Pharmacokinetics And Pharmacodynamics Of S-(-)-pantoprazole Sodium By Different Routes In Healthy Subjects

Pantoprazole is the third generation proton pump inhibitor after omeprazole and lansolazole,and it is mainly used for diseases such as gastric ulcer,duodenal ulcer,reflux esophagitis and other diseases caused by excessive gastric acid.Pantoprazole is relatively stable under neutral and weakly acidic conditions,but it is rapidly activated under strongly acidic conditions.It can selectively acting on gastric mucosal wall cells and inhibiting the activity of H⁺-K⁺-ATPase in the cell wall,so that H⁺in the wall cells can not be transferred to the stomach,further to inhibit the secretion of gastric acid.Pantoprazole plays the most important role in the process of inhibiting acid because that H⁺-K⁺-ATPase is the last process of Wall cell acid production,it not only inhibits the secretion of gastric acid caused by gastrokinin,histamine,and choline,but also inhibits the secretion of some basic gastric acid that is not affected by choline or H₂ receptor blockers.Pantoprazole has the advantage of small interaction between drugs when it is used in combination with other drugs.The clinical use of pantoprazole is a mixture of racemates,in which the ratio of Levo Isomer to dextral Isomer is 1:1,and S-?-?-pantoprazole is its main active component,while R-?-?-pantoprazole is basically inactive.Studies on the pharmacokinetics and pharmacodynamics of the racemate pantoprazole sodium in the human body have been reported in many reports,but the S-?-?-pantoprazole sodium has not yet been listed in China.There is little report on the quantitative effect correlation between pharmacokinetics and pharmacodynamics parameters in healthy volunteers in China.According to the conditions of different patients and the characteristics of drugs,and on the basis of the treatment and rehabilitation of diseases,domestic drug research and development institutions have developed S-?-?-pantoprazole sodium injection and oral dosage forms.In order to further determine the safety and rationality of levopentrazole sodium in the Chinese population,the study measured the content of S-?-?-pantoprazole sodium in plasma by LC-MS/MS with using S-?-?-pantoprazole sodium injection and S-?-?-pantoprazole sodium enteric solution tablets.The intragastric pH of healthy subjects within 24 h was monitored and their pharmacokinetics and pharmacodynamics were compared.Objective Pharmacokinetics of S-?-?-pantoprazole sodium and S-?-?-pantoprazole sodium enteric-coated tablets were evaluated by pharmacokinetic/pharmacodynamic?PK/PD?analysis.as well as effectiveness and safety of the effects of pH in different doses of healthy volunteers.To analyze the dose-effect correlation between pharmacokinetics and pharmacokinetic parameters of S-?-?-pantoprazole sodium injection and S-?-?-pantoprazole sodium enteric-coated tablets,it provides a reference for the development of Phase II clinical trial plan and clinical precision medication.Methods This study used a single-center,randomized,open,positive drug control trial design.The test plan of S-?-?-pantoprazole sodium for injection is as follows:Seventy healthy subjects were screened and grouped according to the randomized method of male and female stratified group and divided into seven groups,five experimental groups and two control groups.Each group includes five men and five women.The experimental group received multi-dose intravenous infusion of S-?-?-pantoprazole sodium for five days.Each dose group includes 20 mg/day,20 mg/12h,40 mg/day,40 mg/12h and 80 mg/day,the control group received multiple doses of pantoprazole sodium for intravenous infusion for five days.Each dose group includes 40 mg/12 h and 80 mg/12 h.Vital signs?body temperature,pulse,respiration,blood pressure?were measured within half an hour before the first dose and after each dose,A series of venous blood samples?4 mL?were collected in heparinized tubes at 0?pre-dose?,10,20,30,35,45,60 and 90 min and 2,3,4,5,6,8 and 12 h post-dose on day 1 and day 5.On days 2,3,and 4,venous blood was collected before drug administration to determine the concentration of drug trough,and LC-MS/MS method was used to determine the plasma concentration of S-?-?-pantoprazole sodium.The intragastric pH was monitored for 24 hours after dosing on day 1 and day 5.The test plan of S-?-?-pantoprazole sodium enteric solution tablets is as follows:thirty healthy subjects were screened and grouped according to the randomized method of male and female stratified group and divided into three groups,Each group includes five men and five women.The experimental group received multiple doses of S-?-?-pantoprazole sodium enteric-coated tablets for 7 days.The doses of each dose group were 20mg/day and40mg/day.The control group was given 40mg/day of pantoprazole sodium enteric-coated tablets for 7 days.Vital signs?body temperature,pulse,respiration,blood pressure?were measured within half an hour before the first dose and after each dose,A series of venous blood samples?4 mL?were collected in heparinized tubes at 0?pre-dose?,10,20,30,35,45,60 and 90 min and 2,3,4,5,6,8 and 12 h post-dose on day 1 and day 7.On days 4,5,and 6,venous blood was collected before drug administration to determine the concentration of drug trough,and LC-MS/MS method was used to determine the plasma concentration of S-?-?-pantoprazole sodium.The intragastric pH was monitored for 24 hours after dosing on day 1 and day 7.The data was analyzed and processed by WinNonlin 6.4software and SPSS18.0 software.Results 1.The main pharmacokinetic parameters after the first dose on the first day of subjects with intravenous infusion of S-?-?-pantoprazole sodium are as follows:C_maxax were2.02±0.41,2.28±0.43,4.68±0.95,4.14±0.75,7.97±1.71,2.37±0.61 and 4.56±0.89?g/mL.AUC_?0-t?were 4.23±3.03,4.35±1.27,9.93±3.23,7.08±2.27,16.93±6.82,4.96±3.26 and 10.16±3.16?g·h/mL.t_1/2/2 were 1.43±0.75,1.50±0.44,1.67±0.20,1.25±0.26,1.73±0.52,1.67±0.76 and1.75±0.57 h,T_max were 0.52±0.04,0.60±0.32,0.50±0.00,0.51±0.03,0.50±0.01,0.50±0.01 and0.53±0.08)h.The main pharmacokinetic parameters after 5 days of continuous administration as follows:C_max were 2.21±0.50,2.29±0.47,4.61±0.84,4.61±0.94,8.01±1.76,2.30±0.62 and 4.50±0.71?g/mL,AUC_?0-t?were 4.27±2.93,4.46±1.57,9.82±3.34,7.15±1.86,16.34±6.91,5.02±3.85 and 10.75±3.82?g·h/mL,t_1/2 were 1.54±0.76,1.52±0.43,1.57±0.22,1.28±0.30,1.69±0.33,1.72±0.78 and 1.80±0.64 h,T_max were 0.50±0.00,0.52±0.03,0.51±0.03,0.51±0.03,0.50±0.00,0.52±0.04 and 0.50±0.00 h,Rac?%?were 1.02±0.09,1.02±0.14,0.99±0.21,1.03±0.08,0.98±0.10,0.98±0.10 and 1.05±0.09.The ratio of time in the stomach to pH>4 in each group after the first day of treatment were 39.2±14.1,35.0±17.9,47.0±15.0,58.5±16.8,51.8±8.3,58.4±16.3 and 66.2±13.2%.The ratio of time in the stomach to pH>6 in each group were 21.3±13.5,17.2±15.8,27.6±14.2,34.1±20.3,34.4±8.6,34.5±15.8 and 40.2±8.5%.The ratio of time in the stomach to pH>4 in each group after five days of treatment were 54.6±20.7,63.5±16.8,50.0±9.7,76.5±14.6,58.1±7.6,69.6±15.4 and 80.2±16.6%.The ratio of time in the stomach to pH>6 in each group were 37.4±23.6,39.1±13.8,34.1±7.0,49.0±13.3,38.8±10.1,48.3±13.7 and49.7±15.7%.The average value of the 24h pH value in the stomach on the first day after administration were 3.42±0.83,3.34±0.95,3.95±0.80,4.55±0.99,4.25±0.49,4.52±0.86 and4.92±0.60.The median value were 2.15?2.70?3.95?5.00?4.20?4.81?5.14.The average value of the 24h pH value in the stomach on the five day after administration were4.43±1.43,4.82±0.79,4.27±0.52,5.43±0.73,4.60±0.51,5.22±0.77 and 5.60±0.85.The median value were 4.35?5.55?4.00?6.10?4.80?4.93?5.80.Twenty-nine subjects had 42adverse events,including vomiting,neutropenia,elevated ALT and AST,dizziness,and abnormal electrocardiogram.All adverse events were relieved without any special measures and no serious maladies.2.The main pharmacokinetic parameters after the first dose on the first day of subjects with S-?