icon-folder.gif   Conference Reports for NATAP  
  58th Annual Meeting of the American Association
for the Study of Liver Diseases
November 2-6, 2007
Boston, MA
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Tibotec HCV Protease Inhibitor
  Reported by Jules Levin
AASLD, Nov 2-6, 2007, Boston, MA
Results Of A Phase I Placebo-Controlled Trial In Healthy Volunteers To Examine The Safety, Tolerability And Pharmacokinetics Of The HCV Protease Inhibitor TMC435350 After Single And Repeated Dosing
K. Simmen1; R. Verloes1; K. Abou Farha2; A. van Vliet2; G. van 't Klooster1; F. Aharchi1; K. Marien1; H. de Kock1 1. Tibotec Pharmaceuticals Ltd., Eastgate Village, Little Island, Cork, Ireland. 2. PRA International EDS, Stationsweg 163, 9471 GP Zuidlaren, Netherlands.
Background: This trial studied the safety, tolerability and plasma pharmacokinetics (PK) of a novel HCV NS3/4A protease inhibitor, TMC435350, after single oral dosing and, in a second step, after 5 days of oral dosing in HCV-negative volunteers.
Methods: The single ascending dose (SAD) part was studied under fed conditions using two panels of 9 males or females followed by an investigation on the effects of fasting. In the multiple ascending dose (MAD) part, 4 panels of 9 volunteers were included. Each panel was designed to have 6 subjects receiving TMC435350 solution and 3 subjects receiving placebo. Safety monitoring included physical examination, vital signs, laboratory parameters (haematology, biochemistry, urinalysis), extensive cardiovascular safety (ECGs, and additional biomarkers and echocardiography during the MAD phase), and adverse events. In the SAD study a full PK profile was evaluated up to 72 h post-dose. In the MAD study, a full PK profile was studied on Days 1 and 5, with samples taken up to 72 h post-dose.
Results: In the SAD study, oral doses up to 600 mg were well tolerated without attaining any dose-limiting toxicity. The plasma exposure increased in a more than dose proportional fashion. A single dose of 200 mg studied under fasted conditions was well tolerated and yielded comparable exposure to the fed condition.
TMC435350 displayed good plasma exposure, with a Tmax of 4-6 hours, which together with a half-life of ~12 hours, supports once daily dosing (qd) in the MAD phase.
In that phase, a starting dose of 100 mg was given qd for 5 days. Subsequent doses were 200 mg qd, 200 mg bid and 400 mg qd. All doses of TMC435350 or placebo were well tolerated. There were no grade 3 or 4 adverse events and no clinically relevant changes from baseline on laboratory parameters, vital signs, ECG recordings and echocardiographic evaluations.
Minor effects observed were mainly gastrointestinal tract related. Mild, short-lasting erythema was also noted after sun exposure in a few subjects receiving the 200 mg bid dose or placebo. The plasma levels of TMC435350 detected 24 hours after the Day 5 dosing were substantially in excess of the replicon EC50 value for all doses.
Conclusions: The data suggest that TMC435350 is safe when given as single doses up to 600 mg and 5 days of dosing up to 400 mg qd. The compound will be further investigated following once-daily administration in HCV patients.
In Vitro Activity And Preclinical Pharmacokinetics Of The HCV Protease Inhibitor, TMC435350
K. Simmen1; O. Lenz1; T. Lin1; G. Fanning1; P. Raboisson1; H. de Kock1; G. van 't Klooster1; A. Rosenquist 2; M. Edlund2; M. Nilsson2; L. Vrang2; B. Samuelsson2
1. Tibotec Pharmaceuticals Ltd., Eastgate Village, Little Island, Cork, Ireland.
2. Medivir AB, Box 1086, SE-141 22 Huddinge, Sweden.
Background: As a class, HCV NS3/4A protease inhibitors have shown promise in clinical trials for the treatment of chronic hepatitis C virus infection. TMC435350 is a novel and potent macrocyclic NS3/4A protease inhibitor. To further assess the potential of TMC435350, we characterized the in vitro activity of TMC435350 alone or in combination with different classes of HCV inhibitors. The plasma pharmacokinetics and tissue distribution were also studied in vivo.
Methods: The effect on HCV RNA level and the emergence of drug-resistant colonies was analyzed in the replicon model with TMC435350 alone, or in combination with interferon alpha, ribavirin, and different HCV polymerase inhibitors. Pharmacokinetic profiles were evaluated following single or repeated dosing in rats. The tissue distribution of TMC435350 was studied in male rats at time points from 0.5 up to 31 hours after a single oral dose of 40 mg/kg.
Results: In biochemical HCV NS3/4a protease assays, TMC435350 exhibited Ki values <0.1nM for subtypes 1a (H77) and 1b (con1) enzymes. TMC435350 was found in the subgenomic genotype1b replicon model to have an EC50 of 8nM and a selectivity index (SI) of > 1000. The combination of TMC435350 with different classes of HCV inhibitors further increases its activity in reducing HCV RNA in an additive to synergistic manner, and further reduced the emergence of resistant replicon colonies.
After single oral administration of a PEG400-based solution of TMC435350 at 40 mg/kg the mean peak plasma concentration (Cmax) was 1430ng/ml and was observed at two hours post-dose (Tmax). The absolute bioavailability of TMC435350 was calculated at 44% after single oral administration of a 40 mg/kg dose.
TMC435350 was found to be extensively distributed to the liver, small- and large intestines (tissue/plasma ratios >35). Concentrations in other organs were similar to plasma. Notably, TMC435350 was still quantifiable in the liver tissue up to 31 hours post-dosing.
Conclusions: TMC435350 is a novel potent and specific HCV protease inhibitor, with good oral bioavailabilty and a favorable liver distribution. In addition, in vitro studies support the potential use of TMC435350 in combination with other HCV inhibitors.