Pharmacokinetics and safety of concentration-controlled oral zidovudine therapy

Study Objective. To evaluate the pharmacokinetics, safety, and feasibility of concentration-controlled oral zidovudine therapy. Design. Randomized, crossover, open-label study. Setting. University-affiliated general clinical research center. Patients. Eight individuals infected with the human immunodeficiency virus with CD4+ lymphocyte counts of 100 cells/μl or greater. Intervention. During the 24-week study, patients received oral zidovudine regimens that consisted of a standard fixed dose of 500 mg/day and a concentration-controlled regimen designed to maintain a steady-state plasma concentration (C(ss)) of 0.187 ± 0.04 mg/L (0.7 ± 0.14 μM). 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). Respective mean changes in hemoglobin were -0.02 g/dl (range - 0.9-0.9 g/dl) and -0.30 g/dl (range -1.5-0.4 g/dl, p=0.67). The absolute neutrophil count decreased 0.90 x 10⁹/L during standard therapy and increased 0.40 x 10⁹/L during concentration-controlled therapy (p=0.07). The regimens 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.