ABSTRACT
<p><b>OBJECTIVE</b>To evaluate the pharmacokinetic profile of telbivudine in healthy Chinese subjects after oral administration of single and multiple doses.</p><p><b>METHODS</b>Forty-two healthy adult male and female subjects 18-40 years of age were randomized into four telbivudine dosing groups of 200 mg, 400 mg, 600 mg and 800 mg. Subjects in the 600 mg group received both a single dose and once daily multiple doses for 8 consecutive days. Telbivudine concentrations in plasma and urine samples collected at different time points before and after the drug administration were measured using HPLC-MS/MS. Pharmacokinetic parameters were calculated by using the non-compartmental approach.</p><p><b>RESULTS</b>After a single dose of 200 mg, 400 mg, 600 mg and 800 mg, tmax (median) were 2.50, 2.00, 2.00 and 2.50 hours respectively; t1/2 were (43.3 +/- 15.2) h, (49.1 +/- 14.4) h, (39.4 +/- 12.1) h and (46.7 +/- 20.8) h respectively; Cmax were (1,753.2 +/- 389.0) ng/ml, (2,586.7 +/- 871.4) ng/ml, (3,703.6 +/- 1,219.0) ng/ml and (3454.6 +/- 953.9) ng/ml respectively; AUC(0-infinity) were (12,843.2 +/- 2,925.6) ng.h(-1).ml(-1), (22,948.9 +/- 5,721.0) ng.h(-1)/ml(-1), (26,440.5 +/- 8,938.1) ng.h(-1).ml(-1) and (28, 820.9 +/- 7 912.9) ng.h(-1).ml(-1) respectively, and CL(R) (600 mg) was (6,545.6 +/- 1 504.4) ml/h. The AUCss from multiple doses was (1,088.5 +/- 299.8) ng/ml; Cmax and AUC accumulation ratio were 1.02 +/- 0.21 and 1.23 +/- 0.26 respectively, which implicated moderated accumulation.</p><p><b>CONCLUSION</b>Pharmacokinetic parameters of telbivudine in Chinese healthy subjects were determined.</p>
Subject(s)
Adolescent , Adult , Female , Humans , Male , Young Adult , Dose-Response Relationship, Drug , Nucleosides , Pharmacokinetics , Pyrimidinones , Pharmacokinetics , ThymidineABSTRACT
Activation of hepatic stellate cells is the earliest step in fibrogeneesis. Alpha-smooth muscle acting [alpha-SMA], expressed by activated hepatic sallate cells, and C-terminal procollagen alpha [III] propeptide [PIIICP] are early markers of fibrogenesis and should precede fibrosis. ASD: Determine if suppression of hepatitis B virus replication with lamivudine would decrease fibrogenesis as measured by immunohistochemical markers. Paried liver biopsies from patients with hepatitis B before and after therapy with lamivudine [n=47] or placebo [n=33] were studied. Alpha-SMA and PIIICP were detected in paraffin-embedded tissue by immunohistochemistry and quantified in a blinded manner by video imaging analysis. Liver biopsies from patients treated with lamivudine showed a significant decrease in alpha-SMA expression [1.06 +/- 0.23 vs. 0.58 +/- 0.11, pre vs. post, P< 0.05]. Placebo recipients had increased levels of alpha -SMA 0.82 +/- 0.14 vs. 1.32 +/- 0.21, P< 0.05]. PIICP was similarly decreased after lamivudine. Among subjects whose Histological Activity Index fibrosis score was unchanged or worsened, the mean changes in alpha-SMA expression was significantly decreased in the lamivudine group compared with placebo. Lamivudine decreased markers of hepatic satellite cell activation and collagen synthesis. Immunohistochemical techniques are sensitive for assessing fibro-genesis and will be useful in trials of antiviral and antifibrotic agents