PHARMACOKINETICS AND SAFETY OF CONCENTRATION-CONTROLLED ORAL ZIDOVUDINE THERAPY

Study Objective. To evaluate the pharmacokinetics, safety, and feasibi lity of concentration-controlled oral zidovudine therapy Design. Rando mized, crossover, open-label study. Setting. University-affiliated gen eral clinical research center. Patients. Eight individuals infected wi th the human immunodeficiency virus with CD4+ lymphocyte counts of 100 cells/mu l or greater. Intervention. During the 24-week study, patien ts received oral zidovudine regimens that consisted of a standard fixe d dose of 500 mg/day and a concentration-controlled regimen designed t o maintain a steady-state plasma concentration (C-ss) of 0.187 +/- 0.0 4 mg/L (0.7 +/- 0.14 mu M). Measurements and Main Results. The mean C- ss during standard therapy was 0.170 +/- 0.024 mg/L versus 0.205 +/- 0 .021 mg/L with the concentration-controlled regimen (p=0.025). Respect ive mean changes in hemoglobin were -0.02 g/dl (range -0.9-0.9 g/dl) a nd -0.30 g/dl (range -1.5-0.4 g/dl, p=0.67). The absolute neutrophil c ount decreased 0.90 x 10(9)/L during standard therapy and increased 0. 40 x 10(9)/L during concentration-controlled therapy (p=0.07). The reg imens did not differ in toxicity. Conclusion. Concentration-controlled oral antiretroviral therapy with zidovudine is feasible and safe, and provides pharmacologic data to determine the regimen's virologic and immunologic benefits.