Clinical pharmacokinetics of lamivudine

Lamivudine (3TC), the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue used in combination with other agents in the tr eatment of human immunodeficiency virus type 1 (HIV-1) infection and as mon otherapy in the treatment of hepatitis B virus (HBV) infection. Lamivudine undergoes anabolic phosphorylation by intracellular kinases to form lamivud ine 5'-triphosphate, the active anabolite which prevents HIV-1 and HBV repl ication by competitively inhibiting viral reverse transcriptase and termina ting proviral DNA chain extension. The pharmacokinetics of lamivudine are similar in patients with HIV-1 or HB V infection, and healthy volunteers. The drug is rapidly absorbed after ora l administration, with maximum serum concentrations usually attained 0.5 to 1.5 hours after the dose. The absolute bioavailability is approximately 82 and 68% in adults and children, respectively. Lamivudine systemic exposure , as measured by the area under the serum drug concentration-time curve (AU C), is not altered when it is administered with food. Lamivudine is widely distributed into total body fluid, the mean apparent v olume of distribution (Vd) being approximately 1.3 L/kg following intraveno us administration. In pregnant women, lamivudine concentrations in maternal serum, amniotic fluid, umbilical cord and neonatal serum are comparable, i ndicating that the drug diffuses freely across the placenta. In postpartum women lamivudine is secreted into breast milk. The concentration of lamivud ine in cerebrospinal fluid (CSF) is low to modest, being 4 to 8% of serum c oncentrations in adults and 9 to 17% of serum concentrations in children me asured at 2 to 3 hours after the dose. In patients with normal renal functi on, about 5% of the parent compound is metabolised to the trans-sulphoxide metabolite, which is pharmacologically inactive. In patients with renal impairment, the amount of trans-sulphoxide metabolit e recovered in the urine increases, presumably as a function of the decreas ed lamivudine elimination. As approximately 70% of an oral dose is eliminat ed renally as unchanged drug, the dose needs to be reduced in patients with renal insufficiency. Hepatic impairment does not affect the pharmacokineti cs of lamivudine. Systemic clearance following single intravenous doses ave rages 20 to 25 L/h (approximately 0.3 L/h/kg). The dominant elimination hal f-life of lamivudine is approximately 5 to 7 hours, and the in vitro intrac ellular half-life of its active 5'-triphosphate anabolite is 10.5 to 15.5 h ours and 17 to 19 hours in HIV-1 and HBV cell lines, respectively. Drug interaction studies have shown that trimethoprim increases the AUC and decreases the renal clearance of lamivudine, although lamivudine does not affect the disposition of trimethoprim. Other studies have demonstrated no significant interaction between lamivudine and zidovudine or between lamivu dine and interferon-alpha-2b. There is limited potential for drug-drug inte ractions with compounds that are metabolised and/or highly protein bound.