Effects of an Al3+- and Mg2+-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin (TG-873870) in healthy Chinese volunteers
Abstract
Yi-fan ZHANG1, Xiao-jian DAI1, Ting WANG2, Xiao-yan CHEN1, Li LIANG2, Hua QIAO2, Cheng-yuan TSAI3, Li-wen CHANG3, Ping-ting HUANG3, Chiung-yuan HSU3, Yu-ting CHANG3, Chen-en TSAI3, Da-fang ZHONG1, *
1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2The First Hospital Affiliated to Lanzhou University, Lanzhou 730000, China; 3TaiGen Biotechnology Co Ltd, Taipei 11470, Taiwan, China
Aim: To evaluate the effects of an Al3+- and Mg2+-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin in healthy humans.
Methods: Two single-dose, open-label, randomized, crossover studies were conducted in 24 healthy male Chinese volunteers (12 per study). In Study 1, the subjects orally received nemonoxacin (500 mg) alone, or an antacid (containing 318 mg of Al3+ and 496 mg of Mg2+) plus nemonoxacin administered 2 h before, concomitantly or 4 h after the antacid. In Study 2, the subjects orally received nemonoxacin (500 mg) alone, or nemonoxacin concomitantly with ferrous sulfate (containing 60 mg of Fe2+) or calcium carbonate (containing 600 mg of Ca2+).
Results: Concomitant administration of nemonoxacin with the antacid significantly decreased the area under the concentration-time curve from time 0 to infinity (AUC0–∞) for nemonoxacin by 80.5%, the maximum concentration (Cmax) by 77.8%, and urine recovery (Ae) by 76.3%. Administration of nemonoxacin 4 h after the antacid decreased the AUC0–∞ for nemonoxacin by 58.0%, Cmax by 52.7%, and Ae by 57.7%. Administration of nemonoxacin 2 h before the antacid did not affect the absorption of nemonoxacin. Administration of nemonoxacin concomitantly with ferrous sulfate markedly decreased AUC0–∞ by 63.7%, Cmax by 57.0%, and Ae by 59.7%, while concomitant administration of nemonoxacin with calcium carbonate mildly decreased AUC0–∞ by 17.8%, Cmax by 14.3%, and Ae by 18.4%.
Conclusion: Metal ions, Al3+, Mg2+, and Fe2+ markedly decreased the absorption of nemonoxacin in healthy Chinese males, whereas Ca2+ had much weaker effects. To avoid the effects of Al3+ and Mg2+-containing drugs, nemonoxacin should be administered ≥2 h before them.
Keywords: nemonoxacin; nonfluorinated quinolone; drug-drug interaction; antacid; ferrous sulfate; calcium carbonate; drug absorption; clinical pharmacokinetics
This work was supported by the US National Institute of Health/National Institute of Environmental Health Grant RO1 ES008146 (Wei ZHENG), the US Department of Defense Contract USAMRMC W81XWH-05-1-0239 (Wei ZHENG), and the National Major Projects from the Ministry of Science and Technology of China (2012ZX09506001-004) (Su ZENG).
* To whom correspondence should be addressed.
E-mail dfzhong@simm.ac.cn
Received 2014-07-10 Accepted 2014-09-02
Keywords:
1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2The First Hospital Affiliated to Lanzhou University, Lanzhou 730000, China; 3TaiGen Biotechnology Co Ltd, Taipei 11470, Taiwan, China
Aim: To evaluate the effects of an Al3+- and Mg2+-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin in healthy humans.
Methods: Two single-dose, open-label, randomized, crossover studies were conducted in 24 healthy male Chinese volunteers (12 per study). In Study 1, the subjects orally received nemonoxacin (500 mg) alone, or an antacid (containing 318 mg of Al3+ and 496 mg of Mg2+) plus nemonoxacin administered 2 h before, concomitantly or 4 h after the antacid. In Study 2, the subjects orally received nemonoxacin (500 mg) alone, or nemonoxacin concomitantly with ferrous sulfate (containing 60 mg of Fe2+) or calcium carbonate (containing 600 mg of Ca2+).
Results: Concomitant administration of nemonoxacin with the antacid significantly decreased the area under the concentration-time curve from time 0 to infinity (AUC0–∞) for nemonoxacin by 80.5%, the maximum concentration (Cmax) by 77.8%, and urine recovery (Ae) by 76.3%. Administration of nemonoxacin 4 h after the antacid decreased the AUC0–∞ for nemonoxacin by 58.0%, Cmax by 52.7%, and Ae by 57.7%. Administration of nemonoxacin 2 h before the antacid did not affect the absorption of nemonoxacin. Administration of nemonoxacin concomitantly with ferrous sulfate markedly decreased AUC0–∞ by 63.7%, Cmax by 57.0%, and Ae by 59.7%, while concomitant administration of nemonoxacin with calcium carbonate mildly decreased AUC0–∞ by 17.8%, Cmax by 14.3%, and Ae by 18.4%.
Conclusion: Metal ions, Al3+, Mg2+, and Fe2+ markedly decreased the absorption of nemonoxacin in healthy Chinese males, whereas Ca2+ had much weaker effects. To avoid the effects of Al3+ and Mg2+-containing drugs, nemonoxacin should be administered ≥2 h before them.
Keywords: nemonoxacin; nonfluorinated quinolone; drug-drug interaction; antacid; ferrous sulfate; calcium carbonate; drug absorption; clinical pharmacokinetics
This work was supported by the US National Institute of Health/National Institute of Environmental Health Grant RO1 ES008146 (Wei ZHENG), the US Department of Defense Contract USAMRMC W81XWH-05-1-0239 (Wei ZHENG), and the National Major Projects from the Ministry of Science and Technology of China (2012ZX09506001-004) (Su ZENG).
* To whom correspondence should be addressed.
E-mail dfzhong@simm.ac.cn
Received 2014-07-10 Accepted 2014-09-02