Pharmacokinetics and Pharmacodynamics Modeling of Lonafarnib in Patients With Chronic Hepatitis Delta Virus Infection
Pharmacokinetics and Pharmacodynamics Modeling of Lonafarnib in Patients With Chronic Hepatitis Delta Virus Infection
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DOI：
10.1002/hep4.1043
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发表时间：
2017-06-01
影响因子：
5.1
通讯作者：
Dahari, Harel
中科院分区：
文献类型：
--
作者：
Canini, Laetitia;Koh, Christopher;Dahari, Harel
异戊二烯化抑制剂洛那法尼（LNF）是一种有效的抗病毒药物，为丁型肝炎病毒（HDV）的治疗提供了突破。本研究使用最大似然法对LNF药代动力学（PK）和药效学（PD）参数进行建模，并使用12例慢性HDV感染患者的数据预测达到99%疗效所需的剂量，这些患者接受LNF 100 mg每日两次（bid）（第1组）或200 mg bid（第2组）治疗28天。LNF-PK模型预测第1组和第2组的平均稳态LNF浓度分别为860 ng/mL和1，734 ng/mL，LNF吸收速率k（a）= 0.43/h，消除速率k（e）= 0.045/h。PK/PD模型确定了0.56小时的平均延迟和使HDV产生降低50%的LNF浓度，EC 50 = 227 ng/mL，希尔因子h = 1.48。HDV在血液中的半衰期为1.87天，并且组1的阻断HDV产生的平均稳态LNF效力为100%= 87.7%，组2的平均稳态LNF效力为100%= 95.2%。在第1组和第2组中分别观察到双相HDV下降，平均1相下降（0.9 log（10）IU/mL和1.32 log（10）IU/mL）。2期两组间无显著差异（P = 0.94），平均斜率为-0.06 log IU/mL/天。该模型表明，类似于610 mg bid的LNF剂量将达到≥ 99%。结论：在慢性HDV患者中进行的第一项PK/PD建模研究表明，LNF剂量增加至3倍（类似于610 mg bid）将达到99%的抗病毒疗效。利托那韦增强的LNF组合可以提供一种以最小的副作用增加LNF功效的方法。模型研究结果为理解HDV动力学提供了重要进展，并为优化丁型肝炎的LNF治疗提供了基础。
The prenylation inhibitor lonafarnib (LNF) is a potent antiviral agent providing a breakthrough for the treatment of hepatitis delta virus (HDV). The current study used a maximum likelihood approach to model LNF pharmacokinetic (PK) and pharmacodynamic (PD) parameters and predict the dose needed to achieve 99% efficacy using data from 12 patients chronically infected with HDV and treated with LNF 100 mg twice daily (bid) (group 1) or 200 mg bid (group 2) for 28 days. The LNF-PK model predicted average steady-state LNF concentrations of 860 ng/mL and 1,734 ng/mL in groups 1 and 2, respectively, with an LNF absorption rate k(a) = 0.43/hour and elimination rate k(e) = 0.045/hour. The PK/PD model identified an average delay of 0.56 hours and an LNF concentration that decreases HDV production by 50%, EC50 = 227 ng/mL, with a Hill factor h = 1.48. The HDV half-life in blood was 1.87 days, and the average steady-state LNF efficacy in blocking HDV production was epsilon = 87.7% for group 1 and epsilon = 95.2% for group 2. A biphasic HDV decline with an average phase 1 decline (0.9 log(10) IU/mL and 1.32 log(10) IU/mL) was observed in groups 1 and 2, respectively. Phase 2 was not significantly (P = 0.94) different between the two groups, with an average slope of -0.06 log IU/mL/day. The model suggests an LNF dose of similar to 610 mg bid would achieve epsilon = 99%. Conclusion: The first PK/PD modeling study in patients with chronic HDV indicates that a similar to 3-fold increase in LNF dose (similar to 610 mg bid) would achieve 99% antiviral efficacy. A ritonavir-boosted LNF combination may provide a means to increase LNF efficacy with minimal side effects. The modeling findings provide an important advance in understanding HDV dynamics and the basis to optimize LNF therapy for hepatitis D.