Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin.
J Antimicrob Chemother
; 70(8): 2322-9, 2015 Aug.
Article
em En
| MEDLINE
| ID: mdl-25971261
ABSTRACT
OBJECTIVES:
Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia. PATIENTS ANDMETHODS:
Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations.RESULTS:
Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir <10 g/dL relative to patients with haemoglobin nadir ≥10 g/dL (6.54 versus 4.48 pmol/10(6) cells; Pâ=â0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/10(6) cells; Pâ=â0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (Pâ=â0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus ≥10 g/dL (Pâ=â0.02), with sensitivity and specificity ≥60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range.CONCLUSIONS:
RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Ribavirina
/
Soro
/
Eritrócitos
/
Sofosbuvir
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos