The pharmacokinetics of lamivudine in healthy Chinese subjects

Abstract

Aims

The purpose of this study was to investigate the pharmacokinetics of daily oral doses of lamivudine administered to healthy Chinese subjects for 1 week.

Methods

Twenty-four subjects were enrolled, 12 males and 12 females, all between the ages of 18 and 40 years. After an overnight fast, all subjects received a single oral dose of 100 mg lamivudine. Blood was obtained before lamivudine administration and at regular intervals to 24 h post dose. Subsequent doses were given once daily for a total of 7 days. On the last day another full pharmacokinetic profile was obtained to 24 h postdose. Timed urine collections were performed for all subjects on day 1 only. Pharmacokinetic parameters were calculated by using standard non compartmental techniques.

Results

Lamivudine was well absorbed in all subjects (t_max 1 h). On day 1 and day 7 the overall geometric mean C_max was 1304 and 1385 ng ml⁻¹, and AUC(0,24h) was 4357 and 4353 ng ml⁻¹ h, respectively. On average 78% of the lamivudine dose was recovered in urine as parent compound. Pharmacokinetic parameters were very similar between male and female subjects, between day 1 and day 7 and in comparison with data obtained in many other pharmacokinetic studies.

Conclusions

This study demonstrated that the pharmacokinetics of lamivudine are essentially identical between Chinese and Caucasian subjects, and between males and females. It confirms 100 mg lamivudine is an appropriate dose for use in Chinese patients, providing adequate exposure for optimal antiviral effect.

Introduction

Lamivudine, 2′3′-dideoxynucleoside 3′-thiacytidine (also known as 3TC, GR109714X), is effective against human immunodeficiency virus (HIV) and chronic hepatitis B virus (HBV). It has two chiral centres, is the (−) enantiomer of a racemic mixture and undergoes intracellular anabolism to the active triphosphate moiety for antiviral effect. It has comparable in vitro potency to other dideoxynucleosides [1].

Pharmacokinetic studies in asymptomatic HIV-infected subjects and normal healthy volunteers of mixed racial origin (Caucasian, Negroid, Asian) have shown that lamivudine is rapidly absorbed following an oral dose, has good (>80%) absolute bioavailability, exhibits linear kinetics and is renally cleared with an elimination half-life of the order of 5–7 h [2]. Following oral administration ≈70% of the total dose is excreted unchanged in the urine and only 5–10% undergoes hepatic metabolism to form a trans-sulphoxide metabolite which is then also renally eliminated. Renal dysfunction has significant effects on the pharmacokinetics of lamivudine [3, 4] whereas hepatic dysfunction has no effect [5].

Lamivudine has now been proven highly effective in the treatment of chronic hepatitis B infection in Chinese patients [6]. As part of the clinical evaluation of lamivudine in China, the present study was carried out to evaluate the pharmacokinetics in Chinese subjects to see if there were differences in exposure (with implications for both efficacy and safety) between Caucasian and Chinese patients. We aimed to confirm that minimally effective AUC and trough data were achieved and to link these data with data in other pharmacokinetic studies of lamivudine.

Methods

Subject population

Twelve male and female subjects (24 in total) were included following regular medical assessments including laboratory safety screens. Subjects did not smoke throughout the study period, were negative for HIV, HCV or drugs of abuse (including alcohol) and took no concomitant medication. All subjects gave written informed consent and the protocol was approved by Peking Union Medical College (PUMC) Hospital Ethics Review Committee.

Study design

This was an open study and was performed at the Clinical Pharmacology Research Centre, PUMC Hospital, Beijing, China. Each subject received a single, daily, oral 100 mg tablet of lamivudine for 7 days. On the pharmacokinetic study days (Days 1 and 7), all subjects underwent an overnight fast and were not allowed food until 4 h postdose.

On days 1 and 7, blood samples (6 ml) providing serum for lamivudine assay were taken; predose (within 5 min prior to last dose on day 7) and at 30, 45 min, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h postdose. Timed urine collections were performed at predose and 0–12, 12–24 h postdose on day 1 only. Serum and urine samples were analysed for lamivudine by a standard h.p.l.c. method using u.v. detection [7] that was validated at PUMC Hospital.

Safety

Safety was evaluated by monitoring adverse events and vital signs, physical examinations, clinical laboratory tests and electrocardiograms. Each subject was questioned periodically throughout the study regarding adverse effects.

Assay performance

The published lamivudine h.p.l.c. assay [7] was developed and adapted for use locally in China at PUMC, with the principal difference being that instead of robotic extraction, samples were processed manually using a vacuum box. Intra-day and interday variability (CV) were 1.4–8.5% and 6.0–11.2%, respectively. Lower limits of detection were 5 ng ml⁻¹ for serum and 1 μg ml⁻¹ for urine.

