Discussion
Urticaria, CKD, TEAEs, anemia, PD, TEAE, allergic reactions
URTICARIA, HYPERSENSITIVITY REACTIONS, ALLERGIC REACTION, HYPERSENSITIVITY REACTION, ANEMIA
The results of this Phase 2 trial show that treatment with IV FCM was generally well tolerated and produced clinically meaningful, dose-proportional increases in mean hemoglobin concentrations in pediatric patients with IDA. FCM has very low immunogenic potential, and its properties permit rapid administration (e.g., 15 min) of large, single doses, which allows for rapid repletion of total body iron and supports the utility of FCM in the treatment of IDA in pediatric patients.The overall nature and incidence of TEAEs and study drug-related TEAEs were similar in the two dose groups. Most TEAEs were Grade 1 or 2 in severity, and no serious TEAE was deemed to be related to the study drug. Urticaria was observed in three FCM recipients in the higher dose group (15 mg/kg) and was the only study drug-related TEAE that occurred in more than one patient. Urticaria may result from a transient hypersensitivity reaction limited to the skin and subcutaneous tissues; however, no consistent dose-response relationship with respect to transient allergic reactions could be established with the small sample size in the present study. A larger series of pediatric patients will have to be monitored to better determine the incidence, severity, and relationship to dose of hypersensitivity reactions to FCM.This study was completed before FCM was approved by US FDA for the treatment of IDA in pediatric patients aged ≥1 year who have either intolerance to oral iron or an unsatisfactory response to oral iron.The safety profile reported here also aligns with safety results from two single-center retrospective cohort studies of pediatric patients treated with FCM.The safety profile in the current study is consistent with that reported in other PK studies with different designs and doses of FCM in adults with IDA.In previous reports in adults with IDA,PK data with other IV iron formulations are available for pediatric populations with CKD. Among 49 patients with PK data from a randomized, double-blind study of IV ferric gluconate in iron-deficient pediatric (age ≤15 years) patients undergoing hemodialysis, a single dose of ferric gluconate (1.5 mg/kg or 3.0 mg/kg) resulted in rapid, dose-dependent increases in mean serum iron concentrations (total iron and ferric gluconate-bound iron).In the current study, FCM resulted in rapid (72 h post-dose), clinically meaningful improvement of PD parameters in pediatric patients with IDA. Maximum mean increases in serum ferritin and TSAT were documented 72 h after administration of a single dose of FCM; the increases from baseline observed in both serum ferritin and TSAT remained consistently higher in patients who received the 15 mg/kg dose than increases in those who received the 7.5 mg/kg dose throughout 4 weeks of follow-up. Treatment with FCM also resulted in rapid and sustained increases in ferritin that were well above the threshold of 10–15 µg/L that is indicative of depleted iron stores in children depending on age.Increases in hemoglobin occurred more slowly and were sustained throughout follow-up in both dose groups. The maximum change in hemoglobin concentration was documented 35 days after administration and was larger in patients who received FCM 15 mg/kg than that in those who received FCM 7.5 mg/kg.According to World Health Organization criteria, anemia is defined as a hemoglobin concentration <11.0 mg/dL in children aged 6–59 months, <11.5 mg/dL in children aged 5–11 years, and <12.0 mg/dL in children aged 12–14 years.The PD results reported here are generally consistent with previous reports from retrospective cohort studies of pediatric patients treated with FCM. Among pediatric patients with IDA and poor response to oral therapy (Limitations of this trial include those typical of similar clinical studies. The population was small and heterogeneous, which tempers the strength of the dose recommendation and any conclusions drawn from the pharmacodynamic data. The duration of follow-up was limited to 35 days, whereas the developmental effects of anemia can be much longer.The results of this study demonstrate that single FCM doses of 7.5 mg/kg and 15 mg/kg FCM can be safely administered intravenously and are well tolerated by pediatric patients aged 1 to 17 years. Dose-related increases in ferritin and TSAT and clinically meaningful increases in mean hemoglobin concentration were observed from baseline to the end of follow-up (Day 35). Improvements in iron indices and increases in hemoglobin were consistently greater with the higher dose of FCM (15 mg/kg) with similar safety profiles, which supports the use of the FCM 15 mg/kg in pediatric patients. FCM was recently approved by the US FDA at a dosage of 15 mg/kg for the treatment of IDA in pediatric patients and is an effective option for patients who are intolerant of or who have an unsatisfactory response to oral iron.