New phase 1 data show the first-in-class oral therapy is not affected by the burden on metabolism via hepatic or renal disease.
A pair of open-label studies show voxelotor (Oxbryta) is well-tolerated in patients with hepatic or renal impairment, and does not require dose adjustment in most cases.
The new findings support the continued use of the first-in-class oral therapy for sickle cell disease in patients with comorbid liver or kidney disease, despite previous concern that impairment from either disease could alter patient exposure to voxelotor.
Investigators, led by Richard A. Preston, MD, of the Miller School of Medicine at University of Miami, sought to interpret the role of impaired renal and hepatic function at varying degrees in patients with sickle cell disease being treated with the deoxygenated sickle hemoglobin polymerization inhibitor.
“As the major route of voxelotor elimination is via metabolism, it is important to evaluate the impact of both renal and hepatic impairment on the plasma and the whole‐blood PK of voxelotor,” they wrote.
Preston and colleagues conducted the 2 phase 1 trials at different institutes in Washington state and Texas—one observing treated patients with severe renal impairment, and the other observing patients varying severities of hepatic dysfunction.
Subjects were screened within 28 days prior to dosing. On day 1, patients with normal renal function (n = 8) and patients with severe renal impairment (n = 8) receiving single oral voxelotor 900 mg. They remained in the clinic for 5 days.
Blood sampling collected 5 times throughout the 28 days, and 3 separate safety evaluations were also conducted. Investigators collected whole-blood and plasma samples for voxelotor pharmacokinetic determination numerous times up to 4 days after treatment.
Another 7 patients each with mild, moderate, and severe hepatic impairment were administered single oral voxelotor 1500 mg—except those with severe hepatic impairment, who received 600 mg. Their outcomes were compared to 7 controls matched for age, sex, and body mass index.
Investigators observed no to little effect of renal function on voxelotor excretion, based on comparable half-life values between patients with severe renal impairment and healthy controls.
Based on metrics of mean concentration-time curve for plasma and whole blood, investigators confirmed it is unnecessary to adjust dosage in sickle cell disease patients with severe renal impairment. Voxelotor plasma and whole-blood exposures were slightly increased among patients with mild and moderate hepatic impairment, again indicating no need for dose adjustment.
However, mean plasma and whole-blood exposures being significantly higher among treated sickle cell disease patients with severe hepatic impairment led to Preston and colleagues recommending a lower voxelotor dose of 1000 mg in such patients.
Across patients with all comorbid conditions and dosages, investigators observed a good tolerance of voxelotor. In fact, investigators concluded, safety and tolerability findings were consistent with those reported in previous voxelotor clinical trials.
“Pharmacokinetic parameters analyzed in this study are not expected to be different in patients with sickle cell disease,” they wrote. “Therefore, voxelotor may be considered as a treatment option for patients with sickle cell disease with renal or hepatic impairment.”
The study, “Pharmacokinetics of Voxelotor in Patients With Renal and Hepatic Impairment,” was published online in the American College of Clinical Pharmacology.