Telbivudine clinical pharmacology

# Clinical Pharmacology

## Pharmacodynamics
In a randomized, partially single-blinded, placebo and active-controlled, four-period crossover trial, 53 healthy subjects were administered Tyzeka 600 mg, a supratherapeutic Tyzeka 1800 mg dose, placebo, and moxifloxacin 400 mg. After 7 days of dosing, Tyzeka did not prolong the QT interval. The maximum placebo-adjusted mean (upper 1-side 95% CI) change from baseline in QTcF on day 7 were 3.4 msec (5.9 msec) for the 600 mg and 4.4 msec (6.9 msec) for the 1800 mg dosing regimens.

## Pharmacokinetics in Adults
The single- and multiple-dose pharmacokinetics of Tyzeka were evaluated in healthy subjects and in patients with chronic hepatitis B. Tyzeka pharmacokinetics are similar between both populations.

### Absorption and Bioavailability
Following oral administration of Tyzeka 600 mg once-daily in healthy subjects (n=12), steady state peak plasma concentration (Cmax) was 3.69  1.25 microgram per mL (mean  SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1  7.2 microgram - hour per mL (mean  SD), and trough plasma concentrations (Ctrough) were approximately 0.2-0.3 microgram per mL. Steady state was achieved after approximately 5 to 7 days of once-daily administration with ~1.5-fold accumulation, suggesting an effective half-life of ~15 hours.

### Effects of Food on Oral Absorption
Tyzeka absorption and exposure were unaffected when a single 600 mg dose was administered with a high-fat (~55 g), high-calorie (~950 kcal) meal. Tyzeka may be taken with or without food.

### Distribution
In vitro binding of telbivudine to human plasma proteins is low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues. Telbivudine was equally partitioned between plasma and blood cells.

### Metabolism and Elimination
No metabolites of telbivudine were detected following administration of -telbivudine in humans. Telbivudine is not a substrate, or inhibitor of the cytochrome P450 (CYP450) enzyme system.
After reaching the peak concentration, plasma concentrations of Tyzeka declined in a biexponential manner with a terminal elimination half-life (T1/2) of 40-49 hours. Tyzeka is eliminated primarily by urinary excretion of unchanged drug. The renal clearance of Tyzeka approaches normal glomerular filtration rate suggesting that passive diffusion is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of Tyzeka. Because renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing hemodialysis require a dose regimen adjustment .

### Special Populations
Gender: There are no significant gender-related differences in Tyzeka pharmacokinetics.
Race: There are no significant race-related differences in Tyzeka pharmacokinetics.
Pediatrics and Geriatrics: Pharmacokinetic studies have not been conducted in children or elderly subjects.
Renal Impairment: Single-dose pharmacokinetics of Tyzeka have been evaluated in subjects (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 4, adjustment of the dose regimen for Tyzeka is recommended in patients with creatinine clearance of less than 50 mL per min .
Renally Impaired Subjects on Hemodialysis: Hemodialysis (up to 4 hours) reduces systemic Tyzeka exposure by approximately 23%. Following dose regimen adjustment for creatinine clearance , no additional dose modification is necessary during routine hemodialysis. When administered on hemodialysis days, Tyzeka should be administered after hemodialysis.
Hepatic Impairment: The pharmacokinetics of Tyzeka following a single 600 mg dose have been studied in subjects (without chronic hepatitis B) with various degrees of hepatic impairment. There were no changes in Tyzeka pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment.

### Drug Interactions
Drug-drug interaction studies show that lamivudine, adefovir dipivoxil, cyclosporine, pegylated interferon alfa-2a, and tenofovir disoproxil fumarate do not alter Tyzeka pharmacokinetics. In addition, Tyzeka does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, cyclosporine, or tenofovir disoproxil fumarate. No definitive conclusion could be drawn regarding the effects of Tyzeka on the pharmacokinetics of pegylated interferon alfa-2a due to the high inter-individual variability of pegylated interferon alfa-2a concentrations. At concentrations up to 12 times that in humans, telbivudine did not inhibit in vitro metabolism mediated by any of the following human hepatic microsomal cytochrome P450 (CYP) isoenzymes known to be involved in human medicinal product metabolism: 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4. Based on the above results and the known elimination pathway of telbivudine, the potential for CYP450-mediated interactions involving telbivudine with other medicinal products is low.