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European Journal of Clinical Pharmacology

, Volume 74, Issue 5, pp 561–569 | Cite as

Evaluation of pharmacokinetic and pharmacodynamic parameters following single dose of sitagliptin in healthy Indian males

  • Ganesh V. Sangle
  • Mohan Patil
  • Nitin J. Deshmukh
  • Sushant A. Shengule
  • Shantibhushan Kamble
  • Kiran Kumar Vuppalavanchu
  • Sushil Kale
  • Mirza Layeeq Ahmed Baig
  • Geetchandra Singh
  • Javed Shaikh
  • Jitendra Tripathi
  • P. Aravindababu
Pharmacodynamics

Abstract

Purpose

Sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes, is reported to be more efficacious in Indian patients than non-Indian patient population. The objective of the study was to evaluate pharmacokinetic and pharmacodynamic (PK/PD) parameters of single-dose sitagliptin 100 mg (Januvia) in healthy Indian male participants.

Method

In a randomised, single-dose, open-label, three-treatment, three-period, three-sequence, crossover bioavailability study, 18 healthy male participants received single-dose of sitagliptin under fasted and fed conditions. PK parameters (Cmax, Tmax, AUC0-∞ and t1/2) were determined using Phoenix WinNonlin software. PD parameters [DPP-IV inhibition, active glucagon-like peptide-1 (GLP-1) and insulin] were determined using established methods.

Results

PK parameters expressed in mean (SD) were Cmax 491.7 (135.9) ng/mL; AUC0-∞ 4256.1 (509.9) ng· hr/mL, Tmax 2.9 (1.0) hr and t1/2 10.4 (3.0) hr. The weighted average (WA) plasma DPP-4 inhibition over 24 h was 89.6% and WA of plasma active GLP-1 over 2 h after standardised meal (geometric mean ratio) was 11.1 (9.9) pM/L which is two- to- four fold higher compared to that reported in other populations. The mean average (SD) AUC of plasma insulin over 2 h of standardised meal was 47.9 (24.9) μIU/mL.

Conclusion

Although, there are differences in pharmacokinetic parameters, no clinically meaningful differences were observed with respect to DPP-IV inhibition between Indian and non-Indian population.

Keywords

Sitagliptin Pharmacodynamics Pharmacokinetics Incretins DPP-IV inhibitors 

Notes

Acknowledgements

The authors thank clinical researchers and participants who participated in this study. We acknowledge Dr. Sai Krishnaveni Chevooru (for editorial support) during the development of the manuscript. Wockhardt Limited (Mumbai, India) funded the study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2018_2433_MOESM1_ESM.docx (14 kb)
ESM 1 (DOCX 14 kb)

