Skip to main content
SpringerLink
Log in

Prediction of glucuronidated drug clearance in pediatrics (≤5 years): An allometric approach

  • Original Paper
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Children are not small adults. The differences between children of different age groups and adults are not merely due to body weight, but also due to physiological and biochemical differences resulting in different rates of drug metabolism or renal clearance. Glucuronidation is an important pathway of drug metabolism. Therefore, the objective of this study is to evaluate the predictive performance of several allometric exponents in children of ≤5 years for the total clearance of drugs which are mainly metabolized by glucuronidation. Four exponents (0.75, 1.0, 1.2, or 1.4) on the body weights and an allometric model developed from adults were evaluated. The four exponents and the allometric model were examined to determine the suitability of the method(s) to predict the clearances of drugs which are glucuronidated in children ≤5 years of age. Based on the analysis of ten drugs, it was noted that the combination of two allometric exponents 1.2 (for children ≤3 months) and 1.0 (for children ≥3 months ≤5 years) can be used to predict mean clearances of drugs which are mainly metabolized by glucuronidation. The suggested approach may be used to estimate a first-in-pediatric dose to initiate a pediatric clinical trial.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alcorn J, McNamara PJ (2002a) Ontogeny of hepatic and renal systemic clearance pathways in infants: part I. Clin Pharmacokinet 41:959–998

    Article  CAS  PubMed  Google Scholar 

  • Alcorn J, McNamara PJ (2002b) Ontogeny of hepatic and renal systemic clearance pathways in infants: part II. Clin Pharmacokinet 41:1077–1094

    Article  CAS  PubMed  Google Scholar 

  • Allegaert K, Anderson BJ, Naulaers G, de Hoon J, Verbesselt R, Debeer A, Devlieger H, Tibboel D (2004) Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates. Eur J Clin Pharmacol 60:191–197

    Article  CAS  PubMed  Google Scholar 

  • Allegaert K, de Hoon J, Verbesselt R, Naulaers G, Murat I (2007) Maturational pharmacokinetics of single intravenous bolus of propofol. Paediatr Anaesth 17:1028–1034

    Article  PubMed  Google Scholar 

  • Aranda JV, Varvarigou A, Beharry K, Bansal R, Bardin C, Modanlou H, Papageorgiou A, Chemtob S (1997) Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant. Acta Paediatr 86:289–293

    Article  CAS  PubMed  Google Scholar 

  • Balis FM, Pizzo PA, Eddy J, Wilfert C, McKinney R, Scott G, Murphy RF, Jarosinski PF, Falloon J, Poplack DG (1989) Pharmacokinetics of zidovudine administered intravenously and orally in children with human immunodeficiency virus infection. J Pediatr 114:880–884

    Article  CAS  PubMed  Google Scholar 

  • Barrett DA, Elias-Jones AC, Rutter N, Shaw PN, Davis SS (1991) Morphine kinetics after diamorphine infusion in premature neonates. Br J Clin Pharmacol 32:31–37

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Barrett DA, Barker DP, Rutter N, Pawula M, Shaw PN (1996) Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions. Br J Clin Pharmacol 41:531–537

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bartelink IH, Boelens JJ, Bredius RG, Egberts AC, Wang C et al (2012) Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet 51:331–345

    Article  CAS  PubMed  Google Scholar 

  • Boucher FD, Modlin JF, Weller S, Ruff A, Mirochnick M, Pelton S, Wilfert C, McKinney R Jr, Crain MJ, Elkins MM et al (1993) Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J Pediatr 122:137–144

    Article  CAS  PubMed  Google Scholar 

  • Capparelli EV, Mirochnick M, Dankner WM, Blanchard S, Mofenson L, McSherry GD, Gay H, Ciupak G, Smith B, Connor JD, Pediatric AIDS (2003) Clinical Trials Group 331 Investigators. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 142:47–52

    Article  CAS  PubMed  Google Scholar 

  • Chamberlain JM, Capparelli EV, Brown KM, Vance CW, Lillis K, Mahajan P, Lichenstein R, Stanley RM, Davis CO, Gordon S, Baren JM, van den Anker JN, Pediatric Emergency Care Applied Research Network (PECARN) (2012) Pharmacokinetics of intravenous lorazepam in pediatric patients with and without status epilepticus. J Pediatr 160:667–672

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chappell WR, Mordenti J (1991) Extrapolation of toxicological and pharmacological data from animals to humans. Adv Drug Res 20:1–116

    Article  CAS  Google Scholar 

  • Chay PC, Duffy BJ, Walker JS (1992) Pharmacokinetic-pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther 51:334–342

    Article  CAS  PubMed  Google Scholar 

  • Choonara I, Lawrence A, Michalkiewicz A, Bowhay A, Ratcliffe J (1992) Morphine metabolism in neonates and infants. Br J Clin Pharmacol 34:434–437

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cohen MN, Christians U, Henthorn T, Vu Tran Z, Moll V, Zuk J, Galinkin J (2011) Pharmacokinetics of single-dose intravenous ketorolac in infants aged 2–11 months. Anesth Analg 112:655–660

