protein	Humans	Unknown	Substrate Inhibitor	Details