Safety and Pharmacokinetics of DO-309 in Healthy Volunteers: Repeated Oral Administration.

DOI 1 Citations 13 References
  • UCHIDA Eiji
    The Second Department of Pharmacology, School of Medicine, Showa-University
  • CHOU Toshihiro
    The Second Department of Pharmacology, School of Medicine, Showa-University
  • HUKAZAWA Ichirou
    Medical Foundation Keiyu -Kai, Obara Hospital
  • NAGUMO Akihiko
    Medical Foundation Keiyu -Kai, Obara Hospital
  • YASUDA Kuninobu
    The Second Department of Pharmacology, School of Medicine, Showa-University
  • KITASHIRO Reiji
    The Second Department of Pharmacology, School of Medicine, Showa-University
  • KOBAYASHI Shinichi
    Department of Pharmacology, St. Marianna University School of Medicine
  • YASUHARA Hajime
    The Second Department of Pharmacology, School of Medicine, Showa-University

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Other Title
  • ＤＯ‐３０９の健康人における安全性と薬物動態　第２報：　反復経口投与試験
  • Repeated Oral Administration
  • 2報: 反復経口投与試験

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Abstract

The safety, tolerabillity and pharmacokinetics of DO-309 (doxofylline: DOX) a new anti-asthmatic agent, were investigated in 18 healthy male volunteers after repeated oral administration of DO-309 (400 mg and 600 mg b.i.d.) or its placebo for 7 days. Values are mean±SD.<BR>All subjects completed the study without any adverse effects. No apparent changes in blood pressure, pulse rate, body temperature or clinical laboratory data were observed in any subjects. Steady-state plasma concentration of DOX was reached within 5-6 days in both treatments. Since non-linear phar-macokinetics was observed for DOX in the single dose study, the accumulation ratio was calculated for each pharmacokinetic parameter obtained from the plasma concentration-time curves after the first and the final dose. In 400 mg b.i.d. treatment, the AUC(0→12h) ratio of DOX was 20.23±13.31, Cmax 6.86±2-97, t1/2 3.70±1.06 and AUMC/AUC 3.23±0.63. About 70% of the total dose administered was recovered in the urine by 48 hours after the final administration. Michaelis-Menten Kinetics failed to simulate plasma concentration-time curves of DOX for the repeated administration. However, a similar value of the accumulation ratio was observed for each pharmacokinetic parameter of DOX in 600 mg b.i.d. traetment as seen in 400 mg treatment suggesting the probabillity of the prediction of a steady state concentration of DOX using the parameters obtained from the first dose.<BR>Repeated dosing of DO-309 both 800 mg/day and 1, 200 mg/day treatments were well tolerated. We concluded that the results support the feasibility of early Phase II study in asthmatic patients.

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