Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

XU Yi-ping; CHEN Bing; RONG Zheng-xing; CHEN Hong-zhuan; ZHANG Jun-dong

doi:10.3969/j.issn.1006-0111.2013.05.005

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2013 > 31(5): 338-343,346

XU Yi-ping, CHEN Bing, RONG Zheng-xing, CHEN Hong-zhuan, ZHANG Jun-dong. Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects[J]. Journal of Pharmaceutical Practice and Service, 2013, 31(5): 338-343,346. doi: 10.3969/j.issn.1006-0111.2013.05.005

Citation:

XU Yi-ping, CHEN Bing, RONG Zheng-xing, CHEN Hong-zhuan, ZHANG Jun-dong. Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects[J]. Journal of Pharmaceutical Practice and Service, 2013, 31(5): 338-343,346. doi: 10.3969/j.issn.1006-0111.2013.05.005

Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

doi: 10.3969/j.issn.1006-0111.2013.05.005

1.
School of Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai 200025, China
2.
School of Medicine, Shanghai Jiaotong University, Shanghai 200025 China
3.
Shanghai sine pharmaceutical R&D center, Shanghai 201206 China

Received Date: 2012-12-17
Rev Recd Date: 2013-04-08

Abstract

Objective To establish a population pharmacokinetic (PPK) model of metformin in healthy Chinese subjects, and evaluate the effect of different physiological factors on pharmacokinetic parameters of metformin. Methods A single dose, open label PK study was designed to assess the pharmacokinetics of metformin in healthy Chinese subjects (11 male and 9 female subjects). After 1 000 mg single dose of metformin sustained release tablets being taken, 0~24 h blood samples of each subject were collected. Concentration of plasma metformin was measured by the LC-MS/MS method. Non-compartment analysis was carried out through Winonlin 5.01 software. A PPK model in healthy Chinese subjects was established by using NONMEM. The effects of body weight and other physiological factors on metformin pharmacokinetics were assessed. Results One-compartment model with first-order absorption was the best for the PPK of metformin and the CL/F, Vd/F and Ka were (95.8±7.46) L/h, (553±45.9) L, and (0.596±0.070)/h, respectively. It was proved that, the simulation of model improved significantly (P<0.05) when body weight was used as the covariate of CL/F and Vd/F. Conclusion The PPK method could be used in the metformin pharmacokinetic study and body weight had statistically significant effect on the clearance of metformin.
- metformin,
- population pharmacokinetics (PPK),
- LC-MS/MS

References

[1]	Krentz AJ,Bailey CJ.Oral antidiabetic agents:current role in type 2 diabetes mellitus[J].Drugs,2005,65(3):385.
[2]	Johansen K.Efficacy of metformin in the treatment of NIDDM,mea-analysis[J].Diabetes care,1999;22(1):33.
[3]	Wildasin EM,Skaar DJ,Kirchain WR,et al.Metformin, apromising oral antihyperglycemic for the treatment of noninsulin-dependent diabetes mellitus[J].J Pharmacother,1997,17(1):62.
[4]	Graham GG,Punt J,Arora M,et al.Clinical pharmacokinetics of metformin[J].Clin Pharmacokinet,2011,50(2):81.
[5]	Jabbour S,Ziring B.Advantages of extended-release metformin in patients with type 2 diabetes mellitus[J].Postgrad Med,2011,123(1):15.
[6]	Schwartz SL,Gordi T,Hou E,et al.Clinical development of metformin extendedrelease tablets for type 2 diabetes:an overview. Expert Opin Drug Metab Toxicol[J].2008,4(9):1235.
[7]	Cullen E, Liao J,Lukacsko P,et al.Pharmacokinetics and dose proportionality of extended-release metformin following administration of 1 000,1 500,2 000 and 2 500 mg in healthy volunteers[J].Biopharm Drug Dispos,2004,25(6):261.
[8]	Sheiner LB,Rosenberg B,Marathe VV.Estimation of population characteristics of pharmacokinetic parameters from routine clinical data[J].J Pharmacokinet Biopharm,1977,5(5):445.[JP+1]
[9]	Vozeh S,Steimer JL,Rowland M,et al.The use of population pharmacokinetics in drug development[J].Clin Pharmacokinet,1996,30(2):81.[JP+1]
[10]	Aarons L,Balant LP,Mentré F,et al.Population approaches in drug development.Report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software[J].Eur J Clin Pharmacol,1994;46(5):389.
[11]	Hong Y,Rohatagi S,Habtemariam B,et al.Population exposureresponse modeling of metformin in patients with type 2 diabetes mellitus[J].J Clin Pharmacol,2008,48(6):696.[JP3]
[12]	Charles B,Norris R,Xiao X,et al.Population pharmacokinetics of metformin in late pregnancy[J].Ther Drug Monit,2006,28(1):67.
[13]	厉伟兰,刘晓东,谢林,等.二甲双胍缓释片人体药代动力学及其相对生物利用度[J].江苏药学与临床研究,2006,14(2):72.
[14]	汤净,钟国平,刘伟东,等.国产盐酸二甲双胍缓释片的人体药动学及相对生物利用度[J].中国新药杂志,2005,14(2):197.
[15]	廉江平,张鹏,李小川,等.盐酸二甲双胍缓释片的药代动力学及相对生物利用度研究[J].西北药学杂志,2007,22(5):227.
[16]	陈勇川,何菊英,唐敏,等.盐酸二甲双胍缓释片人体相对生物利用度及其药代动力学研究[J].第三军医大学学报,2005,27(21):2148.
[17]	杨洁,张银娣,胡刚,等.盐酸二甲双胍缓释片人体药代动力学和相对生物利用度研究[J].南京医科大学学报:自然科学版,2007,27(9):920.
[18]	郑恒,陈雅丽,王莉,等.盐酸二甲双胍缓释片药物动力学及生物等效性研究[J].华中科技大学学报:医学版,2007,36(4):517.
[19]	温新国,张霖泽,黄民,等.盐酸二甲双胍缓释片与国外上市品的药动学比较及体内外相关性研究[J].广东药学院学报,2005,21(3):284.
[20]	Proctor WR,Bourdet DL,Thakker DR.Mechanisms underlying saturable intestinal absorption of metformin[J].Drug Metab Dispos,2008,36(8):1650.
[21]	Robert F,Fendri S,Hary L,et al.Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects[J].Diabetes Metab,2003,29(3):279.
[22]	Briggs GG,Ambrose PJ,Nageotte MP,et al.Excretion of metformin into breast milk and the effect on nursing infants[J].Obstet Gynecol,2005,105(6):1437.
[23]	Pillans PI,Landsberg PG,Fleming AM,et al.Evaluation of dosage adjustment in patients with renal impairment[J].Intern Med J,2003,33(1-2): 10.
[24]	Stepensky D,Friedman M,Raz I,et al.Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect[J].Drug Metab Dispos,2002,30(8):861.
[25]	Lee SH,Kwon KI.Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers[J].Arch Pharm Res,2004,27(7):806.
[26]	Sun L,Kwok E,Gopaluni B,et al.Pharmacokinetic-pharmacodynamic modeling of metformin for the treatment of type II diabetes mellitus[J].Open Biomed Eng J,2011,5,1.

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通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

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Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

1. School of Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai 200025, China

2. School of Medicine, Shanghai Jiaotong University, Shanghai 200025 China

3. Shanghai sine pharmaceutical R&D center, Shanghai 201206 China

Received Date: 2012-12-17

Rev Recd Date: 2013-04-08

Key words:

Abstract: Objective To establish a population pharmacokinetic (PPK) model of metformin in healthy Chinese subjects, and evaluate the effect of different physiological factors on pharmacokinetic parameters of metformin. Methods A single dose, open label PK study was designed to assess the pharmacokinetics of metformin in healthy Chinese subjects (11 male and 9 female subjects). After 1 000 mg single dose of metformin sustained release tablets being taken, 0~24 h blood samples of each subject were collected. Concentration of plasma metformin was measured by the LC-MS/MS method. Non-compartment analysis was carried out through Winonlin 5.01 software. A PPK model in healthy Chinese subjects was established by using NONMEM. The effects of body weight and other physiological factors on metformin pharmacokinetics were assessed. Results One-compartment model with first-order absorption was the best for the PPK of metformin and the CL/F, Vd/F and Ka were (95.8±7.46) L/h, (553±45.9) L, and (0.596±0.070)/h, respectively. It was proved that, the simulation of model improved significantly (P<0.05) when body weight was used as the covariate of CL/F and Vd/F. Conclusion The PPK method could be used in the metformin pharmacokinetic study and body weight had statistically significant effect on the clearance of metformin.

