Pharmacokinetics and pharmacodynamics of voxelotor (GBT440) in healthy adults and patients with sickle cell disease.
Br J Clin Pharmacol
; 85(6): 1290-1302, 2019 06.
Article
en En
| MEDLINE
| ID: mdl-30743314
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.Palabras clave
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Pirazinas
/
Pirazoles
/
Benzaldehídos
/
Anemia de Células Falciformes
/
Antidrepanocíticos
Tipo de estudio:
Clinical_trials
/
Diagnostic_studies
/
Prognostic_studies
Límite:
Adolescent
/
Adult
/
Female
/
Humans
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Male
/
Middle aged
País/Región como asunto:
America do norte
/
Europa
Idioma:
En
Revista:
Br J Clin Pharmacol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos