Zidovudine and Lamivudine Given Once Versus Twice Daily
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to see if the full daily dose of Combivir (zidovudine
      [ZDV]/lamivudine [3TC]) taken once a day is as effective as the usual recommended twice-a-day
      dose.

      Studies have shown that the antiviral activity of ZDV can continue in the body even after
      there does not appear to be any ZDV left in the blood. This occurs because the body breaks
      down the drug into substances that remain active against HIV. The body also breaks down 3TC,
      a drug that is combined with ZDV in the Combivir product, in a similar way. Since antiviral
      activity may continue after Combivir is removed from the body, it may not be necessary to
      take the drug as often as once thought. This study carefully measures levels of the active
      substances in order to find out whether the same amount of antiviral activity occurs with
      less-frequent dosing.
    

Detailed description: 
      Initial dosing regimens of ZDV were based on the plasma half-life of the drug. However,
      recent studies of the intracellular metabolism of ZDV have demonstrated that the active
      anabolite, ZDV-TP, is present within the cell for an extended period of time relative to the
      drug in the plasma. This suggests that antiviral activity may be present for a sufficient
      time frame with less-frequent dosing of the drug. Careful comparison of the rate and extent
      of intracellular phosphorylated ZDV metabolites as a function of schedule will determine
      whether less-frequent dosing has a sound pharmacological basis. Also, the intracellular
      metabolism of 3TC is via different enzymes than that of ZDV and there are quantitative
      differences in the amount of triphosphate formed from both drugs. This study will provide
      information about intracellular metabolites when both ZDV and 3TC are concurrently
      administered.

      This is a study of 2 schedules of Combivir therapy. At study entry or Part I, all patients
      take Combivir twice daily for the 7-day adherence assessment. Patients who have demonstrated
      70 percent or greater adherence [AS PER AMENDMENT 7/20/01: 70 percent compliance with the
      study regimen for Combivir. This corresponds to taking at least 10 of the prescribed 14
      Combivir tablets during the 7 days prior to an adherence assessment, including all scheduled
      doses in the 24-hour period prior to that assessment.], and have taken all scheduled Combivir
      doses in the previous 24 hours, have pharmacokinetic samples obtained and are randomized to
      Group A or Group B in Part II. Group A patients take 2 Combivir tablets once daily; Group B
      patients take 1 Combivir tablet twice daily. After patients have completed the targeted
      duration of Part II (7 days for Group A and 7-14 days for Group B), they are assessed for
      adherence. Patients who have demonstrated 70 percent or greater adherence, and have taken all
      scheduled Combivir doses in the previous 24 hours, have pharmacokinetic samples obtained and
      then change to the alternate dosing schedule. Group A patients take 1 Combivir tablet twice
      daily; Group B patients take 2 Combivir tablets once daily. After patients have completed the
      targeted duration of Part III (7-14 days for Group A and 7 days for Group B), they are
      assessed for adherence. All patients who meet the adherence criteria have pharmacokinetic
      samples obtained. After completion of Part III pharmacokinetic studies, patients have
      completed the study. (Note: Combivir will not be provided in this study.)
    

Intervention name(s): Lamivudine/Zidovudine
Intervention type(s): Drug
Intervention MeSH terms: Lamivudine; Zidovudine; Lamivudine, zidovudine drug combination
Intervention model: Crossover Assignment
Primary purpose: Treatment
Keywords: Zidovudine; Phosphorylation; Drug Administration Schedule; Lamivudine; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Pharmacokinetics; Combivir