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.
"The drug exhibited time-dependent killing, with cidality occurring at 12–24 h of drug exposure. Based on trough serum levels of greater than15 μg/mL in patients treated with deferasirox at 20 mg/kg/d, it should be feasible to maintain serum levels in excess of the MICs of Mucormycotina throughout the entire dosing interval [78, 79]. "
[Show abstract][Hide abstract] ABSTRACT: In recent years, substantial advances have been achieved in the treatment of mucormycosis. It is now clear that early initiation of therapy results in substantially better outcomes, underscoring the need to maintain a high index of suspicion and aggressively biopsy potential lesions. Increasing data support the need for surgical excision of infected and/or necrosed tissue whenever feasible. Based on their superior safety and efficacy, lipid formulations of amphotericin B have become the standard treatment for mucormycosis. Posaconazole may be useful as salvage therapy, but cannot be recommended as primary therapy for mucormycosis based on available data. Pre-clinical and limited retrospective clinical data suggest that combination therapy with lipid formulations of amphotericin and an echinocandin improves survival during mucormycosis. A definitive trial is needed to confirm these results. The use of the iron chelator, deferasirox, as adjunctive therapy also improved outcomes in animal models of mucormycosis. However, its efficacy was not confirmed in a recent, phase 2 clinical trial. Additional study is required of the potential for abrogation of iron acquisition as adjunctive treatment of mucormycosis. Combination polyene-posaconazole therapy was of no benefit in pre-clinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered in selected patients. Large-scale, prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Deferasirox is an oral iron chelator, approved worldwide for the treatment of chronic iron overload due to transfusion. Deferasirox was permitted two years ago in Japan, but there is little known regarding its efficacy and tolerability in clinical practice. Methods: We conducted a retrospective study of 18 patients with transfusion-dependent anemias treated by deferasirox at our institution. The starting dose was individualized and ranged from 6.4 to 26.3 mg/kg/day. Routine clinical laboratory data were followed, and serum ferritin was assessed every 4 weeks. Results: The mean serum ferritin level of 18 patients at the time of deferasirox induction was 3162 ng/ml. 10 of 18 patients could sustain deferasirox treatment for at least 6 months, at an average maintenance dose of 10.8 mg/kg/day. Serum ferritin reduction was observed in 4 patients, at doses less than 20 mg/kg/day. Eighty-nine percent of the patients had adverse events and 13 of them in all ultimately discontinued. Myelodysplastic syndrome (MDS) patients showed poor tolerabil-ity. Severe infections of grade 3 or more were documented in 6 patients, and 2 of them were fatal. Conclusions: The potential for beneficial iron chelation of deferasirox at less than the recommended 20-mg/kg dose was demonstrated. On the contrary, poor tolerability was documented, with adverse events such as severe infections, especially in MDS patients. Although it was not clearly demonstrated that deferasirox was responsible for impaired immunity, careful watching is required to administrate deferasirox.
[Show abstract][Hide abstract] ABSTRACT: A number of surfaces having the same statistical properties are
generated using one stochastic matrix. Additionally, for each surface
obtained according to Markov chain, a corresponding Gaussian surface
with the same mean and standard deviation is also generated. Utilizing
ray-tracing, fields scattered by these surfaces are calculated and
compared. It is shown that for rough surfaces generated according to the
Markov chain and the Gaussian distribution, the field scatters in a
wider range of angles (wider pattern) in proportion to the roughness.
The number of the resulting scattering angles for the Gaussian surfaces
is larger than those generated according to Markov chain. The reason is
that the number of levels which a Markov surface can cover is limited by
the order of the stochastic matrix. However, in the Gaussian case, the
only limits are the mean and the standard deviation
Southeastcon '89. Proceedings. Energy and Information Technologies in the Southeast., IEEE; 05/1989
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