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本帖最后由 StephenW 于 2017-2-13 22:37 编辑
APASL2017 [OP221]
OP221
Pharmacokinetics, safety and tolerability of CMX157, a novel
prodrug of tenofovir, administered as ascending multiple doses
to healthy volunteers and HBV-infected subjects
Somruedee Chatsiricharoenkul1, Tawesak Tanwandee2, Theresa
Matkovits3, Michael Conover3, Jenel Cobb3, Carlos Canizares3,
John Sullivan-Bolyai3
1Siriraj Clinical Research Center, Bangkok, Thailand; 2Department of
Medicine, Division of Gastroenterology, Faculty of Medicine, Siriraj
Hospital, Mahidol University, Bangkok, Thailand; 3ContraVir
Pharmaceuticals Inc., Edison, NJ, USA
Background: CMX157 is a novel prodrug of the acyclic nucleotide
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 oral
dose rat study of 20 mg/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 two, 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 LCMS/
MS methodology.
Result: Data from the 5, 10, 25, 50, and 100 mg 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:
2.0–3.0 and 1.1–2.1 h. Plasma exposure, AUC0–? and Cmax, of
CMX157 was dose-related. AUC0–? and Cmax ranges are
10.0–236 h ng/mL and 3.1–100 ng/mL across the five cohorts. Data
from the 5, 10, 25, and 50 mg cohorts in the HBV-infected subject
study shows CMX157 was rapidly absorbed and eliminated as in the
healthy volunteers. Corresponding tmax and t1/2 ranged across the
cohorts are as follows: 2.0–2.5 and 1.0–1.3 h. Plasma exposure,
AUC0–? and Cmax, of CMX157 was dose-related. AUC0–? and Cmax
ranges are 2.3–112 h and 2.5–52.2 ng/mL across the four cohorts.
CMX157 100 mg HBV-infected cohort, TFV and Viread safety,
tolerability, pharmacokinetic parameters will also be presented.
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.
Conclusion: 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.
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发表于 2017-2-13 22:08
