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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
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发表于 2017-10-22 20:31
