AASLD2017[943]
Pharmacokinetics, Safety and Antiviral Activity
of Tenofovir exalidex(TXL), a Novel Prodrug of
Tenofovir, Administered as Ascending Multiple
Doses to HBV-Infected Subjects: A 28 Day
Study Final Analyses
Tawesak Tanwandee1, Satawat Thongsawat2, Wattana Sukeepaisarnjaroen3,
Pisit Tangkijvanich4, Piyawat Komolmit5,
Anchalee Avihingsanon6, Teerha Piratvisuth7; 1Division of Gastroenterology,
Siriraj Hospital, Bangkok, Thailand; 2Division
of Gastroenterology, Maharaj Nakorn Chiang Mai Hospital,
Bangkok, Thailand; 3Division of Gastroenterology and Hepatology,
Srinagarind Hospital, Chiang Mai, Thailand; 4Hepatitis
and Liver Cancer Unit, King Chulalongkorn Hospital, Bangkok,
Thailand; 5Chulalongkorn University, King Chulalongkorn
Hospital, Bangkok, Thailand; 6HIV Netherlands Australia
Thailand Research Collaboration, Bangkok, Thailand; 7Department
of Gastroenterology and Hepatology, NKC Institute,
Songkla, Thailand
TXL is a novel prodrug of the acyclic nucleotide phosphonate
tenofovir (TFV). By chemically modifying TFV to
include a lipid moiety, there is targeted cellular uptake
through natural lipid absorption pathways and cellular
conversion of TXL into TFV di-phosphate. This novel liver
targeting structure results in decreased systemic circulating
levels of TFV, thereby reducing the potential for renal
and bone side effects. A single dose rat study of 20mg/kg
TXL with an 86% first pass liver extraction demonstrated
extensive liver targeting. The phase 1 multiple ascending
oral dose study (CTRV-CMX-102) reported safety, tolerability
and pharmacokinetics. This multiple dose phase 2
study was designed to investigate safety, pharmacokinetics
and HBV antiviral effects of TXL. This phase 2a proof
of concept study tested multiple ascending oral doses of 5,
10, 25, 50, and 100 mg TXL sequentially to cohorts of 12
HBV-infected subjects randomized 10:2, TXL:300mg tenofovir
disoproxil fumerate(TDF) for 28 days. Plasma levels
of TXL and TFV were quantitated using a validated LC-MS/
MS methodology. Serum levels of HBV DNA were quantitated
using the COBAS® AmpliPrep/COBAS® Taqman®
HBV Test v2. Data from the day 1 single doses of 5mg,
10mg, 25mg, 50mg and 100mg cohorts in HBV-infected
subjects demonstrates that TXL was rapidly absorbed
and eliminated, similar to that observed in the phase 1
healthy volunteer study,. The range of Tmax and t1/2 values
across the cohorts was 2.0-2.81hr and 1.01-2.09 hr, respectively.
Systemic exposures, AUC0-∞ and Cmax, of TXL were
dose-proportional. AUC0-∞ and Cmax ranges were 2.34-
420.86 hr*ng/mL and 2.30-168.97 ng/mL, respectively,
across the five cohorts. TXL and TFV steady state PK parameters,
safety data (including follow-up period to day 210),
and change in HBV DNA data with comparison to TDF will
be presented. TXL appeared to be safe and well tolerated
in these studies. Consistent with a liver-targeted approach,
systemic exposure of parent drug and metabolite was low.
The favorable safety profile, PK profile and clinical antiviral
results warrant further clinical development of TXL as
a component of the HBV cure.
