Pharmacodynamic Effects of Zidovudine 600 mg Once/Day Versus 300 mg Twice/Day in Therapy-Naive Patients Infected With Human Immunodeficiency Virus

Peter J. Ruane, M.B., B.Ch.; Gary J. Richmond, M.D.; Edwin DeJesus, M.D.; Christina E. Hill-Zabala, Pharm.D.; Susan C. Danehower, M.S.; Qiming Liao, Ph.D.; Judy Johnson, M.S.N.; Mark S. Shaefer, Pharm.D.


Pharmacotherapy. 2004;24(3) 

In This Article

Abstract and Introduction

Study Objective: To compare the virologic activity of zidovudine monotherapy administered as 600 mg once/day versus 300 mg twice/day.
Design: Phase II, randomized (1:1), open-label study.
Setting: Thirteen medical centers in the United States.
Patients: Thirty-two antiretroviral-naïve patients infected with human immunodeficiency virus (HIV).
Intervention: Patients were administered either zidovudine 600 mg every 24 hours (16 patients) or 300 mg every 12 hours (16 patients) for 13 days.
Measurements and Main Results: Plasma HIV-1 RNA concentration was measured daily. Study end points were between-group differences in change from baseline of log10-transformed HIV-1 RNA and in rates of viral load decline measured by the slope of HIV-1 RNA over time. At baseline, mean HIV-1 RNA was similar in the once/day and twice/day groups (4.33 and 4.40 log10 copies/ml, respectively). At day 14, a trend toward lower mean reduction in HIV-1 RNA from baseline was observed in the once/day group (-0.585, 95% confidence interval [CI] -0.728 to -0.442 log10 copies/ml) compared with the twice/day group (-0.849, 95% CI -1.067 to -0.630 log10 copies/ml, p=0.056). Viral load reduction also tended to be slower in the once/day group, as indicated by the smaller slope of viral load decline in the once/day group than in the twice/day group during days 1-14 (-0.045 vs -0.065 log10 copies/ml/day, p=0.065). Both zidovudine regimens were similarly well tolerated.
Conclusion: Zidovudine 600 mg once/day has antiviral activity, although less pronounced and more slowly achieved than that seen with zidovudine 300 mg twice/day. No differences were observed between the two treatment groups with respect to safety profile or tolerability.

Zidovudine, a nucleoside reverse transcriptase inhibitor (NRTI) that was initially investigated as an antileukemic agent,[1] later became the first antiretroviral drug developed for use in the treatment of human immunodeficiency (HIV) infection.[2] In 1987, dosing involved high total daily doses of zidovudine 1200 mg, divided and administered as frequently as every 4 hours. Dose reduction was sought during the drug's development to reduce toxicity (myopathy, cytopenia), whereas reduction in dosing frequency was investigated to find a regimen that offered optimal convenience for self-administration.

Research toward these ends eventually led to the establishment in 1996 of the current dosage of zidovudine 300 mg twice/day. Zidovudine has been, and continues to be, a key component of most initial highly active antiretroviral treatment regimens involving a minimum of three drugs.[3] Zidovudine 300 mg is contained in the dual NRTI tablet Combivir (GlaxoSmithKline, Research Triangle Park, NC) with lamivudine 150 mg, and in the triple NRTI tablet Trizivir (GlaxoSmithKline) with lamivudine 150 mg and abacavir 300 mg.

Although antiretroviral drugs requiring twice-daily dosing dominate HIV treatment, demand has increased for potent, effective, and tolerable antiretroviral agents that can be administered once/day to simplify treatment and facilitate adherence.[4] In vivo studies suggest that the elimination half-life of the active intracellular anabolite of zidovudine, zidovudine triphosphate, is longer than that widely reported (< 5 hrs) in earlier in vitro studies.[5,6] One study found that the median steady-state half-life of zidovudine triphosphate was 11 hours (range 5-13 hrs) in peripheral blood mononuclear cells (PBMCs) of five HIV-infected patients.[5] In another study, the steady-state zidovudine triphosphate half-life, determined graphically, was longer than 8 hours in PBMCs of 10 HIV-infected patients.[6] Potentially, once-daily dosing of zidovudine would allow physicians greater flexibility in tailoring zidovudine-containing regimens to individual patient needs. In addition, adherence may be enhanced in some patient populations if all antiretroviral agents in a regimen are administered once/day.

In view of zidovudine triphosphate's long elimination half-life, we evaluated the virologic activity in HIV-infected patients of zidovudine 600 mg once/day compared with the standard regimen of 300 mg twice/day in a proof-of-concept study, COD20002. A companion study, COD10001, examined the pharmacodynamics and intracellular pharmacokinetics of monotherapy with zidovudine 600 mg once/day versus 300 mg twice/day.[7]


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