Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: pharmacodynamic implications.
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.
Zhou
Xiao-Jian
XJ
Idenix Pharmaceuticals Inc., 60 Hampshire Street, Cambridge, Massachusetts 02139, USA. zhou.xiao-jian@idenix.com
Lim
Seng-Gee
SG
Lloyd
Deborah M
DM
Chao
George C
GC
Brown
Nathaniel A
NA
Lai
Ching-Lung
CL
D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D044466:Asian People; D002681:China / Q000208:ethnology; D015331:Cohort Studies; D004279:DNA, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006515:Hepatitis B virus / Q000235:genetics / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D009705:Nucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000077712:Telbivudine; D013936:Thymidine / Q000031:analogs & derivatives; D013997:Time Factors; D016896:Treatment Outcome
D000998:Antiviral Agents; D004279:DNA, Viral; D009705:Nucleosides; D011744:Pyrimidinones; D000077712:Telbivudine; D013936:Thymidine