Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2017

01-06-2017 | Review Article

Clinical Pharmacokinetics and Pharmacodynamics of Antihyperglycemic Medications in Children and Adolescents with Type 2 Diabetes Mellitus

Authors: Fatemeh Akhlaghi, Kelly L. Matson, Amir Hooshang Mohammadpour, Meghan Kelly, Asieh Karimani

Published in: Clinical Pharmacokinetics | Issue 6/2017

Login to get access

Abstract

The incidence of type 2 diabetes mellitus (T2DM) among children and adolescents has been rising. This condition is associated with obesity, and it's prevalence is higher among minority or female youth. Lifestyle modification including diet and exercise is only successful in a small proportion of patients; therefore, pharmacotherapy approaches are needed to treat T2DM among youth. Currently, in the USA, only metformin and insulin are approved for the treatment of T2DM in children. However, several antihyperglycemic agents including exenatide, glimepiride, glyburide, liraglutide, pioglitazone, and rosiglitazone are also used off-label in this population. Moreover, a number of clinical trials are ongoing that are aimed at addressing the safety and efficacy of newer antihyperglycemic agents in this population. Little is known about the safety, efficacy, or pharmacokinetics of antihyperglycemic agents in children or adolescents. Our ability to predict the pharmacokinetics of these agents in youth is hampered first by the lack of information about the expression and activity of drug-metabolizing enzymes and transporters in this population and second by the presence of comorbid conditions such as obesity and fatty liver disease. This article reviews the prevalence of obesity and T2DM in children and adolescents (youth). We then summarize published studies on safety and effectiveness of antihyperglycemic medications in youth. Drug disposition may be affected by age or puberty and thus the expression and activity of different pathways for drug metabolism and xenobiotic transporters are compared between youth and adults followed by a summary of pharmacokinetics studies of antihyperglycemic agents currently used in this population.
Literature
1.
Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes in youth. Diabetes Care. 1999;22(2):345–54.CrossRefPubMed
2.
Gaylor AS, Condren ME. Type 2 diabetes mellitus in the pediatric population. Pharmacotherapy. 2004;24(7):871–8.CrossRefPubMed
3.
Horta BL, Loret de Mola C, Victora CG. Long-term consequences of breastfeeding on cholesterol, obesity, systolic blood pressure and type 2 diabetes: a systematic review and meta-analysis. Acta Paediatr. 2015;104(467):30–7.CrossRefPubMed
4.
Whincup PH, Kaye SJ, Owen CG, Huxley R, Cook DG, Anazawa S, et al. Birth weight and risk of type 2 diabetes: a systematic review. JAMA. 2008;300(24):2886–97.CrossRefPubMed
5.
Mayer-Davis EJ. Type 2 diabetes in youth: epidemiology and current research toward prevention and treatment. J Am Diet Assoc. 2008;108(4 Suppl 1):S45–51.CrossRefPubMed
6.
Copeland KC, Silverstein J, Moore KR, Prazar GE, Raymer T, Shiffman RN, et al. Management of newly diagnosed type 2 Diabetes Mellitus (T2DM) in children and adolescents. Pediatrics. 2013;131(2):364–82.CrossRefPubMed
7.
Hannon TS, Arslanian SA. The changing face of diabetes in youth: lessons learned from studies of type 2 diabetes. Ann N Y Acad Sci. 2015;1353:113–37.CrossRefPubMed
8.
