Comparative bioavailability of ferrous succinate tablet formulations without correction for baseline circadian changes in iron concentration in healthy Chinese male subjects: a single-dose, randomized, 2-period crossover study.

BACKGROUND: Ferrous succinate is used for the treatment of iron deficiency anemia. Determining the bioavailability of iron products is a challenge, because iron is naturally present in the blood and some tissues. Therefore, bioequivalence evaluation of ferrous formulations can be affected by the presence of endogenous iron species. Little information regarding the pharmacokinetics of ferrous supplements is available in the healthy Chinese population. OBJECTIVES: The aim of the study was to assess the comparative bioavailability of 200-mg of a test (ferrous succinate,100 mg × 2, Hunan Huana Pharmaceutical Co., Ltd., Hunan, China) and reference (Sulifei, 100 mg × 2, Nanjing Jinling Pharmaceutical Co., Ltd., Nanjing, China) formulation in healthy Chinese male subjects. The study was conducted to meet Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of ferrous succinate. METHODS: This study utilized a single-dose randomized, 2-period, crossover design with alternate assignment of subjects to treatment (a single 200-mg [100 mg × 2]) or reference formulation groups. Both groups underwent a 4-day diet equilibration before 2 days of treatment and, finally, a 4-day washout period for the bioequivalence study. Blood samples were collected at 8:00 am on every diet equilibration day, 0 (baseline), 1, 2, 3, 4, 4.5, 5, 6, 9, 12, 24, and 36 hours after drug administration. Iron concentrations were determined using an inductively coupled plasma mass spectrometry. Subjects in both groups were given a standardized diet, with known amounts of iron and calories. The formulations were assumed to be bioequivalent if the 90% CI ratios for C(max) were within 70% to 143% and AUC(0-last) were within 80% to 125%-criteria established by the Chinese Food and Drug Administration. Tolerability was monitored throughout the study by assessing clinical parameters (vital signs, chemistry laboratory) and subject reports. RESULTS: Twenty healthy Han Chinese male subjects (mean age, 26.8 years [range, 20-39 years]; weight, 61.9 kg [range, 52-72 kg]; body mass index, 21.5 kg/m(2) [range,19.1-23.8 kg/m(2)]; and baseline iron values, 1271 µg/L [range 1113-1429 µg/L]) were enrolled and completed the study. Without baseline correction for endogenous iron compound, the mean C(max) measurements of iron for the test and reference formulations were 2981 [621.1] and 3028 [707.4] µg/L, respectively; AUC(0-last) values were 48,460 [9242] and 48,390 [8420] µg/L/h, respectively; T(max) values were 4.3 [1.6] and 3.7 [1.3] hours. The 90% CIs for the ratios of C(max) and AUC(0-last) were 89.9% to 109.2% and 92.5% to 107.7%. No significant difference was found between groups with regard to pharmacokinetic parameters. Both test and reference formulations were well tolerated, with only 2 (10%) subjects who received the reference formulation complaining of mild heartburn that resolved after approximately 1 hour. Another subject (5%) complained of nausea 10 minutes after the test administration, which resolved within 2 hours. The relative bioavailability of the test-reference preparations was 101.6%. CONCLUSION: In this single-dose crossover study in healthy Chinese male subjects, the test and reference formulations of ferrous succinate 200-mg (100 mg × 2,) tablets met the criteria for assuming bioequivalence as defined by the Chinese Food and Drug Administration. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-11001646.