First population pharmacokinetic analysis showing increased quinolone metabolite formation and clearance in patients with cystic fibrosis compared to healthy volunteers.
Eur J Pharm Sci
; 123: 416-428, 2018 Oct 15.
Article
em En
| MEDLINE
| ID: mdl-30076955
ABSTRACT
Understanding the pharmacokinetics in patients with cystic fibrosis (CF) is important for dosing. For antibiotics with extensive metabolism, however, a comparison of metabolite formation and elimination between patients with CF and healthy volunteers has never been performed via population modeling. We aimed to compare the population pharmacokinetics of fleroxacin and its Noxide and demethyl metabolites between patients with CF and healthy volunteers. Our analysis included eleven adult patients with CF and twelve healthy volunteers who received 800â¯mg fleroxacin as a single oral dose followed by five doses every 24â¯h from a previously published study. All plasma concentrations and amounts in urine for fleroxacin and its metabolites were simultaneously modelled. The estimates below accounted for differences in body size and body composition via allometric scaling by lean body mass. Oral absorption was slower in patients with CF than in healthy volunteers. For fleroxacin, the population mean in patients with CF divided by that in healthy volunteers was 1.12 for renal clearance, 1.01 for linear nonrenal clearance, 0.83 for saturable exsorption clearance into intestine, and 0.81 for volume of distribution. The formation clearances of Noxide fleroxacin and Ndemethylfleroxacin were 0.520â¯L/h and 0.496â¯L/h in patients with CF; these formation clearances were 0.378â¯L/h and 0.353â¯L/h in healthy volunteers. Renal clearance in patients with CF divided by that in healthy volunteers was 1.53 for Noxide fleroxacin and 1.70 for Ndemethyl fleroxacin. Allometric scaling by lean body mass best explained the variability. While fleroxacin pharmacokinetics was comparable, both formation and elimination clearances of its two metabolites were substantially larger in patients with CF compared to those in healthy volunteers.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fleroxacino
/
Fibrose Cística
/
Anti-Infecciosos
Tipo de estudo:
Diagnostic_studies
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Observational_studies
/
Prognostic_studies
Limite:
Adolescent
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Adult
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Female
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Humans
/
Male
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos