Effect of food, type of food, and time of food intake on deferasirox bioavailability: recommendations for an optimal deferasirox administration regimen.

Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption.

Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload.

BACKGROUND AND OBJECTIVES: Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferoxamine (Desferal, DFO) reduces morbidity and mortality although the administration schedule of slow, parenteral infusions several days each week limits compliance and negatively affects long-term outcome. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. In a phase II study, the tolerability and efficacy of deferasirox were compared with those of DFO in 71 adults with transfusional hemosiderosis. DESIGN AND METHODS: Patients were randomized to receive once-daily deferasirox (10 or 20 mg/kg; n=24 in both groups) or DFO (40 mg/kg, 5 days/week; n=23) for 48 weeks. Results. Both treatments were well tolerated and no patient discontinued deferasirox due to drug-related adverse events. The reported frequency of transient, mild to moderate gastrointestinal disturbances was higher in the deferasirox group than in the DFO group, but these disturbances settled spontaneously without dose interruption in all patients. Decreases in liver iron concentration (LIC) were comparable in the deferasirox 20 mg/kg/day and DFO groups; baseline values of 8.5 and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw, respectively, by week 48. Deferasirox showed a plasma elimination half-life of 8-16 hours, supporting its once-daily administration. INTERPRETATION AND CONCLUSIONS: Deferasirox at daily doses of 10 or 20 mg/kg was well tolerated and, at 20 mg/kg, showed similar efficacy to DFO 40 mg/kg in terms of decreases in LIC.

Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571).

Isolated central nervous system (CNS) relapse occurred in 5 out of 24 patients (20.8%) with chronic myeloid leukemia (CML) lymphoid blast crisis (2), Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL) (2) or CML with biphenotypic markers (1) treated on imatinib mesylate (IM) protocols at our institution. CNS relapse occurred despite peripheral blood (5) and bone marrow (3) complete responses. Median time to CNS relapse was day 32 (range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid (CSF) IM levels were determined in four subsequent patients by liquid chromatography and mass spectrophotometric assay. Levels of IM were found to be approximately two logs lower in CSF than in plasma (0.044 microg/ml (0.088 +/- 0.029 micrro) vs 3.27 microg/ml (6.54 +/- 0.93 microM)). CSF levels were substantially below the concentration required for inhibition of BCR-ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/brain barrier and its implications are discussed.

Imatinib treatment: specific issues related to safety, fertility, and pregnancy.

Imatinib (Gleevec) (formerly STI571) has demonstrated high levels of efficacy in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST) and has been used in more than 12,000 patients participating in clinical trials. Experience from clinical trials with imatinib has largely demonstrated the drug to be well tolerated in humans. Common side effects, usually manageable, include nausea, rash, superficial edema, myelosuppression, muscle cramps, and elevated liver transaminases. With longer follow-up and with further experience with the treatment of patients outside of clinical trials, we are able to report on rarer toxicities, the identification of certain predictors of common toxicities, and the clinical experience with male fertility and pregnancy outcomes.

William James West (1794-1848): abdominal surgeon and distraught father.

William West was an early-nineteenth-century successful small-town surgeon-apothecary who took a major role in the local movement for medical reform. He published the first series of ovariotomies in England in 1837. His son suffered from a type of infantile spasm which West described in the Lancet in 1841, and which is now known as West's syndrome.

Practical management of patients with chronic myeloid leukemia receiving imatinib.

The introduction of imatinib, a specific inhibitor of the Bcr-Abl tyrosine kinase, has dramatically changed the management of chronic myeloid leukemia (CML). More than 10,000 patients worldwide have been treated with imatinib in clinical trials, and a large body of information has accumulated about the use of this drug. The purpose of this article is to review practical guidelines in regard to optimal dosing, monitoring, managing common side effects such as myelosuppression, and potential drug interactions. The treatment recommendations are intended to optimize therapy with imatinib while taking into account a patient's specific circumstances.