Use of Medicines in Children: Pharmacological and Practical Issues
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Abstract
Pediatric patients have very different pharmacokinetic and pharmacodynamic profiles compared to adults. A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in pediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. When considering medication for a child or adolescent, one should be cautious about extrapolating from adult studies or practices. Always remember, children are not small adults. Children tend to have higher rates of metabolism and elimination than adults. As a result, children generally require higher weight-adjusted doses of most medications to achieve similar blood levels as adults. As pharmacokinetics is hard to predict in children, and thus a 'start low and go slow' approach is important. This review details key pharmacological and practical considerations which a healthcare professional should be aware of to understand consequences of drug use and dose adjustments in infants and children.
1. Moore P. Children are not small adults. Lancet. 1998;352(9128):630
2. Ralph E. Drug action and therapy in the infant and child. In: Yaffe J, A randa V, editors . Neonatal and Pediatric pharmacology 3 rd.edition. Philadephia. Lippincott Williams and Wilkins. 2004.pg 20-32
3. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr. 2005;164(9):552–8
4. Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet. 1996; 30: 329–32.
5. Meine Jansen CF. Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir. J Perinat Med. 2005; 33: 364–6.
6. Mooij MG, de Koning BA, Huijsman ML, de Wildt SN. Ontogeny of oral drug absorption processes in children. Expert Opin Drug Metab Toxicol. 2012; 8: 1293–303.
7. Grand RJ, Watkins JB, Torti FM. Development of the human gastrointestinal tract. A review. Gastroenterology. 1976; 70: (5I): 790–810.
8. Pedersen S, Steffensen G. Absorption characteristics of once-a-day slow-release theophylline preparation in children with asthma. J Pediatr 1987; 110: 953–9.
9. Strolin BM, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005; 1: 447–71.
10. Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006; 45: 1077–97
11. Mushak P. Gastro-intestinal absorption of lead in children and adults: overview of biological and biophysico-chemical aspects. Chem Spec Bioavail. 1991; 3: 87–104.
12. Johnson TN, Tanner MS, Taylor CJ, Tucker GT. Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis. Br J Clin Pharmacol. 2001; 51: 451–60.
13. Ginsberg G, Hattis D, Sonawane B, Russ A, Banati P, Kozlak M, Smolenski S, Goble R. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci. 2002; 66:185–200.
14. Benedetti MS, Whomsley R, Canning M. Drug metabolism in the paediatric population and in the elderly. Drug Discov Today. 2007; 12: 599–610.
15. 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: 1157–67.
16. Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther. 2008; 118: 250–67.
17. Massimo C, Knibbe C, Danhof1 M, et al. What is the right dose for children? Br J Clin Pharmacol. 2010;70(4):597-603.
18. Shi R and Derendorf H. Pediatric Dosing and Body Size in Biotherapeutics. Pharmaceutics. 2010;2:389-418.
19. Rodriguez W, Selen A, Avant D et al. Improving Pediatric Dosing Through Pediatric Initiatives: What We Have Learned. Pediatrics. 2008; 121(3):530-41.
20. Johnson TN. Modelling approaches to dose estimation in children. Br J Clin Pharmacol. 2005;59:663-9.
21. Cimpello LB, Khine H, Avner JR. Practice patterns of pediatric versus general emergency physicians for pain management of fractures in pediatric patients. Pediatr Emerg Care. 2004;20:228–32.
22. Vitiello B, Correll C, van Zwieten-Boot B, Zuddas A, Parellada M, Arango C. Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns. Eur Neuropsychopharmacol. 2009;19(9):629-35.
23. Moran-Gates T, Gan L, Park YS, Zhang K, Baldessarini RJ, Tarazi FI. Repeated antipsychotic drug exposure in developing rats: dopamine receptor effects. Synapse. 2006;59: 92–100.
24. Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45:771–91.
