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Current therapy for chronic hepatitis B is suboptimal as a result of limited durable response rates, cumulative viral resistance, and/or poor tolerability. Telbivudine has potent antiviral activity against hepatitis B virus (HBV) in vitro and in the woodchuck model and has a promising preclinical safety profile. In this first clinical study of telbivudine, safety, antiviral activity, and pharmacokinetics were assessed in 43 adults with hepatitis B e antigen-positive chronic hepatitis B. This placebo-controlled dose-escalation trial investigated 6 telbivudine daily dosing levels (25, 50, 100, 200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12 weeks' follow-up. Serum HBV DNA levels were monitored via quantitative polymerase chain reaction. The results indicate that telbivudine was well tolerated at all dosing levels, with no dose-related or treatmentrelated clinical or laboratory adverse events. telbivudine plasma pharmacokinetics were doseproportional within the studied dose range. Marked dose-related antiviral activity was evident, with a maximum at telbivudine doses of 400 mg/d or more. In the 800mg/d cohort, the mean HBV DNA reduction was 3.75 log 10 copies/mL at week 4, comprising a 99.98% reduction in serum viral load. Correspondingly, posttreatment return of viral load was slowest in the highdose groups. Viral dynamic analyses suggested a high degree of efficiency of inhibition of HBV replication by telbivudine and helped refine selection of the optimal dose. In conclusion, these results support expanded clinical studies of this new agent for the treatment of hepatitis B.

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T max to the maximum plasma concentration (C max ) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C max s and the areas under the plasma concentration-time curve from time zero to time t (AUC 0-t s) increased proportionally with dose. At steady-state, the values of C max and AUC 0-t were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C max and from 1.40 to 1.70 for AUC 0-t . While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C max and AUC 0-t . In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.Telbivudine (␤-L-2Ј-deoxythymidine) is an L-configured nucleoside with potent and specific activities against hepatitis B virus (HBV) and other hepadnaviruses and no appreciable activity against human immunodeficiency virus or other viruses (3). The in vitro median effective concentration of telbivudine for reducing extracellular DNA levels in HBV-expressing hepatoma cell line 2.2.15 was 0.19 M (ϳ0.05 g/ml). In woodchucks chronically infected with woodchuck HBV, up to 28 days of telbivudine treatment produced consistent, multilog reductions in circulating serum woodchuck HBV DNA levels (3).In vitro toxicological assessments produced no adverse findings (1-3). The 50% cytotoxic concentration of telbivudine in 2.2.15 cells was Ͼ2,00 M (ϳ500 g/ml), indicating that it has an excellent therapeutic index in cell culture (3). Other in vitro results suggested that telbivudine is unlikely to be associated with hematologic or mitochondrial toxicities, peripheral neuropathy, or myopathy (3). Mutagenic test results were negative (1).Acute and subchronic toxicology studies did not identify any preclinical safety issues for telbivudine. In acute and subchronic (28-day) toxicity studies conducted with rats ...

Factors associated with changes in the smoking behaviour of approximately 6000 schoolchildren (two cohorts aged between 10 and 12 years in 1979) over 12 months are described. They were measured twice as part of a randomized controlled trial of a smoking prevention programme. Four groups were defined: (a) those who became smokers (adopters); (b) those who remained non-smokers; (c) those who became non-smokers (quitters), and, (d) those who remained smokers. Personal and social variables were ordered using a logistic regression model according to the strength of their association with adopting and quitting smoking. Factors distinguishing adopters from children who remained nonsmokers were, being a member of the older cohort, having friends who smoke, having siblings who smoke, approving of cigarette advertising and having a relatively large amount of money to spend each week. Factors distinguishing quitters from children who continued to smoke were, having siblings who do not smoke, being a member of the younger cohort, disapproving of cigarette advertising and having a relatively small amount of money to spend each week. Initial attitude scores were indicative of future smoking behaviour and where smoking behaviour changed, attitudes also changed so that the two remained congruent. The younger cohort improved their knowledge of smoking hazards over the year irrespective of their smoking behaviour. The older cohort showed significant differences in knowledge which were dependent upon smoking category, with 1980 smokers having lower knowledge scores than non-smokers and showing an apparent decrement in their previous knowledge.