Characterisation of individual ferritin response in patients receiving chelation therapy

Borella, Elisa; Oosterholt, Sean; Magni, Paolo; Pasqua, Oscar Della

doi:10.1111/bcp.15290

Cited by 5 publications

(3 citation statements)

References 47 publications

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“…Moreover, as ICS dose was not a covariate in the TTE model; treatment comparisons were performed using the mean and/or mode dose level used during the maintenance phase of treatment. This was based on the underlying dose–response relationships of FP and BUD [ 21 , 35 – 37 ]. As currently used ICS doses yield nearly maximum pharmacological effect, the impact of varying dose level on basal hazard was assumed to be minor.…”

Section: Discussionmentioning

confidence: 99%

Understanding the Clinical Implications of Individual Patient Characteristics and Treatment Choice on the Risk of Exacerbation in Asthma Patients with Moderate–Severe Symptoms

Singh,

Oosterholt,

Pavord

et al. 2023

Adv Ther

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Introduction The assessment of future risk has become an important feature in the management of patients with asthma. However, the contribution of patient-specific characteristics and treatment choices to the risk of exacerbation is poorly understood. Here we evaluated the effect of interindividual baseline differences on the risk of exacerbation and treatment performance in patients receiving regular maintenance doses of inhaled corticosteroids (ICS) or ICS/long-acting beta-agonists (LABA) combination therapy. Methods Exacerbations and changes to asthma symptoms 5-item Asthma Control Questionnaire (ACQ-5) were simulated over a 12-month period using a time-to-event and a longitudinal model developed from phase III/IV studies in patients with moderate–severe asthma ( N = 16,282). Simulations were implemented to explore treatment performance across different scenarios, including randomised designs and real-world settings. Treatment options included regular dosing with ICS monotherapy [fluticasone propionate (FP)] and combination therapy [fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)]. Exacerbation rate was analysed using the log-rank test. The cumulative incidence of events was summarised stratified by treatment. Results Being a woman, smoker, having higher baseline ACQ-5 and body mass index (BMI) and lower forced expiratory volume in the first second (FEV 1 ) are associated with increased exacerbation risk ( p < 0.01). This risk is bigger in winter because of the seasonal variation effect. Across the different scenarios, the use of FP/SAL resulted in a 10% lower annual incidence of exacerbations relative to FP or regular dosing BUD/FOR, independently of baseline characteristics. Similar differences in the annual incidence of exacerbations were also observed between treatments in obese patients (BMI ≥ 25–35 kg/m 2 ) ( p < 0.01) and in patients who do not achieve symptom control on FP monotherapy. Conclusions Individual baseline characteristics and treatment choices affect future risk. Achieving comparable levels of symptom control whilst on treatment does not imply comparable risk reduction, as shown by the lower exacerbation rates in FP/SAL vs. BUD/FOR-treated patients. These factors should be considered as a basis for personalised clinical management of patients with moderate–severe asthma. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-023-02590-2.

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Section: Discussionmentioning

confidence: 99%

Understanding the Clinical Implications of Individual Patient Characteristics and Treatment Choice on the Risk of Exacerbation in Asthma Patients with Moderate–Severe Symptoms

Singh,

Oosterholt,

Pavord

et al. 2023

Adv Ther

Self Cite

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“…Iron overload is an inevitable consequence of blood transfusions in patients affected by haemoglobinopathies. Therefore, the iron chelation therapy (ICT) is necessary to prevent the consequences of hemosiderosis in these patients and to restore the body iron content [ 57 ]. Currently, three iron chelators, approved by the Food and Drug Administration to prevent iron accumulation in patients affected by haemoglobinopathies [ 57 ], are available: deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX).…”

Section: Iron Chelators As Anti-inflammatory Drugsmentioning

confidence: 99%

“…Therefore, the iron chelation therapy (ICT) is necessary to prevent the consequences of hemosiderosis in these patients and to restore the body iron content [ 57 ]. Currently, three iron chelators, approved by the Food and Drug Administration to prevent iron accumulation in patients affected by haemoglobinopathies [ 57 ], are available: deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX). These chelators differ in molecular weight and in intestinal absorption profile [ 58 ].…”

Section: Iron Chelators As Anti-inflammatory Drugsmentioning

confidence: 99%

Emerging Roles of the Iron Chelators in Inflammation

Paola

Tortora

Argenziano

et al. 2022

IJMS

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Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.

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Characterisation of individual ferritin response in patients receiving chelation therapy

Borella

Oosterholt

Magni

et al. 2022

Brit J Clinical Pharma

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Aims To develop a drug–disease model describing iron overload and its effect on ferritin response in patients affected by transfusion‐dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox. Methods Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations. Results An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079–0.0131] vs. 0.0013 [90% CI: 0.0008–0.0018] L/mg mo). In addition to drug‐specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline. Conclusion Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug‐induced changes in iron elimination rate and ferritin production. The use of a semi‐mechanistic parameterisation allowed us to disentangle disease‐specific factors from drug‐specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.

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Characterisation of individual ferritin response in patients receiving chelation therapy

Cited by 5 publications

References 47 publications

Understanding the Clinical Implications of Individual Patient Characteristics and Treatment Choice on the Risk of Exacerbation in Asthma Patients with Moderate–Severe Symptoms

Understanding the Clinical Implications of Individual Patient Characteristics and Treatment Choice on the Risk of Exacerbation in Asthma Patients with Moderate–Severe Symptoms

Emerging Roles of the Iron Chelators in Inflammation

Characterisation of individual ferritin response in patients receiving chelation therapy

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