Society CP. Age limits and adolescents. Paediatr Child Health. 2003;8(9):577–8.CrossRef
9.
Schober E, Holl RW, Grabert M, Thon A, Rami B, Kapellen T, et al. Diabetes mellitus type 2 in childhood and adolescence in Germany and parts of Austria. Eur J Pediatrics. 2005;164(11):705–7.CrossRef
10.
May AL, Kuklina EV, Yoon PW. Prevalence of cardiovascular disease risk factors among US adolescents, 1999–2008. Pediatrics. 2012;129(6):1035–41.CrossRefPubMed
11.
Dabelea D, Bell RA, D’Agostino RB Jr, Imperatore G, Johansen JM, Linder B, et al. Incidence of diabetes in youth in the United States. JAMA. 2007;297(24):2716–24.CrossRefPubMed
12.
SEARCH for Diabetes in Youth Study Group, Liese AD, D’Agostino RB Jr, Hamman RF, Kilgo PD, Lawrence JM, et al. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–8.CrossRef
13.
Rotteveel J, Belksma EJ, Renders CM, Hirasing RA, Delemarre-Van de Waal HA. Type 2 diabetes in children in the Netherlands: the need for diagnostic protocols. Eur J Endocrinol. 2007;157(2):175–80.CrossRefPubMed
14.
Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows NR, Geiss LS, Valdez R, et al. Type 2 diabetes among North adolescents: an epidemiologic health perspective. J Pediatr. 2000;136(5):664–72.CrossRefPubMed
15.
Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas B, Allen K, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346(11):802–10.CrossRefPubMed
16.
Wabitsch M, Hauner H, Hertrampf M, Muche R, Hay B, Mayer H, et al. Type II diabetes mellitus and impaired glucose regulation in Caucasian children and adolescents with obesity living in Germany. Int J Obes Relat Metab Disord. 2004;28(2):307–13.PubMed
17.
Pinhas-Hamiel O, Lerner-Geva L, Copperman NM, Jacobson MS. Lipid and insulin levels in obese children: changes with age and puberty. Obesity (Silver Spring). 2007;15(11):2825–31.CrossRefPubMed
18.
Reinehr T. Clinical presentation of type 2 diabetes mellitus in children and adolescents. Int J Obes (Lond). 2005;29:S105–10.CrossRef
19.
Zdravkovic V, Daneman D, Hamilton J. Presentation and course of type 2 diabetes in youth in a large multi-ethnic city. Diabet Med. 2004;21(10):1144–8.CrossRefPubMed
20.
Kiess W, Böttner A, Raile K, Kapellen T, Müller G, Galler A, et al. Type 2 diabetes mellitus in children and adolescents: a review from a European perspective. Horm Res. 2003;59(Suppl. 1):77–84.PubMed
21.
22.
Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350(23):2362–74.CrossRefPubMed
23.
Roth CL, Reinehr T. Roles of gastrointestinal and adipose tissue peptides in childhood obesity and changes after weight loss due to lifestyle intervention. Arch Pediatr Adolesc Med. 2010;164(2):131–8.CrossRefPubMed
24.
Christensen ML, Franklin BE, Momper JD, Reed MD. Pediatric drug development programs for type 2 diabetes: a review. J Clin Pharmacol. 2015;55(7):731–8.CrossRefPubMed
25.
Gungor N, Hannon T, Libman I, Bacha F, Arslanian S. Type 2 diabetes mellitus in youth: the complete picture to date. Pediatr Clin North Am. 2005;52(6):1579–609.CrossRefPubMed
26.
American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics. 2000;105(3 Pt 1):671–80.CrossRef
27.
Copeland KC, Zeitler P, Geffner M, Guandalini C, Higgins J, Hirst K, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011;96(1):159–67.CrossRefPubMed
28.
Gilliam LK, Brooks-Worrell BM, Palmer JP, Greenbaum CJ, Pihoker C. Autoimmunity and clinical course in children with type 1, type 2, and type 1.5 diabetes. J Autoimmun. 2005;25(3):244–50.CrossRefPubMed
