AEGiS-08IAC: Early markers of hematologic toxicity with FLT therapy.

8th International AIDS Conference

Amsterdam, Netherlands — July 19-24, 1992

Early markers of hematologic toxicity with FLT therapy.

Int Conf AIDS 1992 Jul 19-24; 8:We47 (abstract no. WeB 1012)
Barditch-Crovo P, Ganes D, Duncanson F, van der Horst C, Polsky B, Petty B, Faulkner R, Kuye O, Yacobi A, Lietman P, et al; Johns Hopkins Univ., Baltimore, MD.

OBJECTIVE: To assess the hematologic toxicity of FLT (3'-deoxy-3'-fluorothymidine), an anti-HIV nucleoside analog more potent than zidovudine.

METHODS: 14 AIDS/ARC patients were enrolled in a 16 week concentration-controlled, multiple oral dose study at 0.125 mg/kg q12h initially.

RESULTS: In subjects who received drug for at least 3 weeks at or above an AUC (area under the concentration-time curve) of 300 ng*hr/ml, 11/12 developed significant decreases in hemoglobin, white blood cells, and/or platelet count. In all 7 subjects for whom fasting a.m. levels were available, plasma iron concentrations were increased significantly by Day 5 of therapy (P-value less than .01); 6 of these subjects eventually developed significant decreases in hemoglobin (Hb). In 9 subjects developing a greater than or equal to 15% drop in hemoglobin by Week 4 and for whom reticulocyte counts were available, 7/9 had developed a significant decrease in reticulocyte count by Week 2. Serum immunoreactive erythropoietin levels increased significantly during the first four weeks of therapy in all subjects. The onset and severity of the decrease in Hb at Week 4 appeared to be AUC-dependent; the correlation coefficient for mean AUC during the first week of therapy and per cent decrease in hemoglobin at Week 4 was 0.67 (P-value less than .02). Dose-adjustment to a targeted AUC of 150 ng*hr/ml in 3 subjects was tolerated without significant hematological toxicity.

CONCLUSIONS: Early increases in plasma iron levels may predict the ability of a nucleoside analog to affect hematopoiesis, while a decrease in reticulocyte count may serve as an indicator of who will eventually develop a significant fall in hemoglobin. These results support the value of precise pharmacokinetic and pharmacodynamic evaluation early in a new drug development program.

Keywords: AEGIS, Zidovudine, Biological Markers, AIDS-Related Complex, HIV Infections, Anti-HIV Agents, HIV, Acquired Immunodeficiency Syndrome, Drug Toxicity, Reverse Transcriptase Inhibitors, Hemoglobins, HIV Core Protein p24, Reticulocyte Count, Platelet Count, Human, therapy, toxicity, drug therapy, ICA8
920719
WeB1012