Single-Dose Pharmacokinetics of Milvexian in Participants with Normal Renal Function and Participants with Moderate or Severe Renal Impairment

Abstract

Objective: The aim of this study was to assess the effect of moderate or severe renal impairment on the pharmacokinetic (PK) properties of milvexian.

Methods: This open-label, parallel-group study assessed the PK, safety, and tolerability of a single oral 60 mg dose of milvexian in participants with normal renal function (n = 8; estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2) and participants with moderate (n = 8; eGFR ≥ 30 to ≤ 59 mL/min/1.73 m2) or severe (n = 8; eGFR < 30 mL/min/1.73 m2) renal impairment. Regression analysis was performed using linear regression of log-transformed PK parameters versus eGFR.

Results: Milvexian was well tolerated, with no deaths, serious adverse events, or serious bleeding reported. The maximum milvexian concentration (Cmax) was similar for all groups. Based on a regression analysis of milvexian concentration versus eGFR, participants with eGFR values of 30 and 15 mL/min/1.73 m2, respectively, had area under the curve (AUC) values that were 41% and 54% greater than in participants with normal renal function. Median time to maximum concentration (Tmax) was similar for the three groups (4.5-5.0 h). The half-life increased for participants with moderate (18.0 h) or severe (17.7 h) renal impairment compared with those with normal renal function (13.8 h).

Conclusion: A single dose of milvexian 60 mg was safe and well tolerated in participants with normal renal function and moderate or severe renal impairment. There was a similar increase in milvexian exposure between the moderate and severe renal groups.

Clinical trials registration: This study was registered with ClinicalTrials.gov (NCT03196206, first posted 22 June 2017).

Conflict of interest statement

VP, GA, DL, ZW, SL, AB, and BM are full-time employees of Bristol Myers Squibb. LZ is a full-time employee of Janssen.

© 2022. The Author(s).

Figures

Fig. 1

Mean (± SD) milvexian plasma concentration versus time profile. SD standard deviation.

Fig. 2

Predicted values of milvexian PK parameters based on renal impairment from the regression analysis of eGFRa and CrCLb in a moderate and b severe renal impairment. aPredicted values for each PK parameter and associated 90% CI for eGFR (mL/min/1.73 m2) equal to 15, 30, and 90 were obtained from the linear regression model. GMRs of each PK parameter predicted values were calculated for eGFR values of 30: 90 (moderate renal impairment: normal renal function) and 15: 90 (severe renal impairment: normal renal function). bPredicted values for each PK parameter and associated 90% CI for CrCL (mL/min) equal to 15, 30, and 90 were obtained from the linear regression model. GMRs of each PK parameter predicted values were calculated for CrCL values of 30: 90 (moderate renal impairment: normal renal function) and 15: 90 (severe renal impairment: normal renal function). PK pharmacokinetic, eGFR estimated glomerular filtration rate, CrCL creatinine clearance, GMR geometric mean ratio, CI confidence interval, Cmax maximum observed concentration, AUCt area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration, AUC∞ area under the plasma concentration-time curve from time zero extrapolated to infinite time

Fig. 3

Mean (± SD) aPTT versus time profile. SD standard deviation, aPTT activated partial thromboplastin time

Fig. 4

Mean (± SD) FXI clotting activity versus time profile. SD standard deviation, FXI Factor XI