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Reference (26)

[1]	Krentz AJ,Bailey CJ.Oral antidiabetic agents:current role in type 2 diabetes mellitus[J].Drugs,2005,65(3):385.
[2]	Johansen K.Efficacy of metformin in the treatment of NIDDM,mea-analysis[J].Diabetes care,1999;22(1):33.
[3]	Wildasin EM,Skaar DJ,Kirchain WR,et al.Metformin, apromising oral antihyperglycemic for the treatment of noninsulin-dependent diabetes mellitus[J].J Pharmacother,1997,17(1):62.
[4]	Graham GG,Punt J,Arora M,et al.Clinical pharmacokinetics of metformin[J].Clin Pharmacokinet,2011,50(2):81.
[5]	Jabbour S,Ziring B.Advantages of extended-release metformin in patients with type 2 diabetes mellitus[J].Postgrad Med,2011,123(1):15.
[6]	Schwartz SL,Gordi T,Hou E,et al.Clinical development of metformin extendedrelease tablets for type 2 diabetes:an overview. Expert Opin Drug Metab Toxicol[J].2008,4(9):1235.
[7]	Cullen E, Liao J,Lukacsko P,et al.Pharmacokinetics and dose proportionality of extended-release metformin following administration of 1 000,1 500,2 000 and 2 500 mg in healthy volunteers[J].Biopharm Drug Dispos,2004,25(6):261.
[8]	Sheiner LB,Rosenberg B,Marathe VV.Estimation of population characteristics of pharmacokinetic parameters from routine clinical data[J].J Pharmacokinet Biopharm,1977,5(5):445.[JP+1]
[9]	Vozeh S,Steimer JL,Rowland M,et al.The use of population pharmacokinetics in drug development[J].Clin Pharmacokinet,1996,30(2):81.[JP+1]
[10]	Aarons L,Balant LP,Mentré F,et al.Population approaches in drug development.Report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software[J].Eur J Clin Pharmacol,1994;46(5):389.
[11]	Hong Y,Rohatagi S,Habtemariam B,et al.Population exposureresponse modeling of metformin in patients with type 2 diabetes mellitus[J].J Clin Pharmacol,2008,48(6):696.[JP3]
[12]	Charles B,Norris R,Xiao X,et al.Population pharmacokinetics of metformin in late pregnancy[J].Ther Drug Monit,2006,28(1):67.
[13]	厉伟兰,刘晓东,谢林,等.二甲双胍缓释片人体药代动力学及其相对生物利用度[J].江苏药学与临床研究,2006,14(2):72.
[14]	汤净,钟国平,刘伟东,等.国产盐酸二甲双胍缓释片的人体药动学及相对生物利用度[J].中国新药杂志,2005,14(2):197.
[15]	廉江平,张鹏,李小川,等.盐酸二甲双胍缓释片的药代动力学及相对生物利用度研究[J].西北药学杂志,2007,22(5):227.
[16]	陈勇川,何菊英,唐敏,等.盐酸二甲双胍缓释片人体相对生物利用度及其药代动力学研究[J].第三军医大学学报,2005,27(21):2148.
[17]	杨洁,张银娣,胡刚,等.盐酸二甲双胍缓释片人体药代动力学和相对生物利用度研究[J].南京医科大学学报:自然科学版,2007,27(9):920.
[18]	郑恒,陈雅丽,王莉,等.盐酸二甲双胍缓释片药物动力学及生物等效性研究[J].华中科技大学学报:医学版,2007,36(4):517.
[19]	温新国,张霖泽,黄民,等.盐酸二甲双胍缓释片与国外上市品的药动学比较及体内外相关性研究[J].广东药学院学报,2005,21(3):284.
[20]	Proctor WR,Bourdet DL,Thakker DR.Mechanisms underlying saturable intestinal absorption of metformin[J].Drug Metab Dispos,2008,36(8):1650.
[21]	Robert F,Fendri S,Hary L,et al.Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects[J].Diabetes Metab,2003,29(3):279.
[22]	Briggs GG,Ambrose PJ,Nageotte MP,et al.Excretion of metformin into breast milk and the effect on nursing infants[J].Obstet Gynecol,2005,105(6):1437.
[23]	Pillans PI,Landsberg PG,Fleming AM,et al.Evaluation of dosage adjustment in patients with renal impairment[J].Intern Med J,2003,33(1-2): 10.
[24]	Stepensky D,Friedman M,Raz I,et al.Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect[J].Drug Metab Dispos,2002,30(8):861.
[25]	Lee SH,Kwon KI.Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers[J].Arch Pharm Res,2004,27(7):806.
[26]	Sun L,Kwok E,Gopaluni B,et al.Pharmacokinetic-pharmacodynamic modeling of metformin for the treatment of type II diabetes mellitus[J].Open Biomed Eng J,2011,5,1.

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Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

doi: 10.3969/j.issn.1006-0111.2013.05.005

Abstract

References

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通讯作者: 陈斌, bchen63@163.com

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