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利托那韦的药代动力学和药效学模型 在HDV患者中加强了lonafar  

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才高八斗

发表于 2018-4-6 08:50 |显示全部帖子
EASL 2018 FRI-323
Pharmacokinetics and pharmacodynamics modeling of ritonavir
boosted lonafarnib therapy in HDV patients: A phase 2 LOWRHDV-
3 study
P. Dubey1, C. Koh2, P. Surana2, S. Uprichard1, M.A.T. Han2, N. Fryzek2,
G. Subramanya1, D. Kapuria2, O. Etzion3, V. Takyar2, Y. Rotman2,
C. Yurdaydin4, J. Glenn5, S. Cotler5, T. Heller2, H. Dahari1. 1Loyola
University Medical Center, United States; 2Liver Diseases Branch, NIDDK,
NIH, United States; 3Soroka University Medical Center, Israel; 4University
of Ankara Medical School, Turkey; 5Stanford University School of
Medicine, United States
Email: [email protected]
Background & Aim: The prenylation inhibitor lonafarnib (LNF) has
proven anti-hepatitis D virus (HDV) activity in recent phase 2 clinical
trials. The phase 2 LOWR HDV-3 study conducted with an all-oral
combination of once-daily ritonavir (RTV) boosted LNF was reported
safe and tolerable in patients for up to 6 months of therapy. In the
current study, we sought to model RTV-boosted LNF pharmacokinetics
(PK) and pharmacodynamics (PD) parameters using data from
the LOWR HDV-3 study.
Methods: HDV-infected patients were randomized in LOWR HDV-3
into one of six groups: LNF 50/75/100 mg + RTV 100 mg once daily for
24 weeks (n = 12) or 12 weeks of placebo followed by LNF 50/75/
100 mg + RTV 100 mg once daily for 12 weeks (n = 9). Since frequent
hepatitis B surface antigen (HBsAg), RTV, LNF and HDV RNA kinetics
(0, 6,12,18, 24, 36 hrs, 2, 3, 7,14, 21, 28, 56, 84,112,140,168 days)were
available in the 24 week arm of LNF 50/75/100 mg + RTV 100 mg, 12
patients in this arm were included in the modeling analysis. All
patients were treated with hepatitis B nucleotide analogues. A
modeling framework that includes proliferation of uninfected and
infected cells and accounts for LNF concentration, HDV RNA, alanine
aminotransferase (ALT) and HBsAg kinetics was used to estimate the
LNF PK and PD parameters. The standard Emax model was used to
account for the time-dependent LNF effectiveness in blocking HDV
production.
Results: While HBsAg levels did not change on therapy, four patterns
of HDV RNA response were seen in each dosing group: responders
(triphasic (n = 3), flat-partial responders (n = 3), rebound (n = 3)) and
non-responders (n = 3). ALT normalization was observed in all
triphasic and 2 (out of 3) flat-partial responders. In all 12 patients,
a transient increase in RTV concentrationwas observed with median
(interquartile range, IQR) peak Cmax_RTV = 880 (993)ng/ml during the
first week after initiation of therapy followed by a set point of 257
(297)ng/ml from week 2 onwards. Interestingly, Cmax_RTV >1200 ng/
ml was associated with the triphasic response (1 in each LNF dosing
group) in which there was a continuous HDV decline on treatment.
Based on all 12 patients, the LNF-PK model predicted a median LNF
elimination rate ke = 0.7 (0.3)/day, absorption rate ka = 9.2 (23.7) /day,
and bioavailable fraction F = 1012.7 (682.7) ng/ml. There was no
association between PK parameters and response to therapy (p ≥
0.145). LNF-PD modeling in the 9 responders suggests a median LNF
EC50 of 289 (422) ng/ml, at which LNF’s effectiveness in blocking
viral production reaches to half of its maximum, with Hill coefficient
n = 1.48.
Conclusions: Modeling daily ritonavir boosted lonafarnib indicates a
lower average LNF elimination rate (0.76/day) compared to twice a
day unboosted LNF (1.08/day – Hepatology Communications 2017;
1:288–292), which confirms the role of ritonavir to maintain high
LNF efficacy under low and daily LNF dosing with minimal side
effects.

