Faculty of Medicine, The University of Notre Dame, Sydney, Australia.
University of Groningen, University Medical Centre Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
J Antimicrob Chemother. 2019 Mar 1;74(3):691-698. doi: 10.1093/jac/dky466.
Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients; however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established.
This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed.
Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre-specified target concentrations.
A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required; however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population.
利巴韦林用于治疗肺移植受者的呼吸道副黏病毒感染；然而，尽管由于潜在的病理改变可能会改变其药代动力学特征，但在移植人群中其药代动力学特征仍未知。此外，目前的治疗方案是否能达到预期的暴露目标尚不清楚。
本研究通过评估当前和替代治疗方案，检测利巴韦林在肺移植人群中的药代动力学。
采用 NONMEM 软件中的群体药代动力学模型，对 24 名肺移植受者和 6 名健康志愿者的浓度-时间数据进行分析。采用蒙特卡罗模拟来评估治疗方案达到预定目标浓度的能力。
该模型采用具有一级消除的三室模型能更好地描述利巴韦林的浓度-时间数据，CLCR 和患者类型（即肺移植）被确定为模型中的重要协变量。模拟结果表明，目前的治疗方案在开始治疗后 24 小时内可达到有效的浓度，并在治疗期间增加至治疗水平以上。预测在治疗期间的前 48 小时内给予 8mg/kg q6h 口服，随后给予 8mg/kg q24h 口服，将使>90%的患者在整个治疗过程中表现出在定义的目标范围内的浓度。需要进一步的工作来正式确定目标治疗浓度；然而，本研究为确定肺移植人群中副黏病毒感染的利巴韦林最佳治疗方案提供了有价值的第一步。
