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Concentration‐controlled zidovudine therapy
Author(s) -
Fletcher Courtney V.,
Acosta Edward P.,
Henry Keith,
Page Linda M.,
Gross Cynthia R.,
Kawle Sagar P.,
Remmel Rory P.,
Erice Alejo,
Balfour Henry H.
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90182-5
Subject(s) - zidovudine , medicine , pharmacology , virology , human immunodeficiency virus (hiv) , viral disease
Background Heterogeneity in the response to antiretroviral therapy has been attributed to pharmacologic, immunologic, and virologic differences between patients. Currently available antiretroviral agents used for the treatment of human immunodeficiency virus (HIV) infection in adults are administered in standard fixed doses. The active moiety of nucleoside 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 zidovudine regimen could improve anti‐HIV response compared with the standard fixed‐dose approach. Design At the Outpatient Clinic of the General 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 μmol/L and the 500 mg/day standard dose in a randomized, crossover 24‐week study. Results The concentration‐controlled regimen achieved overall higher systemic concentrations with reduced interpatient variability: steady‐state average zidovudine plasma concentrations were 0.76 μmol/L (coefficient of variation, 12%) versus 0.62 μmol/L (coefficient of variation, 32%) for the standard regimen. There was no difference in safety and tolerance between regimens. Intracellular zidovudine triphosphate concentrations averaged 160 fmol/10 6 peripheral blood mononuclear cells (PBMCs) with concentration‐controlled versus 92 fmol/10 6 PBMCs for standard therapy. The percentage change from baseline in CD4 cells was a 22% increase for the concentration‐controlled regimen versus a 7% decrease with standard therapy. Conclusions These data indicate that pharmacologic variability affects antiretroviral response. Furthermore, these findings provide a framework to characterize the pharmacologic determinants of effect and quantitate their contribution to the heterogeneity in clinical response to optimize therapeutic benefit. Clinical Pharmacology & Therapeutics (1998) 64 , 331–338; doi: