不同剂量注射用泮托拉唑钠在健康人体内的药代动力学和药效学研究

Pharmacokinetics and pharmacodynamics of pantoprazole sodium at different doses in healthy volunteers

目的观察不同剂量注射用泮托拉唑钠在中国健康志愿者体内的药代动力学和药效学特征,并评价其安全性。方法用单中心、随机、开放、平行对照的试验设计,筛选20名健康受试者,采用男女分层区组随机化方法分组,分别静脉滴注40、80 mg注射用泮托拉唑钠(每日2次,连续5 d),给药后监测24 h胃内pH值。用LC-MS/MS法测定左旋泮托拉唑钠血药浓度,数据分别用Win Nonlin 6.4软件和SAS软件分析处理。结果首次静脉滴注注射用泮托拉唑钠后,40、80 mg剂量组后左旋泮托拉唑的主要药动学参数:C_(max)分别为(2.37±0.61)、(4.56±0.89)μg/mL;AUC_(0-t)分别为(4.96±3.26)、(10.16±3.16)μg·h/mL;AUC_(0-∞)分别为(5.17±3.68)、(10.34±3.35)μg·h/mL;t_(1/2)分别为(1.67±0.76)、(1.75±0.57)h;T_(max)分别为(0.50±0.01)、(0.53±0.08)h;连续给药5 d后40、80 mg剂量组左旋泮托拉唑的主要药动学参数:C_(max)分别为(2.30±0.62)、(4.50±0.71)μg/mL;AUC_(0-t)分别为(5.02±3.85)、(10.75±3.82)μg·h/mL;AUC_(0-∞)分别为(5.26±4.35)、(10.98±4.10)μg/mL·h;Cmin,ss分别为(0.03±0.08)、(0.05±0.07)μg/mL;t_(1/2)分别为(1.72±0.78)、(1.80±0.64)h;T_(max)分别为(0.52±0.04)、(0.50±0.00)h。用药第1天后40、80 mg剂量组胃内pH>4的时间比例分别为(38.6±20.9)%、(46.9±16.5)%;pH>6的时间比例分别为(25.5±20.6)%、(32.7±7.9)%;用药第5天后胃内pH>4的时间比例分别为(69.6±15.4)%、(80.2±16.6)%;pH>6的时间比例分别为(48.3±13.7)%、(49.7±15.7)%。结论注射用泮托拉唑钠在健康人体内符合线性药代动力学特征。通过两剂量组药效学参数比较,80 mg剂量组的抑酸效果明显优于40 mg剂量组,且服药后较安全。建议临床使用80 mg每12小时1次。

Objective To investigate the pharmacokinetic and pharmacodynamic properties of pantoprazole sodium at different doses of injection and explore its safety in healthy Chinese volunteers.Methods A single center,randomized,open,and parallel controlled trial was designed for this study.Twenty healthy subjects were screened by a stratified randomization method for men and women to receive multiple doses of pantoprazole sodium of 40 and 80 mg（ twice daily for 5 consecutive days）,respectively. The intragastric pH value was monitored 24 h after administration. S-（-）-pantoprazole sodium concentration was determined by liquid chromatography-mass spectrometry/mass spectrometry（ LC-MS/MS）. The data were analyzed by Win Nonlin 6. 4 software and SAS software respectively. Results After the first intravenous infusion of pantoprazole sodium,the main pharmacokinetic parameters of S-（-）-pantoprazole after 40 and80 mg groups were as follows： C（max）were 2. 37 ± 0. 61 and 4. 56 ± 0. 89 μg/mL; AUC（0-t）4. 96 ± 3. 26 and10. 16 ± 3. 16 μg · h/mL; AUC（0-∞）5. 17 ± 3. 68 and 10. 34 ± 3. 35 μg · h/mL; t（1/2）1. 67 ± 0. 76 and1. 75 ± 0. 57 h; and T（max）0. 50 ± 0. 01 and 0. 53 ± 0. 08 h. After 5 days＇ continuous administration,the main pharmacokinetic parameters were as follows： C（max）were 2. 30 ± 0. 62 and 4. 50 ± 0. 71 μg/mL; AUC（0-t）5. 02 ± 3. 85 and 10. 75 ± 3. 82 μg · h/mL; AUC（0-∞）5. 26 ± 4. 35 and 10. 98 ± 4. 10 μg/mL · h; Cmin,ss0. 03 ± 0. 08 and 0. 05 ± 0. 07 μg/mL; t（1/2）1. 72 ± 0. 78 and 1. 80 ± 0. 64 h; and T（max）0. 52 ± 0. 04 and0. 50 ± 0. 00 h. After the first day of treatment,the both groups had（ 38. 6 ± 20. 9） % and（ 46. 9 ±16. 5） %,respectively of time with gastric juice pH 〉4,and（ 25. 5 ± 20. 6） % and（ 32. 7 ± 7. 9） %respectively with pH 6. In 5 d after the administration,the time percentage of gastric juice pH 4 was（ 69. 6 ± 15. 4） % and（ 80. 2 ± 16. 6） %,respectively,and it of pH 6 was（ 48. 3 ± 13. 7） % and（ 49. 7 ±15. 7） %,respectively. Conclusion The pantoprazole sodium for injection is in accordance with the linear pharmacokinetic characteristics in healthy volunteers. Compared with the pharmacodynamic parameters of 2 doses,the inhibitory effect of 80 mg dose group is better than that of 40 mg dose group,and the higher dose is safer. It is recommended of 80 mg q12 h in clinical practice.