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1886
Pharmacokinetics, Safety and Antiviral Activity of
CMX157, a Novel Prodrug of Tenofovir, Administered
as Ascending Multiple Doses to Healthy Volunteers and
HBV-Infected Subjects
Somruedee Chatsiricharoenkul1, Narapoon Phaiboon3, Theresa
Matkovits2, Michael Conover2, Jenel Cobb2, Jill Greytok2, John Z.
Sullivan-Bolyai2; 1Siriraj Hospital, Bangkok, Thailand; 2ContraVir
Pharmaceuticals Inc., Edison, NJ; 3Acriles Bangkok Ltd., Bangkok,
Thailand
Background and Aims: CMX157 is a novel prodrug of the acyclic
nucleoside phosphonate tenofovir (TFV). By converting TFV
into a lipid moiety through esterification, there is an increase
in oral bioavailability, targeted cellular uptake through natural
lipid absorption pathways and cellular conversion of CMX157
into TFV di-phosphate. A single dose rat study of 20mg/kg
CMX157 demonstrated 86% first pass liver extraction. This
experiment along with other preclinical safety, ADME, and
early toxicology results lead to the development of a clinical
program. The present, multiple dose, studies were designed to
investigate safety, pharmacokinetics and HBV antiviral effects
of CMX157. Methods: In the phase 1 study, multiple ascending
oral doses of 5, 10, 25, 50, and 100 mg CMX157 were
administered sequentially to cohorts of 10 healthy subjects randomized
8:2, active: placebo. In the proof of concept study,
multiple ascending oral doses of 5, 10, 25, 50, and 100
mg CMX157 were administered sequentially to cohorts of 12
HBV-infected subjects randomized 10:2, CMX157: Viread®.
Plasma levels of CMX157 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 v2.0. Results: Preliminary data from the
5mg, 10mg and 25mg cohorts in the healthy volunteer study
shows CMX157 was rapidly absorbed and eliminated. Corresponding
tmax and t1/2 ranged across the cohorts are as follows:
2.4-3.6hr and 1.09-1.3hr. Plasma exposure, AUC0-24h and
Cmax, of CMX157 was dose-related. AUC0-24h and Cmax ranges
are 9.05-60.55 hr*ng/mL and 3.12-27.13ng/mL across the
three cohorts. Safety results, to date, show CMX157 was well
tolerated with no serious adverse events (SAE), no discontinuations
due to adverse events (AE), no dose-limiting toxicities or
dose-dependence of adverse events. Overall, the incidence of
adverse events and laboratory abnormalities was low and similar
among cohorts. All AEs were mild. Dizziness and rhinorrhea
were the most common. Conclusions: CMX157 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 profiles, pharmacokinetic
profiles and in vitro anti-viral results warrant further
clinical development of CMX157 in HBV-infected patients.
Disclosures:
Michael Conover - Employment: Contravir Pharmaceuticals
John Z. Sullivan-Bolyai - Employment: contravir pharmaceuticals
The following people have nothing to disclose: Somruedee Chatsiricharoenkul,
Narapoon Phaiboon, Theresa Matkovits, Jenel Cobb, Jill Greytok
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发表于 2016-10-7 17:35