Pharmacokinetic analysis

The maximum drug concentration in serum (C_max) and the time to C_max (t_max) were obtained directly from the concentration-time data. The terminal rate constant, determined by linear least squares regression (λ_z) and corresponding terminal serum half-life (t_1/2,z) were calculated. Three points were typically included in the terminal phase, confirmed by visual inspection. Non-compartmental pharmacokinetic analysis (using WinNonlin v1.0, SCI software, Cary, North Carolina) was used to calculate parameter estimates. AUC(0,24h), defined as the area under the time-concentration curve to 24 h, was calculated using the trapezoidal rule. For day 7 the accumulation ratio R was calculated (R = AUCτ/AUCt, where t = 24 h and τ = dosing interval at steady state, i.e. 24 h). Apparent oral clearance (CL/F) was determined using Dose/AUC(0,∞) on day 1 and Dose/AUC(0,24h) on day 7. The amount of lamivudine (Ae) recovered in the urine was used to calculate renal clearance (CLr) where the amount excreted to time t (where t is the last time of complete collection) was divided by the area under the curve of serum lamivudine concentration over the same time.

Statistical analysis

Pharmacokinetic parameters are presented as the geometric mean and 95% confidence intervals (95%CI) for each of the following groups: males, females and combined as an overall statistic as well as between day 1 and day 7. The parameter estimates were compared between day 7 and day 1 using analysis of variance (anova) adjusting for gender and day to provide point estimates and 95%CI (with associated P values) of the day 7/day 1 comparison. For comparisons of parameters by the covariates male/female a separate anova for day 1 and day 7 data was used—analyses not presented.

Results

The subjects were well matched for age between males and females (mean age 26 and 24 years for males and females, respectively). On average the females in this study were 25% lighter (mean 50.5 vs 65.9 kg) and 7% shorter than the males.

Serum pharmacokinetics

Day 1 and day 7 pharmacokinetic estimates were essentially identical with no statistically significant differences between parameters after single or repeated doses (Table 1). No significant accumulation (R = 1.01) was seen by comparing AUC(0,24h) values on days 1 and 7. Likewise, comparing C_max values suggested minimal accumulation of around 6%. Statistical comparison of the key parameters of C_max, AUC(0,24h), t_1/2,z, CL/F and CLr by gender again revealed no statistically significant differences with the exception of C_max on day 1 (P = 0.036). Although not significant, it was apparent that there was a slightly higher AUC (≈10%), C_max and consequently reduced CL/F in females.

Table 1.

Lamivudine pharmacokinetic parameters (geometric mean and 95%CI) in healthy Chinese subjects.

Figure 1 shows the mean (±s.d.) concentration-time profiles for all subjects on Day 1 and Day 7. Lamivudine concentrations rose quickly in all subjects, reaching a mean C_max of about 1.4 μg ml⁻¹ at ≈1 h and decayed in an apparent biexponential fashion. Overall geometric mean AUC(0–24 h) was 4357 and 4353 ng ml⁻¹ h (4.4 μg ml⁻¹ h) on Days 1 and 7, respectively, with resulting CL/F values of 22–23 l h⁻¹ (about 0.3 l h⁻¹ kg⁻¹). Trough concentrations (24 h postdose) as measured on Day 1 and 7 were 12±6 and 20±13 ng ml⁻¹, respectively. Determination of the rate constant in the terminal slope yielded t_1/2,z values of, on average, 6–7 h.

Figure 1.

Mean (±s.d.) lamivudine concentrations following oral administration to healthy Chinese subjects on day 1 (□) and day 7 (•).

Urine pharmacokinetics

The pattern of recovery was essentially identical between males and females with the vast majority of excreted lamivudine being recovered in the first 12 h (75%) with a further mean 3.8% being recovered in the 12–24 h collection. The mean total recovery was 78.8% in 24 h. Renal clearance was again similar between males and females with a combined value for all subjects of 18.5±3.6 ml min⁻¹.

Discussion

Lamivudine pharmacokinetic parameter estimates were obtained in healthy Chinese subjects and are comparable with those obtained in many other pharmacokinetic studies carried out in Caucasians [2].

The average systemic exposure (AUC) following a 100 mg tablet dose was shown to be 4.4 μg ml⁻¹ h in this study which is identical to steady-state AUC values seen in HBV infected Caucasian subjects [2] where the AUC is known to correlate with maximum antiviral response. Likewise trough values are maintained above the IC₅₀ value established in vitro [2]. The degree of exposure (both C_max and AUC) was very similar in males or females although slightly higher estimates for exposure in females is likely to be a result of increased dose (in mg kg⁻¹) as the female subjects were on average 25% lighter than their male counterparts.

Consistent with once-daily dosing and the observed half-life (6–7 h) seen in this study and many others, there is a very small degree of accumulation which does not cause toxicological or safety concerns.

The majority of an oral dose (about 80%) is recovered in 0–24 h urine. These data agree well with an absolute bioavailability value established in Caucasian subjects of 85% and imply that there is very little metabolism of lamivudine in Chinese subjects.

In conclusion, the extent of exposure and overall similarity of pharmacokinetic profile in Chinese subjects shows that the 100 mg lamivudine dose is also appropriate for use in patients in South-east Asia.