In vitro potency of inhibition by antiviral drugs of hematopoietic progenitor colony formation correlates with exposure at hemotoxic levels in human immunodeficiency virus-positive humans.
Inhibition of in vitro colony formation of human hematopoietic progenitors (CFU-granulocyte-macrophage, burst-forming unit-erythroid) by the antiviral nucleoside drugs alovudine, zalcitabine, zidovudine, ganciclovir, stavudine, didanosine, lamivudine, and acyclovir was measured. Significant correlations between in vitro 50% inhibitory concentrations and the daily human exposures (area under the concentration-time curve from 0 to 24 h; in micromolar.hour) of these chronically administered drugs in human immunodeficiency virus-positive patients that induced neutropenia or anemia were demonstrated by both linear regression and Spearman rank-order analyses. These quantitative correlations allow estimation of the exposure at which bone marrow toxicity may occur with candidate compounds.
Dornsife
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Division of Experimental Therapy, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709, USA.
Averett
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D000998:Antiviral Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000633:toxicity*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D015224:Dideoxynucleosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000633:toxicity; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D016047:Zalcitabine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000633:toxicity; D015215:Zidovudine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000633:toxicity
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D015215:Zidovudine; D016047:Zalcitabine; C002854:alovudine