-?-pantoprazole sodium enteric-coated tablets:C_maxax were 1635±410,2756±1024 and1536±615 ng/mL,AUC_?0-t?were 3623±1322,7383±3785 and 3276±1302 ng·h/mL,t_1/2 were1.41±0.311,1.55±0.636 and 1.35±0.220 h,T_max were 2.90±1.15,3.55±1.12 and 3.35±1.11 h.The main pharmacokinetic parameters after seven days of continuous administration as follows:C_max,ss were 1704±239,3297±743 and 1832±557 ng/mL,AUC_?0-t,ss?were3587±1040,8189±3399 and 3878±1272 ng·h/mL,t_1/2 were 1.41±0.397,1.58±0.641 and1.45±0.218 h,T_max were 3.15±1.13,2.80±0.919 and 2.70±0.856 h,Rac?%?were1.03±0.194,1.17±0.219 and 1.34±0.699.The ratio of time in the stomach to pH>4 in each group after the first day of treatment were 32.98±10.7,45.37±9.61 and 32.63±14.63%.The ratio of time in the stomach to pH>6 in each group were 15.04±14.76,26.84±10.06 and21.36±14.68%.The ratio of time in the stomach to pH>4 in each group after seven days of treatment were 45.12±11.97,50.76±10.63 and 41.67±7.1%,the ratio of time in the stomach to pH>6 in each group were 28.21±12.21,31.51±6.08 and 26.58±10.08%.The average time of pH>4 in the stomach of each group after the first day of treatment were 7.91±2.57,10.89±2.31 and 7.83±3.51 h.The average time of pH>6 in the stomach of each group were3.61±3.54,6.44±2.41 and 5.13±3.52 h.The average time of pH>4 in the stomach of each group after seven days of treatment were 10.83±2.87,12.16±2.49 and 10±1.7 h and the average time of pH>6 in the stomach of each group were 6.77±2.93,7.55±1.47 and6.38±2.42 h.The average value of the 24h pH value in the stomach on the first day after administration were 3.0±0.7,3.8±0.5 and 3.2±0.8 and mean value of median were2.1±1.1,2.9±1.3 and 2.2±1.2.The average value of the 24h pH value in the stomach on the seventh day day after administration were 3.8±0.7,4.1±0.4 and 3.7±0.5,and mean value of median were 3.3±1.6,3.7±1.3,2.9±1.0.Two subjects had two adverse events and the main symptoms were elevated ALT and abnormal electrocardiogram.All adverse events were relieved without any special measures,and no serious adverse events occurred.Conclusion 1.The average Cmax and AUC_0-?of levopantoprazole were increased with increasing doses after 70 patients received intravenous infusion of 20 mg,40 mg and80 mg of levoparaxolazol for the first time.Using the power function model for dose proportional analysis,the 90%of the Cmax,AUC0-t and AUC_0-?values are in the range of0.8-1.25?linear criterion?,suggesting a clear linear trend.The use of S-?-?-pantoprazole sodium for injection in healthy volunteers showed that 20mg-80mg could effectively inhibit gastric acid secretion and increase gastric pH.As the dose increases,the effect of inhibiting gastric acid secretion tends to increase,and in the same daily dose,the effect of twice a day is better than once a day.The efficacy of the 40mg/12h S-?-?-pantoprazole group was superior to that of the other treatment groups,and similar to the efficacy of the 80mg/12h racemic group.The mean value of the accumulation index?Rac,Accumulation Index?of the 7 groups of subjects was approximately equal to 1,indicating that there was no accumulation of sodium pantoprazole and sodium pantoprazole for injection after multiple consecutive administrations.2.Thirty subjects received oral S-?-?-pantoprazole sodium enteric-coated tablets 20 mg,40 mg and pantoprazole enteric-coated tablets 40 mg once daily.20mg and 40mg dose groups can effectively inhibit gastric acid.With the increasement of dose,the effect of inhibiting gastric acid is enhanced.The total time ratio,mean time of 24h pH>4 and pH>6in the stomach of the 20mg/day levothine group,the mean time and the 24-hour pH value in the stomach were consistent with the 40mg/day control group.Gender differences between dose groups had no significant effect on the main pharmacokinetic parameters AUC,Cmax and T_1/2?P>0.05?.20 mg/day and 40 mg/day S-?-?-pantoprazole sodium enteric-coated tablets groups showed no accumulation in the body after the last administration,...