29.
Rosenbloom AL, Silverstein JH, Amemiya S, Zeitler P, Klingensmith GJ. ISPAD Clinical Practice Consensus Guidelines 2006–2007. Type 2 diabetes mellitus in the child and adolescent. Pediatr Diabetes. 2008;9(5):512–26.CrossRefPubMed
30.
Arslanian SA. Type 2 diabetes mellitus in children: pathophysiology and risk factors. J Pediatr Endocrinol Metab. 2000;13(Suppl. 6):1385–94.PubMed
31.
32.
33.
Benavides S, Striet J, Germak J, Nahata MC. Efficacy and safety of hypoglycemic drugs in children with type 2 diabetes mellitus. Pharmacotherapy. 2005;25(6):803–9.CrossRefPubMed
34.
Jones KL, Arslanian S, Peterokova VA, Park J-S, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes a randomized controlled trial. Diabetes Care. 2002;25(1):89–94.CrossRefPubMed
35.
Yanovski JA, Krakoff J, Salaita CG, McDuffie JR, Kozlosky M, Sebring NG, et al. Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial. Diabetes. 2011;60(2):477–85.CrossRefPubMedPubMedCentral
36.
Kelsey MM, Geffner ME, Guandalini C, Pyle L, Tamborlane WV, Zeitler PS, et al. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. Pediatr Diabetes. 2016;17(3):212–21.CrossRefPubMed
37.
Kahn SE, Lachin JM, Zinman B, Haffner SM, Aftring RP, Paul G, et al. Effects of rosiglitazone, glyburide, and metformin on beta-cell function and insulin sensitivity in ADOPT. Diabetes. 2011;60(5):1552–60.CrossRefPubMedPubMedCentral
38.
Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med. 1998;15(4):297–303.CrossRefPubMed
39.
Kahn SE, Montgomery B, Howell W, Ligueros-Saylan M, Hsu CH, Devineni D, et al. Importance of early phase insulin secretion to intravenous glucose tolerance in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2001;86(12):5824–9.CrossRefPubMed
40.
41.
Padwal RS, Gabr RQ, Sharma AM, Langkaas LA, Birch DW, Karmali S, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011;34(6):1295–300.CrossRefPubMedPubMedCentral
42.
Gottschalk M, Danne T, Vlajnic A, Cara JF. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study. Diabetes Care. 2007;30(4):790–4.CrossRefPubMed
43.
Group TS, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366(24):2247–56.
44.
45.
Micale SJ, Kane MP, Hogan E. Off-label use of liraglutide in the management of a pediatric patient with type 2 diabetes mellitus. Case Rep Pediatr. 2013;2013:703925.PubMedPubMedCentral
46.
Klein DJ, Battelino T, Chatterjee D, Jacobsen LV, Hale PM, Arslanian S. Liraglutide’s safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Technol Ther. 2014;16(10):679–87.CrossRefPubMedPubMedCentral
47.
48.
Dostalek M, Court MH, Yan B, Akhlaghi F. Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus. Br J Pharmacol. 2011;163(5):937–47.CrossRefPubMedPubMedCentral
49.
Dostalek M, Court MH, Hazarika S, Akhlaghi F. Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab Dispos. 2011;39(3):448–55.CrossRefPubMedPubMedCentral
50.
Dostalek M, Akhlaghi F, Puzanovova M. Effect of diabetes mellitus on pharmacokinetic and pharmacodynamic properties of drugs. Clin Pharmacokinet. 2012;51(8):481–99.CrossRefPubMed
51.
Gwilt PR, Nahhas RR, Tracewell WG. The effects of diabetes mellitus on pharmacokinetics and pharmacodynamics in humans. Clin Pharmacokinet. 1991;20(6):477–90.CrossRefPubMed
52.
Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49(2):71–87.CrossRefPubMed
53.
Clarke JD, Cherrington NJ. Nonalcoholic steatohepatitis in precision medicine: unraveling the factors that contribute to individual variability. Pharmacol Ther. 2015;151:99–106.CrossRefPubMedPubMedCentral