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才高八斗

发表于 2018-4-6 08:51 |显示全部帖子
EASL 2018 FRI-323
利托那韦的药代动力学和药效学模型
在HDV患者中加强了lonafarnib治疗:第2阶段LOWRHDV-
3研究
P. Dubey1,C. Koh2,P. Surana2,S. Uprichard1,M.A.T. Han2,N.Fryzek2,
G. Subramanya1,D. Kapuria2,O. Etzion3,V. Takyar2,Y. Rotman2,
C.Yurdaydin4,J.Glenn5,S. Cotler5,T.Heller2,H.Dahari1。 1Loyola
美国大学医学中心; 2肝病科,NIDDK,
NIH,美国; 3以色列索罗卡大学医学中心; 4University
土耳其安卡拉医学院; 5Stanford大学
医学,美国
电子邮件:[email protected]
背景与目的:异戊烯基抑制剂lonafarnib(LNF)具有
在最近的2期临床中证明抗肝炎D病毒(HDV)活性
试验。第2阶段的LOWR HDV-3研究采用全口服药
报道了每日一次利托那韦(RTV)促进的LNF的组合
安全且可耐受长达6个月治疗的患者。在里面
目前的研究中,我们试图模拟RTV增强的LNF药代动力学
(PK)和药效学(PD)参数
LOWR HDV-3研究。
方法:将HDV感染患者随机分入LOWR HDV-3
分为6组:LNF 50/75/100 mg + RTV 100 mg,每日一次
24周(n = 12)或12周安慰剂,然后是LNF 50/75 /
100mg + RTV100mg,每日一次,持续12周(n = 9)。由于频繁
乙型肝炎表面抗原(HBsAg),RTV,LNF和HDV RNA动力学
(0,6,12,18,24,36小时,2,3,7,14,21,28,56,84,112,140,​​168天)为
可用于LNF 50/75/100 mg + RTV 100 mg,12周的24周组
该分支中的患者被纳入建模分析。所有
患者接受乙肝核苷酸类似物治疗。一个
建模框架,其中包括未感染和扩散
感染的细胞并占据LNF浓度,HDV RNA,丙氨酸
转氨酶(ALT)和HBsAg动力学被用来估计
LNF PK和PD参数。标准Emax模型用于
说明了阻断HDV的时间依赖性LNF有效性
生产。
结果:虽然HBsAg水平没有改变治疗,四种模式
的HDV RNA应答在每个给药组中见到:应答者
(三相(n = 3),平面部分响应者(n = 3),反弹(n = 3))和
无应答者(n = 3)。全部观察到ALT归一化
三相和2(平分部分响应者)。在所有12名患者中,
用中位数观察RTV浓度的瞬时增加
(四分位间距离,IQR)峰值Cmax_RTV = 880(993)ng / ml
治疗开始后的第一周,随后是设定点257
(297)ng / ml从第2周开始。有趣的是,Cmax_RTV> 1200ng /
ml与三相应答相关(每次LNF给药1次)
组),其中HDV持续下降。
基于全部12名患者,LNF-PK模型预测中位LNF
消除速率ke = 0.7(0.3)/ day,吸收速度ka = 9.2(23.7)/ day,
和生物利用度F = 1012.7(682.7)ng / ml。没有
PK参数与治疗反应之间的关联(p≥
0.145)。 9名应答者的LNF-PD建模提示中位LNF
EC50为289(422)ng / ml,此时LNF有效阻断
病毒产量达到其最大值的一半,具有希尔系数
n = 1.48。
结论:建模每日利托那韦加强lonafarnib表明a
平均LNF清除率(0.76 /日)低于两倍
日未补贴LNF(1.08 /日 - 2017年肝病学通讯;
1:288-292),这证实了利托那韦维持高的作用
在低和每日LNF给药的情况下LNF功效最低
效果。

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