EASL 2018 FRI-352 替诺福韦的药代动力学 - 药效学模型 Exalidex在HB

StephenW

EASL 2018 FRI-352
Pharmacokinetic-pharmacodynamic modeling of Tenofovir
Exalidex in HBV subjects
R. Foster1, M. Conover1, C. Canizres1, D. Trepanier1, D. Ure1,
T. Matkovits1, P. Mayo2. 1ContraVir Pharmaceuticals, Inc., Drug
Development, Edison, United States; 2University of Alberta, Pharmacy
and Pharmaceutical Sciences, Edmonton, Canada
Email: [email protected]
Background and Aims: Tenofovir Exalidex (TXL), a lipid conjugate
of tenofovir (TFV), is designed to mimic lysophosphatidylcholine to
take advantage of natural lipid uptake pathways and achieve high
intrahepatic concentrations of TFV diphosphate (TFV-PP) while
reducing the peripheral TFV concentrations associated with kidney
and bone toxicities. As it is not routinely feasible to measure
intrahepatic TFV-PP concentrations in patients, a pharmacokineticpharmacodynamic
(PK-PD) modelwas developed to aid and optimize
further clinical development of TXL.
Method: TXL was administered to 50 HBV subjects (fasted) at doses
ranging from 10–100 mg/day orally. The 50 mg cohort (n = 10) was
used to derive PK-PD modeling, as this dose resulted in viral load (VL)
reductions (log10) that were not statistically different from Standard of-
Care (SOC, 300 mg, tenofovir disoproxil fumarate). Steady-state PK
modeling was generated using linear trapezoidal, linear interpolation,
Non-Compartmental Analysis for a 24 hour dosing interval
(NCA, PhoenixWinNonLin Ver. 7.0). A linked PK-PD non-linear mixed
effects (NLME, Monolix 3.2) model was employed, using an inhibitory
Emax model. PK data were also examined using model-dependent
analyses. Data after 28 days dosing was used for the current model.
Results: Maximum VL reductions of up to 3.9 log10 were observed
with 50 mg/day TXL dosing for 28 days. The prodrug, TXL, rapidly
disappeared from plasma, with mean (SD) Cmax, Tmax, AUClast, and
t1/2 values of 51.28 (39.9) ng/ml, 1.60 (0.7) h, 109.44 (84.9) ng.h/ml,
and 2.10 (2.0) h, respectively, at day 28. TFV mean (SD) values for
Cmax, Tmax, AUClast, and t1/2 were 8.51 (2.0) ng/ml, 4.95 (2.2) h,
136.35 (33.5) ng.h/ml, and 23.3 (3.4) hours, respectively. The VL IC50
on Day 29 was 2.92 ng/ml. Additionally, TXL could be described using
a one-compartment model, whereas for TFV the model of best-fit was
multi-exponential.
Conclusion: TXL 50 mg VL reductions were not statistically different
(p = 0.19) from SOC, TDF. The PK-PD relationship after dosing on Day
28 was described using a NCA and inhibitory Emax model for TFV.
TXL was rapidly cleared compared with TFV, and the clinical antiviral
reduction IC50 approximated 3 ng/ml. Modeling promises to be a
useful tool for the further clinical development and optimization
of TXL.