54.
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67.CrossRefPubMed
55.
Anderson GD. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia. 2002;43(s3):53–9.CrossRefPubMed
56.
Harskamp-van Ginkel MW, Hill KD, Becker K, Testoni D, Cohen-Wolkowiez M, Gonzalez D, et al. Drug dosing and pharmacokinetics in children with obesity: a systematic review. JAMA Pediatr. 2015;169(7):678–85.CrossRefPubMedPubMedCentral
57.
Stewart C, Hampton E. Effect of maturation on drug disposition in pediatric patients. Clin Pharm. 1987;6(7):548–64.PubMed
58.
Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Clin Pharmacokinet. 1980;5(6):485–527.CrossRefPubMed
59.
60.
Linday LA, Greenblatt DJ, Warren MP, Harmatz JS, DeCresce R, Cicalese C, et al. Changes in salivary antipyrine pharmacokinetics during adolescence, correlated with age, hormonal levels and Tanner stage. Dev Pharmacol Ther. 1991;16(4):194–202.PubMed
61.
Lasker JM, Wester MR, Aramsombatdee E, Raucy JL. Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin, and omeprazole hydroxylations. Arch Biochem Biophys. 1998;353(1):16–28.CrossRefPubMed
62.
Wester MR, Lasker JM, Johnson EF, Raucy JL. CYP2C19 participates in tolbutamide hydroxylation by human liver microsomes. Drug Metab Dispos. 2000;28(3):354–9.PubMed
63.
Hadama A, Ieiri I, Morita T, Kimura M, Urae A, Irie S, et al. P-hydroxylation of phenobarbital: relationship to (S)-mephenytoin hydroxylation (CYP2C19) polymorphism. Ther Drug Monit. 2001;23(2):115–8.CrossRefPubMed
64.
Kobayashi K, Kogo M, Tani M, Shimada N, Ishizaki T, Numazawa S, et al. Role of CYP2C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes. Drug Metab Dispos. 2001;29(1):36–40.PubMed
65.
Tateishi T, Nakura H, Asoh M, Watanabe M, Tanaka M, Kumai T, et al. A comparison of hepatic cytochrome P450 protein expression between infancy and postinfancy. Life Sci. 1997;61(26):2567–74.CrossRefPubMed
66.
Blanco JG, Harrison PL, Evans WE, Relling MV. Human cytochrome P450 maximal activities in pediatric versus adult liver. Drug Metab Dispos. 2000;28(4):379–82.PubMed
67.
Naraharisetti SB, Lin YS, Rieder MJ, Marciante KD, Psaty BM, Thummel KE, et al. Human liver expression of CYP2C8: gender, age, and genotype effects. Drug Metab Dispos. 2010;38(6):889–93.CrossRefPubMedPubMedCentral
68.
Prasad B, Gaedigk A, Vrana M, Gaedigk R, Leeder JS, Salphati L, et al. Ontogeny of hepatic drug transporters as quantified by LC-MS/MS proteomics. Clin Pharmacol Ther. 2016;100(4):362–70.
69.
Gao X, Christensen M, Burghen G, Velasquez-Mieyer P, Moore K, Donahue S, et al. Pharmacokinetics of metformin in pediatric type 2 diabetic and healthy adult subjects [abstract]. Clin Pharmacol Ther. 2003;73(2):P46.CrossRef
70.
Sánchez-Infantes D, Díaz M, López-Bermejo A, Marcos MV, de Zegher F, Ibáñez L. Pharmacokinetics of metformin in girls aged 9 years. Clin Pharmacokinet. 2011;50(11):735–8.CrossRefPubMed
71.
Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51(5):277–304.CrossRefPubMed
72.
Turner KC, Christensen M, Connor JD, Moore KT, Gao X, Donahue SR. Pharmacokinetics of a glyburide/metformin combination tablet in children and adolescents with type 2 diabetes [abstract]. Clin Pharmacol Ther. 2003;73(2):P66.CrossRef
73.
Christensen ML, Meibohm B, Capparelli EV, Velasquez-Mieyer P, Burghen GA, Tamborlane WV. Single- and multiple-dose pharmacokinetics of pioglitazone in adolescents with type 2 diabetes. J Clin Pharmacol. 2005;45(10):1137–44.CrossRefPubMed