References

  1. 1.
    Whiting D, Guariguata L, Weil C, Shaw J (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321CrossRefPubMedGoogle Scholar
  2. 2.
    International Diabetes Federation IDF. (2015) Diabetes atlas 7. http://www.idf.org/about-diabetes/facts-figures. Accessed march 14,2017
  3. 3.
    Gerich J (2010) DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res Clin Pract 90:131–140CrossRefPubMedGoogle Scholar
  4. 4.
    Drucker D (2003) Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs 12:87–100CrossRefPubMedGoogle Scholar
  5. 5.
    Mohan V, Yang W, Son H et al (2009) Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract 83:106–116CrossRefPubMedGoogle Scholar
  6. 6.
    Kim Y, Hahn S, Oh T et al (2013) Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia 56:696–708CrossRefPubMedGoogle Scholar
  7. 7.
    Sudhakaran C, Kishore U, Anjana R et al (2011) Effectiveness of Sitagliptin in Asian Indian patients with type 2 diabetes-an Indian tertiary diabetes care center experience. Diab Technol Ther 13:27–31CrossRefGoogle Scholar
  8. 8.
    Awadhesh S (2015) Incretin response in Asian type 2 diabetes: are Indians different? Indian J Endocrinol Metab 19:30–38CrossRefGoogle Scholar
  9. 9.
    Chu X, Bleasby K, Yabut J et al (2007) Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther 321:673–683CrossRefPubMedGoogle Scholar
  10. 10.
    Ieiri I, Takane H, Hirota T, Otsubo K, Higuchi S (2006) Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. Expert Opin Drug Metab Toxicol 2:651–674CrossRefPubMedGoogle Scholar
  11. 11.
    Sissung T, Baum C, Kirkland C et al (2010) Pharmacogenetics of membrane transporters: an update on current approaches. Mol Biotechnol 44:152–167CrossRefPubMedGoogle Scholar
  12. 12.
    Mushtaq S, Mayee K, Amreen S et al (2014) A study on the current prescribing patterns of dipeptidyl peptidase 4 inhibitors in a multi speciality hospital outpatient setting. Asian J Pharm Clin Res 7:134–136Google Scholar
  13. 13.
    Tatosian D, Guo Y, Schaeffer A et al (2013) Dipeptidyl Peptidase-4 inhibition in patients with type 2 diabetes treated with Saxagliptin, Sitagliptin, or Vildagliptin. Diabetes Ther 4:431–442CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Herman G, Stevens C, Van Dyck K et al (2005) Pharmacokinetics and pharmacodynamics of single doses of sitagliptin, an inhibitor of dipeptidyl peptidase-IV, in healthy participants: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 78:675–688CrossRefPubMedGoogle Scholar
  15. 15.
    Herman G, Mistry G, Yi B et al (2011) Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males. Br J Clin Pharmacol 71:429–436CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bergman A, Stevens C, Zhou Y et al (2006) Pharmacokinetic and pharmacodynamics properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther 28:55–72CrossRefPubMedGoogle Scholar
  17. 17.
    Arun K, Meda V, Kucherlapati V et al (2012) Pharmacokinetic drug interaction between gemfibrozil and sitagliptin in healthy Indian male volunteers. Eur J Clin Pharmacol 68:709–714CrossRefGoogle Scholar
  18. 18.
    Vincent S, Reed J, Bergman A et al (2007) Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] sitagliptin in humans. Drug Metab Dispos 35:533–538CrossRefPubMedGoogle Scholar
  19. 19.
    Hartley H (1961) The modified gauss-Newton method for the fitting of non-linear regression functions by least squares. Technometrics 3:269–228CrossRefGoogle Scholar
  20. 20.
    Ramachandran A, Snehalatha C, Vijay V (2004) Low risk threshold for acquired diabetogenic factors in Asian Indians. Diabetes Res Clin Pract 65:189–195CrossRefPubMedGoogle Scholar
  21. 21.
    Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V, Indian Diabetes Prevention Programme (IDPP) (2006) Indian diabetes prevention Programme (IDPP): the Indian diabetes prevention programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian-Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 49:289–297CrossRefPubMedGoogle Scholar
  22. 22.
    Knowler W, Barrett-Connor E, Fowler S, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group (2002) Diabetes prevention program research group. reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403CrossRefPubMedGoogle Scholar
  23. 23.
    Gerstein H, Yusuf S, Bosch J et al (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368:1096–1105CrossRefPubMedGoogle Scholar
  24. 24.
    Ramachandran A, Snehalatha C, Mary S, Selvam S, Kumar CKS, Seeli AC, Shetty AS (2009) Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian diabetes prevention Programme-2 (IDPP-2). Diabetologia 52:1019–1026CrossRefPubMedGoogle Scholar
  25. 25.
    Scott R, Loeys T, Davies M et al (2008) Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab 10:959–969CrossRefPubMedGoogle Scholar
  26. 26.
    Williams-Herman D, Johnson J, Teng R, Luo E, Davies MJ, Kaufman KD, Goldstein BJ, Amatruda JM (2009) Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin 25:569–583CrossRefPubMedGoogle Scholar
  27. 27.
    Rosenstock J, Brazg R, Andryuk P, Lu K, Stein P, Sitagliptin Study 019 Group (2006) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized double-blind, placebo-controlled, parallel-group study. Clin Ther 28:1556–1568CrossRefPubMedGoogle Scholar
  28. 28.
    Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P, Sitagliptin Study 035 Group (2007) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 9:733–745CrossRefPubMedGoogle Scholar
  29. 29.
    Qualmann C, Nauck M, Holst J et al (1995) Insulinotropic actions of intravenous glucagon-like peptide-1 (GLP-1) [7-36 amide] in the fasting state in healthy subjects. Acta Diabetol 32:13–16CrossRefPubMedGoogle Scholar
  30. 30.
    Williams-Herman D, Engel S, Round E et al (2010) Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10246 patients with type 2 diabetes. BMC Endocr Disord 10:7CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sangle G, Lauffer L, Grieco A et al (2012) Novel biological action of the dipeptidylpeptidase-IV inhibitors, sitagliptin, as a glucagon-like peptide-1 secretagogue. Endocrinology 153:564–573CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ganesh V. Sangle
    • 1
  • Mohan Patil
    • 1
  • Nitin J. Deshmukh
    • 1
  • Sushant A. Shengule
    • 1
  • Shantibhushan Kamble
    • 2
  • Kiran Kumar Vuppalavanchu
    • 2
  • Sushil Kale
    • 2
  • Mirza Layeeq Ahmed Baig
    • 2
  • Geetchandra Singh
    • 2
  • Javed Shaikh
    • 2
  • Jitendra Tripathi
    • 2
  • P. Aravindababu
    • 2
  1. 1.Diabetes Research Lab, New Drug DiscoveryWockhardt Research CentreAurangabadIndia
  2. 2.Clinical Pharmacokinetics and Biopharmaceutics DepartmentWockhardt Research CentreAurangabadIndia

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