Pharmacokinetics of Voxelotor in Patients With Renal and Hepatic Impairment

Abstract

Two open-label studies assessed the safety, tolerability, and pharmacokinetics of Oxbryta (voxelotor) in subjects with hepatic or renal impairment. Eight subjects with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m 2) and 8 healthy age-, sex-, and body mass index-matched controls were administered a single oral dose of voxelotor 900 mg. Seven patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment and healthy age-, sex-, and body mass index-matched controls (7:7:7:7) were administered a single oral dose of voxelotor 1500 mg, except those with severe hepatic impairment (600 mg). There was no apparent effect of renal function on the excretion of voxelotor based on comparable half-life values between subjects with severe renal impairment and healthy matched controls. Mean area under the concentration-time curve from time 0 to infinity (AUC 0-inf) values were lower by approximately 50% (plasma) and 25% (whole blood) in subjects with severe renal impairment compared with controls. Accordingly, dose adjustment is not required in patients with severe renal impairment. Voxelotor plasma and whole-blood exposures were slightly increased in subjects with mild and moderate hepatic impairment. Mean AUC 0-inf values were approximately 9% to 18% higher compared with those of healthy matched controls. Dose adjustment is therefore not required in patients with mild or moderate hepatic impairment. Voxelotor mean AUC 0-inf values were approximately 90% higher in subjects with severe hepatic impairment. A lower voxelotor dose (1000 mg) is recommended for patients with severe hepatic impairment. Voxelotor was well tolerated in all treatment groups.

Model‐informed drug development of voxelotor in sickle cell disease: Population pharmacokinetics in whole blood and plasma

“…Voxelotor PK in plasma and whole blood were not significantly impacted by renal impairment in this analysis, which is consistent with the results of a previously published study 22 in which only minor effects of severe renal impairment (eGFR <30 ml/min/1.73 m 2 ) on voxelotor exposure were observed compared with controls, suggesting that dose adjustment is not warranted in this patient population. In contrast, voxelotor exposure was ~ 90% higher in patients with severe hepatic impairment (Child‐Pugh C) compared with controls, and a lower voxelotor dose (1000 mg) is recommended in this patient population in the approved prescribing information 22 …”

“…In contrast, voxelotor exposure was ~ 90% higher in patients with severe hepatic impairment (Child-Pugh C) compared with controls, and a lower voxelotor dose (1000 mg) is recommended in this patient population in the approved prescribing information. 22 In conclusion, these analyses demonstrated that voxelotor PK in both plasma and whole blood can be adequately described using a joint model. Mean exposures and percent Hb occupancy were greater with voxelotor 1500 versus 900 mg q.d.…”

“…Whole blood and plasma voxelotor exposures were slightly elevated in patients with unrestricted food status compared with patients who fasted or avoided high‐fat meals prior to PK sample collection; however, they were less than 20% for all parameters and not likely to be clinically significant. There was a trend toward higher voxelotor exposures with lower cystatin C levels (17% to 35% higher at 0.5 to 0.7 vs. 1.0 to 2.6 mg/L), indicating that renal impairment did not impact voxelotor elimination or that there were too few patients with values outside the normal range (0.6 to 1 mg/L) 22 to detect any impact (cystatin C data were only available for 161 patients in HOPE, and only 34 of these patients had a value above 1 mg/L).…”

Spotlight Commentary – Voxelotor: A new kid on the block in the treatment of sickle cell disease

“…There was no apparent effect of renal function on the excretion of voxelotor based on comparable half-life (t 1/2 ) values between subjects with severe renal impairment and healthy controls, and these results indicate that no dose adjustment is needed for patients with impaired renal function, and renal function was shown to have minor effects on voxelotor exposure, since excretion of the drug is mainly nonrenal. 8 However, it is important to note that voxelotor has not been evaluated in patients with end-stage renal disease requiring dialysis.…”

“…Impaired renal function is a relatively frequent and sometimes serious complication in patients with SCD, and Preston et al 8 evaluated the safety, tolerability, and PK of voxelotor in subjects with various degrees of renal insufficiency. Eight subjects with severe renal impairment (eGFR <30 ml/min/1.73 m 2 ) and eight healthy matched controls were administered a single oral dose of voxelotor 900 mg.…”