25. Aman MG, Hollway JA, McDougle CJ, et al. Cognitive effects of risperidone in children with autism and irritable behavior. J. Child Adolesc. Psychopharmacol. 2008;18:227–36.
26. Impicciatore P, Choonara I, Clarkson A, Provasi D, Pandolfini C, Bonati M. Incidence of adverse drug reactions in paediatric in/outpatients: a systematic review and meta-analysis of prospective studies. Br J Clin Pharmacol. 2001; 52: 77–83.
27. Clavenna A, Bonati M. Adverse drug reactions in childhood: a review of prospective studies and safety alerts. Arch Dis Child. 2009; 94: 724–8.
28. Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol. 2015;79(3):357-69.
29. Klassen TP, Hartling L, Hamm M, van der Lee JH, Ursum J, Offringa M. StaR Child Health: an initiative for RCTs in children. Lancet. 2009; 374: 1310–2.
30. Noah B. Just a spoonful of sugar: drug safety for pediatric populations. J Law Med Ethics. 2009; 37: 280–91.
31. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ. 2000; 320: 79–82.
32. Verica Ivanovska, Carin MA, Liset van Dijk, Aukje K, Mantel-Teeuwisse. Pediatric Drug Formulations: A Review of Challenges and Progress. Pediatrics. 2014;134(2).
33. World Health Organization. Development of Paediatric Medicines: Points to Consider in Formulation. Geneva, Switzerland: World Health Organization; 2012. WHO Technical Report Series, No. 970, Annex 5.
34. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv. 2007;4(1):37–45.
35. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol. 2007;59(8):1043–55.
36. Brown WJ, Buist NR, Gipson HT, Huston RK, Kennaway NG. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet. 1982;1(8283):1250.
37. World Health Organization. Promoting Safety of Medicines for Children. Geneva, Switzerland.World Health Organization; 2007.
38. Whittaker A, Currie AE, Turner MA, Field DJ, Mulla H, Pandya HC. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F236-40.
39. Lass J, Naelapää K, Shah U, et al. Hospitalised neonates in Estonia commonly receive potentially harmful excipients. BMC Pediatr. 2012;12:136.
40. Salunke S, Giacoia GP, Tuleu C. The STEP (safety and toxicity of excipients for paediatrics) database. Part 1-A need assessment study. Int J Pharm. 2012;435(2):101–11
41. Nahata MC. Lack of pediatric drug formulations. Pediatrics. 1999;104 :607–9.
42. Nahata MC, Allen LV Jr. Extemporaneous drug formulations. Clin Ther. 2008;30(11): 2112–9.
43. Choonara I, Conroy S. Unlicensed and off label drug use in children: implications for safety. Drug Saf. 2002;25(1):1–5
44. Stoltenberg I, Winzerburg G, Breitkreutz J. Solid oral forms for children—formulations, excipients and acceptance issues. J App Ther Res. 2010;7(4):141–6.
45. Stoltenberg I, Breitkreutz J. Orally disintegrating mini-tablets (ODMTs)—a novel solid oral dosage form for paediatric use. Eur J Pharm Biopharm. 2011; 78(3):462–9.
46. Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M; European Paediatric Formulation Initiative (EuPFI). Delivery devices for the administration of paediatric formulations: overview of current practice, challenges and recent developments. Int J Pharm. 2011;415(1–2):221–31.
47. WHO, “Medicines: medicines for children,” Fact Sheet 341, World Health Organization, Geneva, Switzerland, 2010.
48. Bush A. Strategies for effective collaboration between investigator sites and the pharmaceutical industry in pediatrics. Paediatr Drugs. 2006;8(5):271-7.
49. Abernethy DR, Burckart GJ. Pediatric dose selection. Clin Pharmacol Ther. 2010;87(3):270–271.
50. Liu XI, Momper JD, Rakhmanina N, et al. Physiologically Based Pharmacokinetic Models to Predict Maternal Pharmacokinetics and Fetal Exposure to Emtricitabine and Acyclovir. J Clin Pharmacol. 2020;60(2):240–255.
