Pharmacodynamics and safety of ferric carboxymaltose: a multiple-dose study in patients with iron-deficiency anaemia secondary to a gastrointestinal disorder.

This multiple-dose Phase I/II study provided pharmacodynamics and pharmacokinetics data on the therapeutic benefit of ferric carboxymaltose (FCM, Ferinject) and evaluated the safety and tolerability of this intravenous (i.v.) iron preparation. Two doses of iron as FCM were given as i.v. infusion over 15 min, 500 mg iron given once weekly for up to 4 weeks (Cohort 1) or 1000 mg iron weekly for 2 weeks (Cohort 2), in patients with a total requirement > or = 1000 mg iron (total cumulative maximum dose < or = 2000 mg iron). Adults with moderate to severe, stable iron-deficiency anaemia (IDA) (haemoglobin [Hb] < or = 11.0 g/dl, serum ferritin < 100 microg/l, transferrin saturation [TSAT] < 16%) due to a gastrointestinal (GI) disorder were included. Pharmacodynamics variables: proportion of patients achieving values within the reference range for Hb (men: 14.0-18.0 g/dl, women: 12.0-16.0 g/dl), serum ferritin (20-500 microg/l), TSAT (16-45%) and proportion of patients with an increase in Hb of at least 2.0 g/dl. Pharmacokinetics variables: total serum iron levels at time of maximum serum iron concentration during the fast elimination phase and at trough time-points. Safety assessments: the incidence of adverse events (AEs) and changes in vital signs, physical examinations, and clinical laboratory parameters. In Cohorts 1 and 2, 14/20 (70%) versus 19/26 (73%) of patients completed the study. Individual calculated iron deficits were 1000-2100 mg. The mean cumulative dose of FCM in Cohorts 1 and 2 was 1800 mg and 1563 mg iron, respectively. At baseline, patients in both cohorts had similar Hb levels (mean 8.7 g/dl in both cohorts). More than 97% of patients demonstrated a clinically meaningful increase in Hb levels (> or = 1.0 g/dl) during the study. By the week 4 follow-up visit, an increase of at least 2.0 g/dl was achieved by 15/20 (75%) and by 19/26 (73.1%) patients in Cohorts 1 and 2, respectively, and the mean increase in Hb was 3.2 g/dl in Cohort 1 and 3.3 g/dl in Cohort 2. By day 28, 3/6 (50%) patients in Cohort 1 had achieved normal Hb levels, and by the 4-week post-treatment followup visit 7/19 patients (37%) in Cohort 1 and 12/25 (48%) in Cohort 2 had reached Hb levels within the reference range. Serum ferritin levels increased rapidly at the start of treatment and remained in the reference range throughout the study; increases were greater in Cohort 2. Mean baseline TSAT values were similar in both cohorts (24.2% in Cohort 1, 20.7% in Cohort 2), and were within the reference range at the week 4 follow-up visit for 41.0 and 39.1% of the patients in Cohorts 1 and 2, respectively. The incidence of AEs occurring after the first administration of FCM (treatment-emergent AEs, TEAE) was generally low and similar in Cohorts 1 (11/20 [55.0%]) and 2 (13/26 [50.0%]). Most TEAEs were mild; only 2/ 20 patients (10.0%) in Cohort 1 and 3/26 (11.5%) in Cohort 2 had TEAEs of moderate intensity. There were no AEs of severe intensity, serious AEs, or deaths. Most AEs were considered by the investigator to be unrelated or unlikely to be related to the study medication. Since accumulation of serum iron was not observed, a dosing interval of 3-4 days (500 mg iron) or 1 week (1000 mg iron) was demonstrated to be adequate. The increase in serum ferritin and TSAT at the 4-week follow-up visit is indicative of a repletion of the iron stores. The results suggest that doses up to 1000 mg i.v. iron administered as FCM over 15 min arewell tolerated and effective in the treatment of patients with IDA due to a GI disorder.