Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin.
Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin.
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接受索磷布韦联合利巴韦林的 HCV 患者的血清和细胞利巴韦林药代动力学和浓度效应分析。
DOI：
10.1093/jac/dkv122
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Kiser,JenniferJ
中科院分区：
文献类型：
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作者：
Rower,JosephE;Meissner,EricG;Jimmerson,LeahC;Osinusi,Anu;Sims,Zayani;Petersen,Tess;Bushman,LaneR;Wolfe,Pamela;McHutchison,JohnG;Kottilil,Shyamasundaran;Kiser,JenniferJ
目的利巴韦林浓度可能会影响丙型肝炎病毒 (HCV) 的治疗结果。我们使用 NIAID SPARE 试验期间收集的样本对红细胞 (RBC) 中的利巴韦林血清和细胞内单磷酸利巴韦林 (RBV-MP) 和三磷酸利巴韦林 (RBV-TP) 药代动力学进行了建模，以探讨与治疗结果和贫血发生的关系。 患者和方法感染 HCV 基因型 1 (GT1) 的个体接受了治疗 作为 NIAID SPARE 试验的一部分，使用 400 毫克索磷布韦和低剂量或基于体重的利巴韦林。使用 NONMEM 建立浓度模型，并使用非配对检验或 Pearson rho 相关性与治疗结果相关联。 结果 相对于血红蛋白最低点 ≥10 g/dL 的患者，血红蛋白最低点 <10 g/dL 的受试者第 14 天的平均 RBV-MP 浓度较高（6.54 比 4.48） pmol/106 个细胞；P= 0.02)。此外，与复发患者相比，获得持续病毒学应答 (SVR) 的受试者第 14 天的 RBV-MP 平均浓度趋于更高（4.97 vs 4.09 pmol/106 个细胞；P= 0.07）。受试者工作特征曲线表明，第 14 天，SVR 的 RBV-MP 浓度阈值为 4.4 pmol/106 个细胞（P= 0.06），血红蛋白最低值 <10 与 ≥10 g/dL 的阈值为 6.1 pmol/106 个细胞（P= 0.02），灵敏度和特异性≥60%。剂量模拟显示，每天一次 800 mg 利巴韦林在第 14 天产生的 RBV-MP 浓度在 4.4-6.1 pmol/106 细胞范围内。结论第 14 天红细胞中的 RBV-MP 浓度与贫血和 SVR 相关。在接受 24 周索磷布韦加利巴韦林治疗的 HCV GT1 疾病患者中，确定了 RBV-MP 的治疗范围，这表明在无干扰素治疗方案中个体化利巴韦林剂量的潜在药理学基础。
ObjectivesRibavirin 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 and methodsIndividuals 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 unpairedt-tests or Pearson's rho correlations.ResultsAverage 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/106cells;P= 0.02). 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/106cells;P= 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/106cells for SVR (P= 0.06) and 6.1 pmol/106cells for haemoglobin nadir <10 versus ≥10 g/dL (P= 0.02), 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/106cells range.ConclusionsRBV-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.