This dose-escalation study evaluated the safety, pharmacokinetics, and antiviral activity of telbivudine in HBV-infected patients during 4 weeks of oral, once-daily treatment. The results of studies of the safety and antiviral activity of telbivudine, detailed elsewhere (6
), demonstrated that telbivudine is well tolerated without clinically significant adverse events throughout treatment and across all dose levels from 25 to 800 mg/day. Compared to placebo, there were no significant changes in hematologic values and there were no significant abnormalities in clinical laboratory data throughout the trial. Clinical adverse events were all mild, and there was no apparent dose-related or treatment-related pattern in the incidence of adverse events (6
). A profound, dose-related virologic response was observed with all doses tested, with serum HBV DNA reductions of 3.5 to 4.0 log10
achieved with doses of 400 to 800 mg/day by the end of 4 weeks of treatment.
The pharmacokinetics of telbivudine were evaluated over a period of 8 h in this first clinical trial conducted with HBV-infected patients. While this sampling interval proved to be inadequate for a full pharmacokinetic characterization of telbivudine, it did capture essential pharmacokinetic parameters, such as Cmax, Tmax, and a significant portion of AUC (approximately 60%, based on model-predicted steady-state exposure), therefore allowing assessment of the dose proportionality and the dose-response relationship. The study results indicated that telbivudine is rapidly absorbed after oral dosing, with Cmax reached within 1 to 3 h. Pharmacokinetic parameters of drug exposure, including Cmax and AUC0-t, are dose proportional over the dose range studied. While the absolute oral bioavailability of telbivudine remains unknown, the dose-proportional behavior of telbivudine plasma kinetics indicates consistent absorption of the drug across all dose cohorts. In this study, telbivudine was administered with no restriction on food intake. A food-effect study later showed that a high-calorie, high-fat meal had no effect on the pharmacokinetics of telbivudine (unpublished data).
Over the 8-h period, telbivudine exhibits an apparent single-phase decline, with a short observed t1/2
. This phase later proved to represent an early distribution-elimination phase, as the presence of a second, slower elimination phase was evidenced by the substantial steady-state levels of telbivudine that remained measurable 24 h after dosing (predose trough levels; Fig. and Table ) in cohorts receiving ≥100 mg/day. A modeling approach was used to characterize this unobserved second elimination phase by flipping the steady-state predose data over to 24 h. Although the lack of datum points between 8 and 24 h prevents the model from generating high-precision estimates of pharmacokinetic parameters, the analysis nevertheless identified the second elimination phase, which had a mean estimated terminal half-life in the range of 29.5 to 41.3 h. The model-predicted values of the AUC from 0 to 8 h were in excellent agreement with the experimental data, indicative of the adequacy of the fitting results. Recent studies with healthy volunteers with intensive sampling up to 168 h postdosing confirmed the existence of this second elimination phase (unpublished data). The second phase starts approximately 16 to 24 h after dosing, with a long observed terminal-phase t1/2
of approximately 40 h. This long plasma terminal-phase t1/2
of telbivudine is consistent with the long intracellular t1/2
(14 h) of
the active triphosphate form of the drug observed in HepG2 cells (5
). The long half-life of plasma telbivudine and its intracellular triphosphate reflect a sustained exposure of the drug within HBV-infected cells and support the use of once-daily dosing.
Following daily oral dosing, telbivudine accumulated slightly, as evidenced by approximately 15 to 50% increases in Cmax
at steady state, as well as substantial steady-state predose levels. Of note, the 800-mg cohort exhibited a higher than expected mean predose trough level (2.65 μg/ml) associated with a large SD (2.01 μg/ml). This was apparently caused by the fact that two patients in this group took the steady-state intensive pharmacokinetic dose in less than 12 h of the time that they took the previous day's dose. Unpublished results from several pharmacokinetic studies with healthy volunteers with sampling beyond 24 h showed an accumulation factor of 1.2 to 1.6, based on the ratio of the steady-state AUC from 0 to 24 h to the single-dose AUC from 0 to 24 h, therefore confirming the findings of the present study. The results from those studies further demonstrated that the drug does not accumulate further once steady state is achieved after 5 to 7 days of once-daily treatment (8
; unpublished data).
The dose-related virologic response (6
) prompted a more detailed evaluation of the telbivudine pharmacokinetic-pharmacodynamic relationship. An Emax
model was successfully fitted to the individual serum HBV DNA reduction at week 4 versus the pharmacokinetic exposure (Cmax
) data. The dose-response relationship was more pronounced at steady state, suggesting the importance of maintaining continuous drug exposure, which is ensured by good adherence to treatment, to achieving better antiviral activity. Consistent with the dose-proportional pharmacokinetics of telbivudine, a more profound viral load reduction was observed in patients enrolled in the higher-dose groups. The Emax
model analyses further indicated that a nearly maximal virologic response was obtained with the plasma exposure achieved with 400- to 800-mg telbivudine doses, and only a minimal incremental virologic response could be gained even with substantially higher doses. Therefore, the results of this exposure parameter-based pharmacokinetic-pharmacodynamic analysis are in full agreement with those of a previous dose-based Emax
analysis, which demonstrated that a nearly maximal reduction of circulating serum HBV DNA (~3.5 to 4.0 log10
) was obtained by week 4 with telbivudine doses between 400 to 800 mg. Based on these findings, telbivudine doses appropriate for further clinical evaluation were selected, and doses higher than 800 mg/day were not evaluated (6
), despite the excellent safety profile and dose-proportional pharmacokinetics.
In summary, this clinical evaluation demonstrates that telbivudine exhibits dose-proportional pharmacokinetics and exposure-dependent pharmacodynamics and is well tolerated by patients with chronic HBV infection (6
). This favorable profile of telbivudine supports ongoing phase III trials for evaluation of the safety and efficacy of longer-term treatment with telbivudine in patients with chronic hepatitis B.