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Pharmacokinetics, Safety and Tolerability of DA-6034, an Anti-Inflammatory Agent, After Single and Multiple Oral Administrations in Healthy Volunteers

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Abstract

Background and Objectives

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. DA-6034 has been shown to be effective in an IBD model and has demonstrated a good toxicological profile in preclinical studies. This study evaluated the tolerability, safety and pharmacokinetics of DA-6034 in healthy volunteers.

Methods

A double-blind, randomized, placebo-controlled, ascending-dose study was conducted in 67 healthy volunteers. In the single-ascending-dose study, 10, 20, 50, 100 or 200 mg of DA-6034 was administered orally to 40 subjects; in the multiple-ascending-dose study, 40, 100 or 200 mg/day of DA-6034 was administered orally to 27 subjects for 7 days. Serial blood and urine samples were taken for pharmacokinetic analysis. Plasma drug concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed throughout the study.

Results

DA-6034 had minimal absorption, and the pharmacokinetic parameters were highly variable among subjects. For both the single- and multiple-dose administrations, the coefficients of variation of the area under the plasma concentration–time curve to the last observation (AUClast) and the area under the plasma concentration–time curve over the dosing interval at steady state (AUCss,τ) ranged from 16.0 to 125.0 %. At doses of up to 200 mg of DA-6034, the mean maximum plasma concentration (C max) was <3 ng/mL, and the urine recovery ratio was 0.3 % of the dose, indicating a lack of absorption. Twenty-two mild adverse events were reported in 14 subjects. There were no serious adverse events and no significant changes in the safety assessment.

Conclusion

DA-6034 was well tolerated and minimally absorbed in healthy volunteers. The non-systemic, local exposure of the gastrointestinal tract to DA-6034 may be advantageous for IBD treatment.

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Acknowledgments

This research was conducted with the support of Dong-A Pharm. Inc. The authors do not have any conflicts of interest to declare.

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Author notes

  1. Kwang-Hee Shin

    Present address: Department of Clinical Pharmacy, College of Pharmacy, Kyungpook National University, Daegu, Korea

Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea

    Jieon Lee, Kwang-Hee Shin, Kyoung Soo Lim & In-Jin Jang

  2. Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Korea

    Jung-Ryul Kim

  3. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeong-gi, Korea

    Jae-Yong Chung

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  1. Jieon Lee
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  2. Kwang-Hee Shin
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  3. Jung-Ryul Kim
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  4. Kyoung Soo Lim
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Correspondence to Jae-Yong Chung.

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Lee, J., Shin, KH., Kim, JR. et al. Pharmacokinetics, Safety and Tolerability of DA-6034, an Anti-Inflammatory Agent, After Single and Multiple Oral Administrations in Healthy Volunteers. Clin Drug Investig 34, 37–42 (2014). https://doi.org/10.1007/s40261-013-0147-0

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