51. Liu XI, Momper JD, Rakhmanina NY, et al. Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling. Clin Pharmacokinet. 2020;59(11):1433-1450.
2. Ralph E. Drug action and therapy in the infant and child. In: Yaffe J, A randa V, editors . Neonatal and Pediatric pharmacology 3 rd.edition. Philadephia. Lippincott Williams and Wilkins. 2004.pg 20-32
3. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr. 2005;164(9):552–8
4. Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet. 1996; 30: 329–32.
5. Meine Jansen CF. Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir. J Perinat Med. 2005; 33: 364–6.
6. Mooij MG, de Koning BA, Huijsman ML, de Wildt SN. Ontogeny of oral drug absorption processes in children. Expert Opin Drug Metab Toxicol. 2012; 8: 1293–303.
7. Grand RJ, Watkins JB, Torti FM. Development of the human gastrointestinal tract. A review. Gastroenterology. 1976; 70: (5I): 790–810.
8. Pedersen S, Steffensen G. Absorption characteristics of once-a-day slow-release theophylline preparation in children with asthma. J Pediatr 1987; 110: 953–9.
9. Strolin BM, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005; 1: 447–71.
10. Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006; 45: 1077–97
11. Mushak P. Gastro-intestinal absorption of lead in children and adults: overview of biological and biophysico-chemical aspects. Chem Spec Bioavail. 1991; 3: 87–104.
12. Johnson TN, Tanner MS, Taylor CJ, Tucker GT. Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis. Br J Clin Pharmacol. 2001; 51: 451–60.
13. Ginsberg G, Hattis D, Sonawane B, Russ A, Banati P, Kozlak M, Smolenski S, Goble R. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci. 2002; 66:185–200.
14. Benedetti MS, Whomsley R, Canning M. Drug metabolism in the paediatric population and in the elderly. Drug Discov Today. 2007; 12: 599–610.
15. 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: 1157–67.
16. Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther. 2008; 118: 250–67.
17. Massimo C, Knibbe C, Danhof1 M, et al. What is the right dose for children? Br J Clin Pharmacol. 2010;70(4):597-603.
18. Shi R and Derendorf H. Pediatric Dosing and Body Size in Biotherapeutics. Pharmaceutics. 2010;2:389-418.
19. Rodriguez W, Selen A, Avant D et al. Improving Pediatric Dosing Through Pediatric Initiatives: What We Have Learned. Pediatrics. 2008; 121(3):530-41.
20. Johnson TN. Modelling approaches to dose estimation in children. Br J Clin Pharmacol. 2005;59:663-9.
21. Cimpello LB, Khine H, Avner JR. Practice patterns of pediatric versus general emergency physicians for pain management of fractures in pediatric patients. Pediatr Emerg Care. 2004;20:228–32.
22. Vitiello B, Correll C, van Zwieten-Boot B, Zuddas A, Parellada M, Arango C. Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns. Eur Neuropsychopharmacol. 2009;19(9):629-35.
23. Moran-Gates T, Gan L, Park YS, Zhang K, Baldessarini RJ, Tarazi FI. Repeated antipsychotic drug exposure in developing rats: dopamine receptor effects. Synapse. 2006;59: 92–100.
24. Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45:771–91.
25. Aman MG, Hollway JA, McDougle CJ, et al. Cognitive effects of risperidone in children with autism and irritable behavior. J. Child Adolesc. Psychopharmacol. 2008;18:227–36.
26. Impicciatore P, Choonara I, Clarkson A, Provasi D, Pandolfini C, Bonati M. Incidence of adverse drug reactions in paediatric in/outpatients: a systematic review and meta-analysis of prospective studies. Br J Clin Pharmacol. 2001; 52: 77–83.
27. Clavenna A, Bonati M. Adverse drug reactions in childhood: a review of prospective studies and safety alerts. Arch Dis Child. 2009; 94: 724–8.
28. Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol. 2015;79(3):357-69.
29. Klassen TP, Hartling L, Hamm M, van der Lee JH, Ursum J, Offringa M. StaR Child Health: an initiative for RCTs in children. Lancet. 2009; 374: 1310–2.
30. Noah B. Just a spoonful of sugar: drug safety for pediatric populations. J Law Med Ethics. 2009; 37: 280–91.
31. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ. 2000; 320: 79–82.
32. Verica Ivanovska, Carin MA, Liset van Dijk, Aukje K, Mantel-Teeuwisse. Pediatric Drug Formulations: A Review of Challenges and Progress. Pediatrics. 2014;134(2).
33. World Health Organization. Development of Paediatric Medicines: Points to Consider in Formulation. Geneva, Switzerland: World Health Organization; 2012. WHO Technical Report Series, No. 970, Annex 5.
34. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv. 2007;4(1):37–45.
35. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol. 2007;59(8):1043–55.
36. Brown WJ, Buist NR, Gipson HT, Huston RK, Kennaway NG. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet. 1982;1(8283):1250.
37. World Health Organization. Promoting Safety of Medicines for Children. Geneva, Switzerland.World Health Organization; 2007.
38. Whittaker A, Currie AE, Turner MA, Field DJ, Mulla H, Pandya HC. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F236-40.
39. Lass J, Naelapää K, Shah U, et al. Hospitalised neonates in Estonia commonly receive potentially harmful excipients. BMC Pediatr. 2012;12:136.
40. Salunke S, Giacoia GP, Tuleu C. The STEP (safety and toxicity of excipients for paediatrics) database. Part 1-A need assessment study. Int J Pharm. 2012;435(2):101–11
41. Nahata MC. Lack of pediatric drug formulations. Pediatrics. 1999;104 :607–9.
42. Nahata MC, Allen LV Jr. Extemporaneous drug formulations. Clin Ther. 2008;30(11): 2112–9.
43. Choonara I, Conroy S. Unlicensed and off label drug use in children: implications for safety. Drug Saf. 2002;25(1):1–5
44. Stoltenberg I, Winzerburg G, Breitkreutz J. Solid oral forms for children—formulations, excipients and acceptance issues. J App Ther Res. 2010;7(4):141–6.
45. Stoltenberg I, Breitkreutz J. Orally disintegrating mini-tablets (ODMTs)—a novel solid oral dosage form for paediatric use. Eur J Pharm Biopharm. 2011; 78(3):462–9.
46. Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M; European Paediatric Formulation Initiative (EuPFI). Delivery devices for the administration of paediatric formulations: overview of current practice, challenges and recent developments. Int J Pharm. 2011;415(1–2):221–31.
47. WHO, “Medicines: medicines for children,” Fact Sheet 341, World Health Organization, Geneva, Switzerland, 2010.
48. Bush A. Strategies for effective collaboration between investigator sites and the pharmaceutical industry in pediatrics. Paediatr Drugs. 2006;8(5):271-7.
49. Abernethy DR, Burckart GJ. Pediatric dose selection. Clin Pharmacol Ther. 2010;87(3):270–271.
50. Liu XI, Momper JD, Rakhmanina N, et al. Physiologically Based Pharmacokinetic Models to Predict Maternal Pharmacokinetics and Fetal Exposure to Emtricitabine and Acyclovir. J Clin Pharmacol. 2020;60(2):240–255.
51. Liu XI, Momper JD, Rakhmanina NY, et al. Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling. Clin Pharmacokinet. 2020;59(11):1433-1450.
| Files | ||
| Issue | Vol 11, No 2 (Spring 2023) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v11i2.13366 | |
| Keywords | ||
| Pediatric; Pharmacokinetics; Drug Safety | ||
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How to Cite
1.
Bhargava S, Mishra P, Rana S. Use of Medicines in Children: Pharmacological and Practical Issues. J Pharm Care. 2023;11(2):110-116.
