Pharmacokinetics and pharmacodynamics of voxelotor (GBT440) in healthy adults and patients with sickle cell disease

Abstract

Aims Voxelotor (previously GBT440) is a haemoglobin (Hb) modulator that increases Hb‐oxygen affinity, thereby reducing Hb polymerization and sickling of red blood cells (RBCs), being developed as a once‐daily oral drug to treat sickle cell disease (SCD). This first‐in‐human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of voxelotor in healthy volunteers and SCD patients. Methods A total of 40 healthy volunteers (100, 400, 1000, 2000 or 2800 mg) and 8 SCD patients (1000 mg) were randomly assigned to a single dose of voxelotor once daily (n = 6 per group) or placebo (n = 2 per group). Twenty‐four healthy volunteers received multiple doses of voxelotor once daily for 15 days (300, 600 or 900 mg, n = 6 per group) or placebo (n = 2 per group). Results Voxelotor was well tolerated and exhibited a linear pharmacokinetic profile and a half‐life ranging from 61 ± 7 h to 85 ± 7 h. High partitioning into the RBC compartment provides evidence of highly specific binding to Hb. Voxelotor exhibited a concentration‐dependent left‐shift of oxygen equilibrium curves. Percent Hb modification following 900 mg voxelotor for 15 days was 38 ± 9%. Terminal half‐life of voxelotor in SCD patients (50 ± 3 h) was shorter than in healthy volunteers. Evaluation of erythropoietin, exercise testing, and haematologic parameters were consistent with normal oxygen delivery during both rest and exercise. Conclusion This first‐in‐human study demonstrates voxelotor was well tolerated in SCD patients and healthy volunteers and established proof of mechanism on increasing Hb‐oxygen affinity.

Systematic Review of Voxelotor: A First‐in‐Class Sickle Hemoglobin Polymerization Inhibitor for Management of Sickle Cell Disease

“…The first two publications were reports from a phase I/II, two‐center, randomized, double‐blind, placebo‐controlled study (GBT440‐001) to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of voxelotor (Table 1). 16, 17 The first part of this study had a single ascending dose (SAD) design and the second part a multiple ascending dose (MAD) design. Both parts included healthy subjects and patients with SCD.…”

“…In the first part (SAD design), 40 healthy subjects were randomized to receive a single dose of voxelotor (100, 400, 1000, 2000 or 2800 mg; n=6 for each dose) or placebo (n=2 for each dose). The SCD arm included six patients who received a single dose of voxelotor (1000 mg) and two patients who received placebo 17 . In the second part (MAD design), 24 healthy subjects were randomized in a 3:1 ratio to receive voxelotor (300, 600, or 900 mg once daily) or placebo for 15 days 17 .…”

Voxelotor: novel drug for sickle cell disease

“…It is mainly metabolized by Phase I and II metabolisms, mediated primarily by CYP3A4 with major route of elimination in urine and faeces. 26 Findings from the pharmacodynamic studies indicate that treatment with Voxelotor has a dose-dependent increase in Hb oxygen affinity as shown by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was linearly correlated with Voxelotor exposure. Also, the drug demonstrates a dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and % reticulocytes).…”

“…Also, the drug demonstrates a dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and % reticulocytes). 26…”

Voxelotor: A Ray of Hope for Sickle Disease

“…In vitro studies carried out with blood samples of sickle cell disease patients and in vivo studies carried out in animals revealed that voxelotor is highly specific for Hb and possesses a favorable half-life requiring once-daily dosing. Furthermore, studies have also shown that voxelotor increases the affinity between Hb and oxygen, decreases sickling of HbS, corrects the deformity of the sickled RBCs, decreases blood viscosity, extends the half-life of RBCs, and exhibits a favorable linear pharmacokinetic vs. pharmacodynamics relationship [9][10][11].…”