THE PHARMACOKINETICS AND PHARMACODYNAMICS OF THE ORAL IRON CHELATOR DEFERIPRONE (L1) IN RELATION TO HEMOGLOBIN LEVELS

Recently, we demonstrated that administration of the orally active iro n chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron exc retion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of wh om had received a packed red cell transfusion of 15 cc/kg, 72 hours pr ior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical pra ctice however, thalassemia patients' suppression of endogenous erythro poiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to tra nsfusion. We hypothesized that hemoglobin levels will affect the abili ty of deferiprone to chelate iron, Ten regularly transfused patients w ith homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, wer e treated with deferiprone 75 mg/kg/day, administered every 6 hours (o r every 12 hours) for 72 hours immediately prior to a blood transfusio n in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion . The deferiprone-induced 24-hour urinary iron excretion was similar d uring both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given ever y 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 ho urs (p = 0.79). However, the calculated 23-hour area under the plasma concentration-time curve (AUC(0-24)) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 /- 1,601.6 mgmin/l), than that observed when deferiprone was administ ered every 12 hours (8,250.1 +/- 1,235.7 mgmin/l) (p = 0.04). The pha rmacokinetics of deferiprone when administered immediately prior to tr ansfusions are different from those following transfusions. More studi es assessing total body iron excretion are needed to determine the con tribution of the fecal route in iron excretion.