Clinical Pharmacokinetics

, Volume 36, Issue 1, pp 41–66 | Cite as

Clinical Pharmacokinetics of Lamivudine

  • Mark A. Johnson
  • Katy H. P. Moore
  • Geoffrey J. Yuen
  • Alan Bye
  • Gary E. Pakes
Review Articles Drug Disposition

Abstract

Lamivudine (3TC), the negative enantiomer of 2′-deoxy-3′-thiacytidine, is a dideoxynucleoside analogue used in combination with other agents in the treatment of human immunodeficiency virus type 1 (HIV-1) infection and as monotherapy in the treatment of hepatitis B virus (HBV) infection. Lamivudine undergoes anabolic phosphorylation by intracellular kinases to form lamivudine 5′-triphosphate, the active anabolite which prevents HIV-1 and HBV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension.

The pharmacokinetics of lamivudine are similar in patients with HIV-1 or HBV infection, and healthy volunteers. The drug is rapidly absorbed after oral 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 (AUC), is not altered when it is administered with food.

Lamivudine is widely distributed into total body fluid, the mean apparent volume of distribution (Vd) being approximately 1.3 L/kg following intravenous administration. In pregnant women, lamivudine concentrations in maternal serum, amniotic fluid, umbilical cord and neonatal serum are comparable, indicating that the drug diffuses freely across the placenta. In postpartum women lamivudine is secreted into breast milk. The concentration of lamivudine in cerebrospinal fluid (CSF) is low to modest, being 4 to 8% of serum concentrations in adults and 9 to 17% of serum concentrations in children measured at 2 to 4 hours after the dose.

In patients with normal renal function, 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 metabolite recovered in the urine increases, presumably as a function of the decreased lamivudine elimination. As approximately 70% of an oral dose is eliminated renally as unchanged drug, the dose needs to be reduced in patients with renal insufficiency. Hepatic impairment does not affect the pharmacokinetics of lamivudine. Systemic clearance following single intravenous doses averages 20 to 25 L/h (approximately 0.3 L/h/kg). The dominant elimination half-life of lamivudine is approximately 5 to 7 hours, and the in vitro intracellular half-life of its active 5′-triphosphate anabolite is 10.5 to 15.5 hours 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 lamivudine and iterferon-α-2b. There is limited potential for drug-druginteractions with compounds that are metabolised and/or highly proteinbound.

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Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • Mark A. Johnson
    • 1
  • Katy H. P. Moore
    • 2
  • Geoffrey J. Yuen
    • 2
  • Alan Bye
    • 2
  • Gary E. Pakes
    • 2
  1. 1.Department of Clinical PharmacologyGlaxo Wellcome Research and Development Inc.Greenford, MiddlesexEngland
  2. 2.Glaxo Wellcome IncorporatedUSA

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