StephenW

EASL 2018 FRI-352
替诺福韦的药代动力学 - 药效学模型
Exalidex在HBV科目
R.Foster1，M.Conover1，C.Canizres1，D.Turpanier1，D.Ure1，
T. Matkovits1，P. Mayo2。 1ContraVir制药公司，药物
发展，美国爱迪生; 2阿尔伯塔大学药剂学
和加拿大埃德蒙顿的药物科学
电子邮件：[email protected]
背景和目标：替诺福韦Exalidex（TXL），一种脂质缀合物
替诺福韦（TFV）被设计用来模拟溶血磷脂酰胆碱
利用天然脂质摄取途径并实现高水平
肝内浓度的二磷酸TFV（TFV-PP）
减少与肾相关的末梢TFV浓度
和骨骼毒性。因为测量不是常规可行的
肝内TFV-PP浓度在患者体内的药代动力学
（PK-PD）模型用于辅助和优化
TXL的进一步临床开发。
方法：给予50名HBV受试者（禁食）剂量的TXL
口服10-100毫克/天。 50毫克队列（n = 10）是
用于推导PK-PD建模，因为该剂量导致病毒载量（VL）
减少（log10）与标准 -
护理（SOC，300mg，替诺福韦二吡呋酯富马酸盐）。稳态PK
使用线性梯形，线性插值生成建模，
非间隔分析24小时给药间隔
（NCA，PhoenixWinNonLin版本7.0）。一个连接的PK-PD非线性混合
效应（NLME，Monolix 3.2）模型被采用，使用抑制剂
Emax模型。 PK数据也使用模型依赖性进行检查
分析。目前的模型使用28天给药后的数据。
结果：观察到最大VL降低达3.9log10
50毫克/天TXL给药28天。前药TXL很快
从血浆消失，平均（SD）Cmax，Tmax，AUClast和
t1 / 2值为51.28（39.9）ng / ml，1.60（0.7）h，109.44（84.9）ng.h / ml，
和2.10（2.0）h，分别在第28天.TFV平均值（SD）值
Cmax，Tmax，AUClast和t1 / 2分别为8.51（2.0）ng / ml，4.95（2.2）h，
136.35（33.5）ng.h / ml和23.3（3.4）小时。 VL IC50
在第29天为2.92ng / ml。另外，TXL可以用来描述
一室模型，而TFV则是最适合的模型
多指数。
结论：TXL 50 mg VL降低无统计学差异
（p = 0.19）来自SOC，TDF。第一天给药后的PK-PD关系
28被描述为使用NCA和TFV的抑制性Emax模型。
与TFV和临床抗病毒药物相比，TXL被迅速清除
减少IC50接近3ng / ml。建模承诺是一个
进一步临床开发和优化的有用工具
的TXL。

Hepbest

EASL 2018 FRI-352 Pharmacokinetic-pharmacodynamic modeling of Tenofovir Exalidex in HBV subjects R. Foster1, M. Conover1, C. Canizres1, D. Trepanier1, D. Ure1, T. Matkovits1, P. Mayo2. 1ContraVir Pharmaceuticals, Inc., Drug Development, Edison, United States; 2University of Alberta, Pharmacy and Pharmaceutical Sciences, Edmonton, Canada
Email: [email protected]
Background and Aims:
Tenofovir Exalidex (TXL), a lipid conjugate of tenofovir (TFV), is designed to mimic lysophosphatidylcholine to take advantage of natural lipid uptake pathways and achieve high intrahepatic concentrations of TFV diphosphate (TFV-PP) while reducing the peripheral TFV concentrations associated with kidney and bone toxicities. As it is not routinely feasible to measure intrahepatic TFV-PP concentrations in patients, a pharmacokineticpharmacodynamic (PK-PD) modelwas developed to aid and optimize further clinical development of TXL.

Method:
TXL was administered to 50 HBV subjects (fasted) at doses ranging from 10–100 mg/day orally. The 50 mg cohort (n = 10) was used to derive PK-PD modeling, as this dose resulted in viral load (VL) reductions (log10) that were not statistically different from Standard of- Care (SOC, 300 mg, tenofovir disoproxil fumarate). Steady-state PK modeling was generated using linear trapezoidal, linear interpolation, Non-Compartmental Analysis for a 24 hour dosing interval (NCA, PhoenixWinNonLin Ver. 7.0). A linked PK-PD non-linear mixed effects (NLME, Monolix 3.2) model was employed, using an inhibitory Emax model. PK data were also examined using model-dependent analyses. Data after 28 days dosing was used for the current model.