    Article  CAS  PubMed  Google Scholar 

  • de Wildt SN, Kearns GL, Hop WC, Murry DJ, Abdel-Rahman SM, van den Anker JN (2001) Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. Clin Pharmacol Ther 70:525–531

    Article  PubMed  Google Scholar 

  • de Wildt SN, Kearns GL, Hop WC, Murry DJ, Abdel-Rahman SM, van den Anker JN (2002) Pharmacokinetics and metabolism of oral midazolam in preterm infants. Br J Clin Pharmacol 53:390–392

    Article  PubMed Central  PubMed  Google Scholar 

  • Glazier DS (2010) A unifying explanation for diverse metabolic scaling in animals and plants. Biol Rev Camb Philos Soc 85(1):111–138

    Article  PubMed  Google Scholar 

  • Hartley R, Green M, Quinn M, Levene MI (1993) Pharmacokinetics of morphine infusion in premature neonates. Arch Dis Child 69(1 Spec No):55–58

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jacqz-Aigrain E, Wood C, Robieux I (1990) Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol 39:191–192

    Article  CAS  PubMed  Google Scholar 

  • Kearns GL, Bocchini JA Jr, Brown RD, Cotter DL, Wilson JT (1985) Absence of a pharmacokinetic interaction between chloramphenicol and acetaminophen in children. J Pediatr 107:134–139

    Article  CAS  PubMed  Google Scholar 

  • Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS et al (2003) Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 349:1157–1167

    Article  CAS  PubMed  Google Scholar 

  • Levy G, Khanna NN, Soda DM, Tsuzuki O, Stern L (1975) Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and d-glucaric acid excretion. Pediatrics 55:818–825

    CAS  PubMed  Google Scholar 

  • Mahmood I (2006) Prediction of drug clearance in children from adults: a comparison of several allometric methods. Br J Clin Pharmacol 61:545–557

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mahmood I (2007) Prediction of drug clearance in children: impact of allometric exponents, body weight and age. Ther Drug Monit 29:271–278

    Article  PubMed  Google Scholar 

  • Mahmood I (2009) Application of fixed exponent 0.75 to the prediction of human drug clearance: an inaccurate and misleading concept. Drug Metab Drug Interaction 24:57–81

    Article  CAS  Google Scholar 

  • Mahmood I (2010a) Prediction of drug clearance in children 3 months and younger: an allometric approach. Drug Metabol Drug Interact 25:25–34

    Article  CAS  PubMed  Google Scholar 

  • Mahmood I (2010b) Theoretical versus empirical allometry: facts behind theories and application to pharmacokinetics. J Pharm Sci 99(7):2927–2933

    CAS  PubMed  Google Scholar 

  • Mahmood I (2013) Prediction of drug clearance in preterm and term neonates: different exponents for different age groups? In: Pharmacokinetic allometric scaling in pediatric drug development. Pine House Publishers, MD, pp 88–100

  • Mahmood I (2013) Prediction of clearance in children from adult clearance: allometric scaling versus exponent 0.75. In: Pharmacokinetic allometric scaling in pediatric drug development. Pine House Publishers, MD, pp 41–55

  • McDermott CA, Kowalczyk AL, Schnitzler ER, Mangurten HH, Rodvold KA, Metrick S (1992) Pharmacokinetics of lorazepam in critically ill neonates with seizures. J Pediatr 120:479–483

    Article  CAS  PubMed  Google Scholar 

  • McMohan TA, Bonner JT (1983) Proportions and size. In: On size and life. Scientific American Library, New York, pp 25–67

  • McRorie TI, Lynn AM, Nespeca MK, Opheim KF, Slattery JT (1992) The maturation of morphine clearance and metabolism. AJDC 146:972–976

    CAS  PubMed  Google Scholar 

  • Mikkelsen S, Feilberg VL, Christensen CB, Lundstrøm KE (1994) Morphine pharmacokinetics in premature and mature newborn infants. Acta Paediatr 83:1025–1028

    Article  CAS  PubMed  Google Scholar 

  • Mirochnick M, Capparelli E, Dankner W, Sperling RS, van Dyke R, Spector SA (1998) Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrob Agents Chemother 42:808–812

    PubMed Central  CAS  PubMed  Google Scholar 

  • Murry DJ, Oermann CM, Ou CN, Rognerud C, Seilheimer DK, Sockrider MM (1999) Pharmacokinetics of ibuprofen in patients with cystic fibrosis. Pharmacotherapy 19:340–345

    Article  CAS  PubMed  Google Scholar 

  • Nahata MC, Powell DA (1981) Bioavailability and clearance of chloramphenicol after intravenous chloramphenicol succinate. Clin Pharmacol Ther 30:368–372

    Article  CAS  PubMed  Google Scholar 

  • Nahata MC, Powell DA (1983) Comparative bioavailability and pharmacokinetics of chloramphenicol after intravenous chloramphenicol succinate in premature infants and older patients. Dev Pharmacol Ther 6:23–32

