Recent insight on improving the iron chelation efficacy of deferasirox by adjuvant therapy in transfusion dependent beta thalassemia children with sluggish response

ABSTRACT

Background: Deferasirox is the first line of treatment in iron overload. In spite of the many studies concerning the efficacy of deferasirox, some patients remain unresponsive to deferasirox.

Methods: One hundred and sixty patients were enrolled in stratified-randomized controlled study. Patients were randomly divided into four regimens, group I (n = 40) received 30 mg/kg deferasirox, group II (n = 40) received 20 mg omeprazole and 30 mg/kg deferasirox, group III (n = 40) received 400 mg vitamin E and 30 mg/kg deferasirox and group IV (n = 40) received 420 mg silymarin and 30 mg/kg deferasirox. Blood specimens were collected from each patient for up to 24 h, and then plasma deferasirox concentrations were inspected.

Results: Silymarin, Vitamin E, and omeprazole significantly increased the peak plasma concentration of deferasirox (P < 0.001) by 27.9, 14.9 and 2.4 fold, respectively, as compared to deferasirox alone. The bioavailability of deferasirox was improved up to 3.03, 3.57, and 4.98-fold, respectively, following administration of omeprazole, vitamin E, and silymarin compared to deferasirox alone.

Conclusion: Silymarin, vitamin E, and omeprazole represent promising adjuvant therapy to improve the chelation efficacy of deferasirox that might also be further applied to enhance the pharmacokinetics of deferasirox to overcome the lack of response.

KEYWORDS:

• Deferasirox
• pharmacokinetic
• silymarin
• thalassemia Major
• vitamin E

Article highlights

• This study showed that DFX-SLN has a greater iron chelation effect by 69.52%as compared to DFX alone (P<0.01).

• DFX became long acting chelator in patients taking omeprazole among the three combinations. These results indicated that CYP450 plays a key role in the elimination of DFX in patients.

• The pharmacokinetic results were consistent with the clinical efficacy results as the in-vivo results proved that the combined regimen influenced pharmacokinetics properties of DFX followed by the highest efficacy according to serum ferritin levels.

• The mean packed red cell transfusions during 6 months before starting of omeprazole, vitamin E and silymarin were 6.10, 5.97 and 6.10 units, which decreased to 4.63,2.93 and 3.13 units after treatment (P<0.01).

• Both monotherapy and combined therapy declared negative correlations between AUC_0–24 of deferasirox and serum ferritin.

Acknowledgments

All authors extend sincere thanks and gratitude to Springer Nature Author Service for English language editing. The authors would also thank Dr. Michel Y. Fares (teaching assistant of Analytical Department, Faculty of Pharmacy, Nahda university) and Dr. Mohammed E. Draz (lecturer of analytical chemistry, Faculty of Pharmacy, Delta University), for their efforts and their support in bioanalytical assay.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

EM Hamed: Experiment, data entry, statistics and writing

RRS. Hussein: Experiment, concept, study design andwriting.

MH Meabed: Experiment, concept and study design.

UF Aly: Experiment, concept, planning of study design, statistics and writing

Additional information

Funding

This work was not funded.