Disclosures:
Tawesak Tanwandee - Grant/Research Support: Contravir, Merck, SillaJen,
Gilead, Inovio
Teerha Piratvisuth - Advisory Committees or Review Panels: Bristol Myers
Aquibb, Merck; Grant/Research Support: Bristol Myers Squibb, Gilead,
Roche, MSD, Novartis, Fibrosis, Bayer; Speaking and Teaching: Bristol Myers
Aquibb, Roche, Merck, Novartis, GSK
The following people have nothing to disclose: Satawat Thongsawat,
Wattana Sukeepaisarnjaroen, Pisit Tangkijvanich, Piyawat Komolmit,
Anchalee Avihingsanon 作者: StephenW 时间: 2017-10-22 20:31
TXL is a novel prodrug of the acyclic nucleotide phosphonate tenofovir (TFV). By chemically modifying TFV to include a lipid moiety, there is targeted cellular uptake through natural lipid absorption pathways and cellular conversion of TXL into TFV di-phosphate. This novel liver targeting structure results in decreased systemic circulating levels of TFV, thereby reducing the potential for renal and bone side effects. A single dose rat study of 20mg/kg TXL with an 86% first pass liver extraction demonstrated extensive liver targeting. The phase 1 multiple ascending oral dose study (CTRV-CMX-102) reported safety, tolerability and pharmacokinetics. This multiple dose phase 2 study was designed to investigate safety, pharmacokinetics and HBV antiviral effects of TXL. This phase 2a proof of concept study tested multiple ascending oral doses of 5, 10, 25, 50, and 100 mg TXL sequentially to cohorts of 12 HBV-infected subjects randomized 10:2, TXL:300mg tenofovir disoproxil fumerate(TDF) for 28 days. Plasma levels of TXL and TFV were quantitated using a validated LC-MS/ MS methodology. Serum levels of HBV DNA were quantitated using the COBAS® AmpliPrep/COBAS® Taqman® HBV Test v2. Data from the day 1 single doses of 5mg, 10mg, 25mg, 50mg and 100mg cohorts in HBV-infected subjects demonstrates that TXL was rapidly absorbed and eliminated, similar to that observed in the phase 1 healthy volunteer study,. The range of Tmax and t1/2 values across the cohorts was 2.0-2.81hr and 1.01-2.09 hr, respectively. Systemic exposures, AUC0-∞ and Cmax, of TXL were dose-proportional. AUC0-∞ and Cmax ranges were 2.34- 420.86 hr*ng/mL and 2.30-168.97 ng/mL, respectively, across the five cohorts. TXL and TFV steady state PK parameters, safety data (including follow-up period to day 210), and change in HBV DNA data with comparison to TDF will be presented. TXL appeared to be safe and well tolerated in these studies. Consistent with a liver-targeted approach, systemic exposure of parent drug and metabolite was low. The favorable safety profile, PK profile and clinical antiviral results warrant further clinical development of TXL as a component of the HBV cure.
TXL是无环核苷酸膦酸替诺福韦(TFV)的新型前药。通过化学修饰TFV以包括脂质部分,通过天然脂质吸收途径和TXL细胞转化成TFV二磷酸的靶向细胞摄取。这种新的肝靶向结构导致TFV的全身循环水平降低,从而降低肾和骨骼副作用的潜力。 20mg / kg TXL的单次剂量大鼠研究,86%的第一次肝脏提取显示广泛的肝靶向。 1期多次上升口服剂量研究(CTRV-CMX-102)报道了安全性,耐受性和药代动力学。本次多剂量第2期研究旨在调查TXL的安全性,药代动力学和HBV抗病毒作用。本阶段2a概念研究证明,将5,10,25,50和100 mg TXL的多次上升口服剂量依次列为12名HBV感染受试者的队列,随机分组为10:2,TXL:300mg替诺福韦替夫唑立方案(TDF)为28天。使用经验证的LC-MS / MS方法定量TXL和TFV的血浆水平。使用COBAS®AmpliPrep /COBAS®Taqman®HBV Test v2定量HBV DNA的血清水平。在HBV感染的受试者中,来自第1天单次剂量5mg,10mg,25mg,50mg和100mg队列的数据表明,TXL被快速吸收和消除,类似于第1期健康志愿者研究中观察到的。队列中的Tmax和t1 / 2值的范围分别为2.0-2.81小时和1.01-2.09小时。 TXL的系统暴露AUC0-∞和Cmax是剂量成比例的。在这五个队列中,AUC0-∞和Cmax范围分别为2.34-420.86小时* ng / mL和2.30-168.97ng / mL。 TXL和TFV稳态PK参数,安全数据(包括随访期至210天)以及HBV DNA数据与TDF相比的变化。在这些研究中,TXL似乎是安全和耐受性良好的。与肝靶向方法一致,母体药物和代谢物的全身暴露较低。有利的安全性,PK特征和临床抗病毒结果必须进一步临床开发TXL作为HBV治疗的一个组成部分。作者: antiHBVren 时间: 2017-10-23 17:38