74.
Malloy J, Capparelli E, Gottschalk M, Guan X, Kothare P, Fineman M. Pharmacology and tolerability of a single dose of exenatide in adolescent patients with type 2 diabetes mellitus being treated with metformin: a randomized, placebo-controlled, single-blind, dose-escalation, crossover study. Clin Ther. 2009;31(4):806–15.CrossRefPubMed
75.
Fineman M, Flanagan S, Taylor K, Aisporna M, Shen LZ, Mace KF, et al. Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet. 2011;50(1):65–74.CrossRefPubMed
76.
Petri KC, Jacobsen LV, Klein DJ. Comparable liraglutide pharmacokinetics in pediatric and adult populations with type 2 diabetes: a population pharmacokinetic analysis. Clin Pharmacokinet. 2015;54(6):663–70.CrossRefPubMedPubMedCentral
77.
Tirucherai GS, LaCreta F, Ismat FA, Tang W, Boulton DW. Pharmacokinetics and pharmacodynamics of dapagliflozin in children and adolescents with type 2 diabetes mellitus. Diabetes Obes Metab. 2016;18(7):678–84.CrossRefPubMed
78.
Miyagi SJ, Milne AM, Coughtrie MW, Collier AC. Neonatal development of hepatic UGT1A9: implications of pediatric pharmacokinetics. Drug Metab Dispos. 2012;40(7):1321–7.CrossRefPubMedPubMedCentral
79.
Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther. 2008;118(2):250–67.CrossRefPubMed
80.
Salem F, Johnson TN, Abduljalil K, Tucker GT, Rostami-Hodjegan A. A re-evaluation and validation of ontogeny functions for cytochrome P450 1A2 and 3A4 based on in vivo data. Clin Pharmacokinet. 2014;53(7):625–36.CrossRefPubMed
81.
Novo Nordisk A/S. Efficacy and safety of liraglutide in combination with metformin compared to metformin alone, in children and adolescents with type 2 diabetes (Ellipse™). [ClinicalTrials.gov identifier: NCT01541215]. US National Institutes of Health, ClinicalTrials.gov. https://​www.​clinicaltrials.​gov. Accessed 19 Oct 2016.
82.
AstraZeneca. Safety and efficacy study of exenatide once weekly in adolescents with type 2 diabetes. [ClinicalTrials.gov identifier: NCT01554618]. US National Institutes of Health, ClinicalTrials.gov. https://​www.​clinicaltrials.​gov. Accessed 19 Oct 2016.
Metadata
Title
Clinical Pharmacokinetics and Pharmacodynamics of Antihyperglycemic Medications in Children and Adolescents with Type 2 Diabetes Mellitus
Authors
Fatemeh Akhlaghi
Kelly L. Matson
Amir Hooshang Mohammadpour
Meghan Kelly
Asieh Karimani
Publication date
01-06-2017
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0472-6

Other articles of this Issue 6/2017

Clinical Pharmacokinetics 6/2017 Go to the issue

Review Article

Clinical Pharmacokinetics and Pharmacodynamics of Naloxegol, a Peripherally Acting µ-Opioid Receptor Antagonist

Original Research Article

Disease–Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis

Original Research Article

Pharmacokinetic and Pharmacodynamic Properties of Faster-Acting Insulin Aspart versus Insulin Aspart Across a Clinically Relevant Dose Range in Subjects with Type 1 Diabetes Mellitus

Original Research Article

A Two-Way Steady-State Pharmacokinetic Interaction Study of Doravirine (MK-1439) and Dolutegravir

Erratum

Erratum to: A Two-Way Steady-State Pharmacokinetic Interaction Study of Doravirine (MK-1439) and Dolutegravir

Systematic Review

Lack of Clinical Pharmacokinetic Studies to Optimize the Treatment of Neglected Tropical Diseases: A Systematic Review