A randomized, open-label, 5-period, balanced crossover study to evaluate the relative bioavailability of eltrombopag powder for oral suspension (PfOS) and tablet formulations and the effect of a high-calcium meal on eltrombopag pharmacokinetics when administered with or 2 hours before or after PfOS.
Clin Ther
; 34(3): 699-709, 2012 Mar.
Article
en En
| MEDLINE
| ID: mdl-22336488
ABSTRACT
BACKGROUND:
Bioavailability of the tablet formulation of eltrombopag, an oral thrombopoietin receptor agonist indicated for the treatment of chronic immune thrombocytopenia, is reduced by chelation of polyvalent cations (eg, calcium). A powder for oral suspension (PfOS) formulation has been developed for use in pediatrics.OBJECTIVE:
We aimed to assess the bioavailability of eltrombopag PfOS relative to the tablet formulation and the effect of a high-calcium meal on PfOS bioavailability.METHODS:
In this single-dose, open-label, randomized-sequence, crossover study, healthy subjects received 25 mg eltrombopag orally as a tablet fasted and as PfOS fasted or with, 2 hours before, or 2 hours after a high-calcium meal. Noncompartmental pharmacokinetic parameters were estimated from plasma concentration-time data collected over 72 hours post-dose. Tolerability was assessed by laboratory tests, physical examinations, and adverse events (AEs).RESULTS:
The 40 enrolled subjects included 22 males and 18 females of white/European (60%) or African-American/African (40%) heritage with mean (SD) (mininum, maximum) age of 34 (12) (19, 62) years, weight of 75 (12) (54, 101) kg, and body mass index of 25.8 (2.9) (19.7, 30) kg/m(2). Plasma eltrombopag AUC(0-∞) was higher for the PfOS than the tablet (geometric least-squares mean ratio [GMR] 1.22; 90% CI 1.08-1.38). Plasma eltrombopag AUC(0-∞) was reduced when the PfOS was administered with a high-calcium meal (GMR 0.25; 90% CI 0.224-0.287) or 2 hours after a meal (GMR 0.53; 90% CI 0.470-0.601), and, to a lesser extent, when administered 2 hours before a meal (GMR 0.80; 90% CI 0.711-0.908). The absorption lag time and t(½) did not differ between treatments; T(max) was delayed 1 hour when the PfOS was dosed with a high-calcium meal. AEs were not serious and mild or moderate in intensity. AEs reported in >1 subject included headache (11 subjects; 27.5%), presyncope (3 subjects, 7.5%), and vomiting (2 subjects, 5%). No clinically significant trends in laboratory tests or vital signs were observed.CONCLUSIONS:
In a healthy adult volunteer population, bioavailability of eltrombopag PfOS was greater than the tablet and was reduced when administered with or 2 hours before or after a high-calcium meal; this effect was attenuated with PfOS dosing 2 hours before the meal. Eltrombopag was generally well tolerated.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Benzoatos
/
Calcio
/
Interacciones Alimento-Droga
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Alimentos
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Hidrazinas
Tipo de estudio:
Clinical_trials
Límite:
Adolescent
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Adult
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Clin Ther
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos