CONCENTRATION-CONTROLLED ZIDOVUDINE THERAPY

Background: Heterogeneity in the response to antiretroviral therapy ha s been attributed to pharmacologic, immunologic, and virologic differe nces between patients, Currently available antiretroviral agents used for the treatment of human immunodeficiency virus (HIV) infection in a dults are administered in standard fixed doses, The active moiety of n ucleoside anti-HIV drugs is the intracellular anabolite. Therefore the heterogeneity in response to nucleoside agents may arise as a result of pharmacologic variability at both the systemic and cellular level, Objectives: To determine whether a novel concentration-controlled zido vudine regimen could improve anti-HIV response compared with the stand ard fixed-dose approach. Design:At the Outpatient Clinic of the Genera l Clinical Research Center at the University of Minnesota, 20 persons with HIV infection received an oral regimen of zidovudine designed to achieve a target concentration in plasma of 0.7 mu mol/L and the 500 m g/day standard dose in a randomized, crossover 24-week study. Result: The concentration-controlled regimen achieved overall higher systemic concentrations with reduced interpatient variability: steady-state ave rage zidovudine plasma concentrations were 0.76 mu mol/L (coefficient of variation, 12%) versus 0.62 mu mol/L (coefficient of variation, 32% ) for the standard regimen. There was no difference in safety and tole rance between regimens. Intracellular zidovudine triphosphate concentr ations averaged 160 fmol/10(6) peripheral brood mononuclear cells (PBM Cs) with concentration-controlled versus 92 fmol/10(6) PBMCs for stand ard therapy. The percentage change from baseline in CD4 cells was a 22 % increase for the concentration-controlled regimen versus a 7% decrea se with standard therapy. Conclusions: These data indicate that pharma cologic variability affects antiretroviral response. Further-more, the se findings provide a framework to characterize the pharmacologic dete rminants of effect and quantitate their contribution to the heterogene ity in clinical response to optimize therapeutic benefit.