Prediction of Transporter-Mediated Drug-Drug Interactions for Baricitinib

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-∞] ) 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 μM. Using ibuprofen and diclofenac in vitro IC₅₀ values of 4.4 and 3.8 μM toward OAT3, 1.2 and 1.0 AUC_(0-∞) ratios of baricitinib were predicted. These predictions suggest clinically relevant drug-drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.

Figure 1

In vitro uptake studies (a) Time‐dependent uptake of 10 μM ¹⁴C‐baricitinib (0.44 μCi/mL) in vector control (VC; ▲), VC + 100 μM probenecid (Δ), organic anion transporter (OAT)3 (■), and OAT3 + 100 μM probenecid (□) in transfected HEK‐PEAK cells. Data are presented as mean ± SD (N = 3 separate wells). (b) Time‐dependent uptake of 10 μM baricitinib in VC (▲), VC + 100 μM cimetidine (Δ), multidrug and toxin extrusion protein (MATE)2‐K (■), and MATE2‐K + 100 μM cimetidine (□) transfected HEK‐PEAK cells. Data are presented as mean ± SD (N = 3 separate wells). (c) Concentration‐dependent uptake of ¹⁴C‐baricitinib in VC (Δ) and OAT3 (□) transfected HEK‐PEAK cells treated for 1 min (N = 3 separate wells). The solid line represents the fitted total uptake, the dotted line represents the fitted uptake into VC, and the dashed line represents the predicted OAT3‐mediated uptake. (d) Concentration‐dependent uptake of baricitinib in VC and MATE2‐K transfected HEK‐PEAK cells treated for 1 min (N = 3 separate wells). The solid line represents the fitted total uptake, the dotted line represents the fitted uptake into VC, and the dashed line represents the predicted MATE2‐K‐mediated uptake. (e) Inhibition of the OAT3‐mediated uptake of ¹⁴C‐baricitinib (0.5μM) by probenecid (0.1–100 μM). The solid line represents the fitted uptake and circles represent the individual observations (N = 3 separate wells). (f) Inhibition of the OAT3‐mediated uptake of ¹⁴C‐baricitinib (0.5 μM) by ibuprofen (0.1–100 μM). The solid line represents the fitted uptake and circles represent the individual observations (N = 3 separate wells). (g) Bidirectional transport (A to B and B to A) of baricitinib in Madin‐Darby canine kidney (MDCK)‐multidrug resistance protein 1, in the presence and absence of 5 μM LSN335984 (P‐glycoprotein‐specific inhibitor). (h) Bidirectional transport (A to B and B to A) of baricitinib in MDCK‐breast cancer resistance protein (BCRP), in the presence and absence of 15 μM of GF120918 (BCRP inhibitor).

Figure 2

(a) Linear scale and (b) log scale arithmetic mean concentration vs. time profiles for baricitinib following administration of a single 4‐mg dose with (○) or without (●) 1,000 mg b.i.d. probenecid in 18 healthy subjects. Error bars show one‐sided SD.

Figure 3

(a) Predicted and individual observed plasma baricitinib concentration vs. time profiles following a single oral dose of 4‐mg baricitinib. Points represent the observed values. The solid line represents the mean predicted concentration, and the dashed lines represent the predicted 5th and 95th percentiles. (b) Cumulative urine excretion of baricitinib following a single oral dose of 4‐mg baricitinib. Points represent the observed data. The solid black line represents the predicted mean cumulative amount of baricitinib excreted in urine. The dash lines represent the predicted 5th and 95th percentiles. (c) Effect of increasing dose on baricitinib area under the concentration‐time curve (AUC)_(0–t),ss after q.d. dosing for 10 days. The squares represent the observed data2 and the line represents the predicted data. Observed data are presented as geometric mean ± SD. (d) Effect of increasing dose on baricitinib peak plasma concentration steady‐state (C_max,ss) after q.d. dosing for 10 days. The squares represent the observed data2 and the line represents the predicted data. (e) Predicted and observed plasma probenecid concentration vs. time profiles following b.i.d. dosing of 1,000 mg probenecid. Circles represent the observed data. The solid line represents the mean predicted concentration, and the dash lines represent the predicted 5th and 95th percentiles. (f) Observed and predicted plasma concentration vs. time profiles for baricitinib in the presence of 1,000 mg probenecid. Open triangles represent the observed baricitinib concentrations in the presence of probenecid. The solid red line represents the predicted mean concentration of baricitinib in the presence of probenecid. The dashed lines represent the predicted 5th and 95th percentiles. (g) Cumulative urine excretion of baricitinib following a single oral dose of 4‐mg baricitinib in the presence of probenecid. Red circles represent the observed data. The solid red line represents the predicted mean cumulative amount of baricitinib excreted in urine in the presence of probenecid. The dashed lines represent the predicted 5th and 95th percentiles. (h) Predicted plasma concentration vs. time profiles for baricitinib in the presence (red) and absence (black) of 800‐mg ibuprofen. The solid lines represent the mean predicted concentrations and the dashed lines represent the 5th and 95th percentiles.