Results:
Maximum VL reductions of up to 3.9 log10 were observed with 50 mg/day TXL dosing for 28 days. The prodrug, TXL, rapidly disappeared from plasma, with mean (SD) Cmax, Tmax, AUClast, and t1/2 values of 51.28 (39.9) ng/ml, 1.60 (0.7) h, 109.44 (84.9) ng.h/ml, and 2.10 (2.0) h, respectively, at day 28. TFV mean (SD) values for Cmax, Tmax, AUClast, and t1/2 were 8.51 (2.0) ng/ml, 4.95 (2.2) h, 136.35 (33.5) ng.h/ml, and 23.3 (3.4) hours, respectively. The VL IC50 on Day 29 was 2.92 ng/ml. Additionally, TXL could be described using a one-compartment model, whereas for TFV the model of best-fit was multi-exponential.

Conclusion:
TXL 50 mg VL reductions were not statistically different (p = 0.19) from SOC, TDF. The PK-PD relationship after dosing on Day 28 was described using a NCA and inhibitory Emax model for TFV. TXL was rapidly cleared compared with TFV, and the clinical antiviral reduction IC50 approximated 3 ng/ml. Modeling promises to be a useful tool for the further clinical development and optimization of TXL.

EASL 2018 FRI-352替诺福韦Exalidex在HBV受试者中的药代动力学 - 药效学模型R.Foster1，M.Conover1，C.Canizres1，D.Turpanier1，D.Ure1，T.Matkovits1，P.Mayo2。 1ContraVir Pharmaceuticals，Inc.，Drug Development，Edison，美国; 2加拿大埃德蒙顿艾伯塔大学药学和药学科学系
电子邮件：[email protected]
背景和目标：
替诺福韦Exalidex（TXL）是替诺福韦（TFV）的脂质缀合物，其被设计为模拟溶血磷脂酰胆碱以利用天然脂质摄取途径并实现高肝内浓度的TFV二磷酸（TFV-PP），同时降低与肾相关的外周TFV浓度和骨骼毒性。由于测量患者的肝内TFV-PP浓度通常不可行，开发了药代动力学药效学（PK-PD）模型以帮助和优化TXL的进一步临床发展。

方法：
将TXL给予50名HBV受试者（禁食），口服剂量范围为10-100毫克/天。 50mg组群（n = 10）用于推导PK-PD建模，因为该剂量导致病毒载量（VL）减少（log10），其与标准治疗无关（SOC，300mg，替诺福韦二吡呋酯富马酸酯）。使用线性梯形，线性插值，24小时给药间隔的非室间分析（NCA，PhoenixWinNonLin Ver.7.0）产生稳态PK建模。使用抑制性Emax模型，使用连接的PK-PD非线性混合效应（NLME，Monolix 3.2）模型。 PK数据也使用模型依赖性分析进行检查。目前的模型使用28天给药后的数据。

结果：
在50mg /天TXL给药28天时观察到最大VL减少量高达3.9log10。前药TXL从血浆迅速消失，平均（SD）Cmax，Tmax，AUClast和t1 / 2值分别为51.28（39.9）ng / ml，1.60（0.7）h，109.44（84.9）ng.h / ml （2.0）h和2.10（2.0）h .Cmax，Tmax，AUClast和t1 / 2的TFV平均值（SD）分别为8.51（2.0）ng / ml，4.95（2.2）h，136.35（33.5） ng.h / ml和23.3（3.4）小时。第29天的VL IC50为2.92ng / ml。此外，TXL可以用一室模型来描述，而对于TFV来说，最佳拟合模型是多指数的。

结论：
TXL 50 mg VL降低与SOC，TDF没有统计学差异（p = 0.19）。使用NCA和TFV的抑制性Emax模型描述了第28天给药后的PK-PD关系。与TFV相比，TXL被迅速清除，并且临床抗病毒减少IC50接近3ng / ml。建模将成为进一步临床开发和优化TXL的有用工具。