A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade, ICL670) in patients with transfusion-dependent anemias and iron-overload: a Phase I study in Japan.

First Department of Internal Medicine (Hematology/Oncology), Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
International Journal of Hematology (Impact Factor: 1.68). 08/2008; 88(1):73-81. DOI: 10.1007/s12185-008-0115-2
Source: PubMed

ABSTRACT The pharmacokinetics (PK) and pharmacodynamics (PD) of the once-daily, oral ironchelating agent, deferasirox (Exjade, ICL670), have been evaluated further in a Phase I, openlabel, multicenter, dose-escalation study in Japanese patients with myelodysplastic syndromes, aplastic anemia, and other anemias. Deferasirox was initially administered as a single dose of 5 (n = 6), 10 (n = 7), 20 (n = 6) or 30 (n = 7) mg/(kg day) and then after 7 days seven daily doses were administered. Linear PK (C (max) and AUC) were observed at all doses after a single dose and at steady state, and dose-dependent iron excretion was observed. Pharmacokinetic/pharmacodynamic parameters were similar to those reported in a Caucasian beta-thalassemia cohort. Following the single- and multiple-dose phases, 21 of 26 patients progressed to a 3-year extension phase of the study, where dose reductions and increases [5-30 mg/(kg day)] were allowed following safety and efficacy assessments. In the interim, 1-year data show that deferasirox was well tolerated, with generally infrequent and mild adverse events. Reductions in serum ferritin levels were observed and a negative iron balance achieved at doses of 20-30 mg/(kg day). These data suggest that deferasirox has a stable and predictable PK/PD profile, irrespective of underlying disease or race, and a predictable and manageable safety profile suitable for chronic administration.

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    ABSTRACT: In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.
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    ABSTRACT: Iron accumulation is a consequence of regular red cell transfusions, and can occur as a result of ineffective erythropoiesis secondary to increased intestinal iron absorption, in patients with various anemias. Without appropriate treatment, iron overload can lead to increased morbidity and mortality. Deferasirox is an oral iron chelator effective for reduction of body iron in iron-overloaded patients with transfusion-dependent anemias and non-transfusion-dependent thalassemia, with a well-established safety profile. This review summarizes the clinical pharmacokinetics, pharmacodynamics, and drug-drug interaction profile of deferasirox, and the claims supporting once-daily dosing for effective chelation. Sustained labile plasma iron suppression is observed with no rebound between doses, protecting organs from potential tissue damage. Increased iron excretion positively correlates with increased deferasirox exposure; to optimize iron removal transfusional iron intake, body iron burden and safety parameters should also be considered. Deferasirox dispersible tablets should be taken ≥30 min before food due to an effect of food on bioavailability. Dosing is consistent across pediatric and adult patients and there is no ethnic sensitivity. Dose adjustment is required for patients with hepatic impairment and may be considered upon coadministration with strong uridine diphosphate glucuronosyltransferase inducers or bile acid sequestrants (coadministration should be avoided where possible), and patients should be monitored upon coadministration with cytochrome P450 (CYP) 3A4/5, CYP2C8, or CYP1A2 substrates. Coadministration with hydroxyurea, a fetal hemoglobin modulator, does not appear to impact deferasirox pharmacokinetics. In summary, a substantial body of clinical and pharmacokinetic data are available for deferasirox to guide its optimal use in multiple patient populations and clinical circumstances.
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