    CAS  PubMed  Google Scholar 

  • Olkkola KT, Maunuksela EL, Korpela R, Rosenberg PH (1988) Kinetics and dynamics of postoperative intravenous morphine in children. Clin Pharmacol Ther 44:128–136

    Article  CAS  PubMed  Google Scholar 

  • Olkkola KT, Maunuksela EL, Korpela R (1989) Pharmacokinetics of postoperative intravenous indomethacin in children. Pharmacol Toxicol 65:157–160

    Article  CAS  PubMed  Google Scholar 

  • Pacifici GM, Franchi M, Colizzi C, Giuliani L, Rane A (1988) Glutathione S-transferase in humans: development and tissue distribution. Arch Toxicol 6:265–269

    Article  Google Scholar 

  • Packard GC, Birchard GF (2008) Traditional allometric analysis fails to provide a valid predictive model for mammalian metabolic rates. J Exp Biol 211:3581–3587

    Article  PubMed  Google Scholar 

  • Peeters MY, Allegaert K, Blussé van Oud-Alblas HJ, Cella M, Tibboel D, Danhof M, Knibbe CA (2010) Prediction of propofol clearance in children from an allometric model developed in rats, children and adults versus a 0.75 fixed-exponent allometric model. Clin Pharmacokinet 49:269–275

    Article  CAS  PubMed  Google Scholar 

  • Pokela ML, Olkkola KT, Seppälä T, Koivisto M (1993) Age-related morphine kinetics in infants. Dev Pharmacol Ther 20(1–2):26–34

    CAS  PubMed  Google Scholar 

  • Saint-Maurice C, Cockshott ID, Douglas EJ, Richard MO, Harmey JL (1989) Pharmacokinetics of propofol in young children after a single dose. Br J Anaesth 63:667–670

    Article  CAS  PubMed  Google Scholar 

  • Sharma PK, Garg SK, Narang A (2003) Pharmacokinetics of oral ibuprofen in premature infants. J Clin Pharmacol 43:968–973

    Article  CAS  PubMed  Google Scholar 

  • Strange RC, Howie AF, Hume R, Matharoo B, Bell J (1989) The development expression of alpha- mu- and pi-class glutathione S-transferases in human liver. Biochim Biophys Acta 993:186–190

    Article  CAS  PubMed  Google Scholar 

  • Thalji AA, Carr I, Yeh TF, Raval D, Luken JA, Pildes RS (1980) Pharmacokinetics of intravenously administered indomethacin in premature infants. J Pediatr 97:995–1000

    Article  CAS  PubMed  Google Scholar 

  • Walson PD, Halvorsen M, Edge J, Casavant MJ, Kelley MT (2013) Pharmacokinetic comparison of acetaminophen elixir versus suppositories in vaccinated infants (aged 3 to 36 months): a single-dose, open-label, randomized, parallel-group design. Clin Ther 35:135–140

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Peeters MY, Allegaert K, van Oud-Alblas HJ, Krekels EH et al (2012) A bodyweight-dependent allometric exponent for scaling clearance across the human life-span. Pharm Res 29:1570–1581

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang C, Sadhavisvam S, Krekels EH, Dahan A, Tibboel D, Danhof M, Vinks AA, Knibbe CA (2013) Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model. Clin Drug Investig 33:523–534

    Article  PubMed  Google Scholar 

  • Wang C, Allegaert K, Peeters MY, Tibboel D, Danhof M, Knibbe CA (2014) The allometric exponent for scaling clearance varies with age: a study on seven propofol datasets ranging from preterm neonates to adults. Br J Clin Pharmacol 77:149–159

    Google Scholar 

  • Weiss CF, Glazko A, Weston JK (1960) Chloramphenicol in the new born infant. N Engl J Med 262:787–794

    Article  CAS  PubMed  Google Scholar 

  • West D, West BJ (2013) Physiologic time: a hypothesis. Phys Life Rev 10:310–324

    Google Scholar 

  • White CR, Seymour RS (2005) Sample size and mass range effects on the allometric exponent of basal metabolic rate. Comp Biochem Physiol A Mol Integr Physiol 142:74–78

    Article  PubMed  Google Scholar 

  • White CR, Cassey P, Blackburn TM (2007) Allometric exponents do not support a universal metabolic allometry. Ecology 88:315–323

    Article  PubMed  Google Scholar 

  • Wieser W (1984) A distinction must be made between the ontogeny and the phylogeny of metabolism in order to understand the mass exponent of energy metabolism. Respir Physiol 55:1–9

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

There is no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Hematology, Office of Blood Review and Research (OBRR), Center for Biologic Evaluation and Research, Food and Drug Administration, 1401, Rockville Pike, Rockville, MD, 20852, USA

    Iftekhar Mahmood

Authors
  1. Iftekhar Mahmood
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Iftekhar Mahmood.

Additional information

The views expressed in this article are those of the author and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mahmood, I. Prediction of glucuronidated drug clearance in pediatrics (≤5 years): An allometric approach. Eur J Drug Metab Pharmacokinet 40, 53–59 (2015). https://doi.org/10.1007/s13318-014-0178-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-014-0178-9

Keywords

Search

Navigation