Pharmacokinetics in Adults
The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects.
Absorption and Bioavailability:
Following single oral doses of 100 mg, the peak serum lamivudine concentration (C
max) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 ± 0.56 mcg per mL and 1.05 ± 0.32 mcg per mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC[0-24 h]) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 mcg•hour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (C
max), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably.
After oral administration of lamivudine once daily to HBV-infected adults, the AUC and C
max increased in proportion to dose over the range from 5 mg to 600 mg once daily.
Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the 10-mg per mL oral solution.
Effects of Food on Oral Absorption:
Lamivudine tablets (HBV) may be administered with or without food. The 100-mg tablet was administered orally to 24 healthy subjects on 2 occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states.
Distribution:
The apparent volume of distribution after IV administration of lamivudine to 20 HIV-1-infected subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.
Binding of lamivudine to human plasma proteins is less than 36%.
In vitrostudies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.
Metabolism:
Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Serum concentrations of this metabolite have not been determined. Lamivudine is not significantly metabolized by cytochrome P450 enzymes.
Elimination:
The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.
In most single-dose trials with plasma sampling for up to 48 or 72 hours after dosing, the observed mean elimination half-life (t½) ranged from 13 to 19 hours. In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg per kg.
Specific Populations
Patients with Renal Impairment
The pharmacokinetic properties of lamivudine have been determined in healthy adults and in adults with impaired renal function, with and without hemodialysis (Table 5).
Table 5. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Oral Dose of Lamivudine in Adults with Varying Degrees of Renal Function
|
Parameter | Creatinine Clearance Criterion
(Number of Subjects) |
≥
80 mL/min
(n = 9) | 20-59 mL/min
(n = 8) | <20 mL/min
(n = 6) |
| Creatinine clearance (mL/min) | 97
(range 82-117)
| 39
(range 25-49)
| 15
(range 13-19)
|
| C
max (mcg/mL)
| 1.31 ± 0.35 | 1.85 ± 0.40 | 1.55 ± 0.31 |
| AUC (mcg•h/mL) | 5.28 ± 1.01 | 14.67 ± 3.74 | 27.33 ± 6.56 |
| Cl/F (mL/min) | 326.4 ± 63.8 | 120.1 ± 29.5 | 64.5 ± 18.3 |
T
max was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment
[see Dosage and Administration (
2.4)]
.
Hemodialysis increases lamivudine clearance from a mean of 64 to 88 mL per min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.
The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B is not known.
Patients with Hepatic Impairment
The pharmacokinetic properties of lamivudine in adults with hepatic impairment are shown in Table 6. Subjects were stratified by severity of hepatic impairment.
Table 6. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Dose of Lamivudine in Adults with Normal or Impaired Hepatic Function
|
Parameter |
Normal
(n = 8) | Impairment
a |
Moderate
(n = 8) | Severe
(n = 8) |
| C
max (mcg/mL)
| 0.92 ± 0.31 | 1.06 ± 0.58 | 1.08 ± 0.27 |
| AUC (mcg•h/mL) | 3.96 ± 0.58 | 3.97 ± 1.36 | 4.30 ± 0.63 |
| T
max (h)
| 1.3 ± 0.8 | 1.4 ± 0.8 | 1.4 ± 1.2 |
| Cl/F (mL/min) | 424.7 ± 61.9 | 456.9 ± 129.8 | 395.2 ± 51.8 |
| Clr (mL/min) | 279.2 ± 79.2 | 323.5 ± 100.9 | 216.1 ± 58.0 |
a Hepatic impairment assessed by aminopyrine breath test.
Pharmacokinetic parameters were not altered by diminishing hepatic impairment. Safety and efficacy of lamivudine tablets (HBV) have not been established in the presence of decompensated liver disease
[see Indications and Usage (
1)]
.
Patients Post-Hepatic Transplant
Fourteen HBV-infected adult subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, 2 weeks after 100-mg once-daily dosing (pre-transplant), and 3 months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal impairment; consequently, transplant patients with renal impairment had generally higher exposure than patients with normal renal function. Safety and efficacy of lamivudine tablets (HBV) have not been established in this population
[see Indications and Usage (
1)]
.
Pregnant Women
The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers were similar at similar doses. Lamivudine pharmacokinetics were studied in 36 pregnant women with HIV during 2 clinical trials conducted in South Africa (3 to 6 times the recommended daily dosage for HBV). Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.
Pediatric Patients
Lamivudine pharmacokinetics were evaluated in a 28-day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged 2 to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, 3 mg per kg once daily, 1.5 mg per kg twice daily, or 4 mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine T
max was 0.5 to 1 hour. In general, both C
max and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age 2 and declined from 2 to 12 years, where values were then similar to those seen in adults. A dose of 3 mg per kg given once daily produced a steady-state lamivudine AUC (mean 5,953 ng•hour per mL ± 1,562 SD) similar to that associated with a dose of 100 mg per day in adults.
Geriatric Patients
The pharmacokinetics of lamivudine after administration of lamivudine tablets (HBV) to subjects over 65 years have not been studied
[see Use in Specific Populations (
8.5)]
.
Male and Female Patients
There are no significant or clinically relevant gender differences in lamivudine pharmacokinetics.
Racial Groups
There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics.
Drug Interaction Studies
Effect of Lamivudine on the Pharmacokinetics of Other Agents
Based on
in vitrostudy results, lamivudine at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2 or OCT3.
Effect of Other Agents on the Pharmacokinetics of Lamivudine
Lamivudine is a substrate of MATE1, MATE2-K, and OCT2
in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant, and no dose adjustment of lamivudine is needed.
Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.
Interferon Alfa
There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.
Ribavirin
In vitrodata indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.
Sorbitol (Excipient)
Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC
(0-24), 14%, 32%, and 36% in the AUC
(∞), and 28%, 52%, and 55% in the C
maxof lamivudine.
Trimethoprim/Sulfamethoxazole
Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC
∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine.
Zidovudine
No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).
