Pediatric Clinics of North America - CIPERJ

ORAL IRON CHELATORS
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Other oral chelators in development
Deferitrin (GT56-252) is an orally active tridentate iron chelator. It is
a derivative of desferrithiocin, an oral chelator that showed good iron excretion
in animal studies but had unacceptable renal toxicity, so the structure of
deferitrin was modified to limit this toxicity [92]. In a phase 1 study, 26 adult
patients who had thalassemia were treated with at least one dose of deferitrin,
ranging from 3 to 15 mg/kg [93]. The drug’s half-life was 2 to 4 hours
and similar at all dose levels. Thus, once-daily dosing is not adequate with
this medication. One serious adverse event occurred: hypoglycemic coma believed
unrelated to deferitrin in a patient who had pre-existing diabetes. No
significant laboratory abnormalities or electrocardiogram changes occurred.
Further early phase clinical trials are ongoing.
Pyridoxal isonicotinoyl hydraxone (PIH) is a tridentate iron chelator introduced
in 1979. When orally administered to iron-overloaded rats, PIH analogs
were 2.6 to 2.8 times more effective at removing hepatic iron than deferoxamine,
but deferoxamine was more effective at removing iron from cultured
myocytes [94]. When given in combination with deferoxamine, the PIH analogs
had a synergistic effect, suggesting that there may be a future role of
this drug in combination chelation therapy [94]. A study in which 30 mg/kg
per day of PIH was administered to patients who had thalassemia resulted
in mean iron excretion of only 0.12 mg/kg per day, which is lower than the
amount required to maintain negative iron balance in most regular transfused
patients [95,96]. It is possible, however, that higher doses might increase efficacy.
Further studies are needed to evaluate this drug’s potential.
Managing chelation therapy
Children who have iron overload who require chelation therapy generally
should be managed in conjunction with an experienced hematologist. Special
considerations for children include the potential for adverse effects on
growth and bone development with excess chelation, and these risks must
be balanced against the risk for organ damage with prolonged iron accumulation.
A variety of measurements can be used to determine when chelation
therapy should be initiated for transfusional iron overload, including a cumulative
transfusional iron burden of 120 mL/kg or greater, liver iron concentration
of at least 7 mg/g dry weight [97], and serum ferritin levels
persistently elevated above 1000 mg/L. Typically, chelation therapy is not
administered to children younger than 2 years of age, and often it is deferred
until at least 3 or 4 years of age. When administering chelation to children
younger than 5 years old, lower doses of chelation usually are used to avoid
toxicity [97]. The available chelator options and their toxicities should be
discussed with patients and their families. Oral chelation often is used first
line in children given that subcutaneous administration is painful, which
limits compliance. Serial ferritin and liver and cardiac iron measurements