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Interspecies Scaling for the Prediction of Drug Clearance in Children

Application of Maximum Lifespan Potential and an Empirical Correction Factor

Clinical Pharmacokinetics volume 49, pages 479–492 (2010)Cite this article

Abstract

Background and Objective

Interspecies pharmacokinetic scaling is widely used to predict pharmacokinetic parameters in adult humans but has not been used for the prediction of pharmacokinetic parameters in children. The current study was undertaken to evaluate whether or not drug clearance in children from adult rat, dog and human clearance values could be predicted allometrically.

Methods

Four methods (simple allometry, maximum lifespan potential [MLP], MLP with an empirical correction factor and a fixed exponent of 0.75 in association with adult data) were used for the prediction of drug clearance in children. The first three methods included adult animal (rat and dog) data and human data, whereas the fixed exponent of 0.75 included only adult human data.

Results

The results of this study indicated that simple allometry would systematically overpredict drug clearance in children, whereas application of MLP would underpredict drug clearance in children. Therefore, an empirical correction factor was introduced into MLP, which substantially improved the prediction of drug clearance in children. Prediction based on a fixed exponent of 0.75 and adult human clearance was highly erratic and inferior to the prediction of drug clearance in children from MLP or MLP with an empirical correction factor.

Conclusions

Overall, the results of the study indicated that interspecies scaling using adult rat, dog and human clearance values could be useful to predict drug clearance in children in different age groups.

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Table I
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References

  1. Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part I. Clin Pharmacokinet 2002; 41: 959–98

    PubMed  CAS  Article  Google Scholar 

  2. Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part II. Clin Pharmacokinet 2002; 41: 1077–94

    PubMed  CAS  Article  Google Scholar 

  3. Hayton WL. Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS Pharm Sci 2000; 2: 1–7

    Google Scholar 

  4. Hayton WL, Kneer J, de Groot R, et al. Influence of maturation and growth on cefetamet pivoxil pharmacokinetics: rational dosing for infants. Antimicrob Agents Chemother 1996; 40: 567–74

    PubMed  CAS  Google Scholar 

  5. Reigner BG, Blesch KS. Estimating the starting dose for entry into humans: principles and practice. Eur J Clin Pharmacol 2002; 57: 835–45

    PubMed  CAS  Article  Google Scholar 

  6. Collins JM, Zaharko S, Dedrick RL, et al. Potential roles for pre-clinical pharmacology in phase I clinical trials. Cancer Treat Rep 1986; 70: 73–80

    PubMed  CAS  Google Scholar 

  7. Mahmood I, Green MD, Fisher JE. Selection of the first time dose in humans: comparison of different approaches based on interspecies scaling of clearance. J Clin Pharmacol 2003; 43: 692–7

    PubMed  CAS  Google Scholar 

  8. Mahmood I. Interspecies pharmacokinetic scaling: principles and application of allometric scaling. Rockville (MD): Pine House Publishers, 259–87

  9. Mahmood I. Pediatric pharmacology and pharmacokinetics. Rockville, MD: Pine House Publishers, 2008: 184–216

    Google Scholar 

  10. Mahmood I. Prediction of drug clearance in children: impact of allometric exponents, body weight, and age. Therap Drug Monitor 2007; 29: 271–8

    Article  Google Scholar 

  11. Mahmood I. Pediatric pharmacology and pharmacokinetics. Rockville (MD): Pine House Publishers, 2008: 142–83

    Google Scholar 

  12. Mahmood I. Prediction of drug clearance in children from adults: a comparison of several allometric methods. Br J Clin Pharmacol 2006; 61: 545–57

    PubMed  CAS  Article  Google Scholar 

  13. Schmidt-Nielsen K. Why is animal size so important? Cambridge: Cambridge University Press; 1984; 1–6

    Book  Google Scholar 

  14. Boxenbaum H. Interspecies pharmacokinetic scaling and the evolutionary comparative paradigm. Drug Metab Rev 1984; 15: 1071–121

    PubMed  CAS  Article  Google Scholar 

  15. Knibbe CA, Zuideveld KP, Aarts LP, et al. Allometric relationships between the pharmacokinetics of propofol in rats, children and adults. Br J Clin Pharmacol 2005; 59: 705–11

    PubMed  CAS  Article  Google Scholar 

  16. Sacher G. Relation of lifespan to brain weight and body weight in mammals. In: Wolstenholme GEW, O’Connor M, editors. CIBA Foundation colloquium on aging. Vol. 1. London: Churchill, 1959: 115–41

    Google Scholar 

  17. Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30: 329–32

    PubMed  CAS  Article  Google Scholar 

  18. Michiels M, Monbaliu J, Hendriks R, et al. Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog. Arzneimittelforschung 1987; 37: 1159–67

    PubMed  CAS  Google Scholar 

  19. Gross AS, Goh YD, Addison RS, et al. Influence of grapefruit juice on cisapride pharmacokinetics. Clin Pharmacol Ther 1999; 65: 395–401

    PubMed  CAS  Article  Google Scholar 

  20. Kearns GL, Robinson PK, Wilson JT, et al., Pediatric Pharmacology Research Unit Network. Cisapride disposition in neonates and infants:in vivo reflection of cytochrome P450 3A4 ontogeny. Clin Pharmacol Ther 2003; 74: 312–25

    PubMed  CAS  Article  Google Scholar 

  21. Sawada Y, Hanano M, Sugiyama Y, et al. Prediction of the disposition of β-lactam antibiotics in humans from pharmacokinetic parameters in animals. J Pharmacokinet Biopharm 1984; 12: 241–61

    PubMed  CAS  Article  Google Scholar 

  22. Varghese M, Khan AJ, Kumar K, et al. Pharmacokinetic evaluation of cefoperazone in infants. Antimicrob Agents Chemother 1985; 28: 149–50

    PubMed  CAS  Article  Google Scholar 

  23. Rosenfeld WN, Evans HE, Batheja R, et al. Pharmacokinetics of cefoperazone in full-term and premature neonates. Antimicrob Agents Chemother 1983; 23: 866–9

    PubMed  CAS  Article  Google Scholar 

  24. Chartrand SA, Marks MI, Johnston JT, et al. Cefoperazone pharmacokinetics in acute childhood meningitis. J Pediatr 1983; 103: 991–5

    PubMed  CAS  Article  Google Scholar 

  25. Hutchaleelaha A, Chow HH, Mayersohn M. Comparative pharmacokinetics and interspecies scaling of amphotericin B in several mammalian species. J Pharm Pharmacol 1997; 49: 178–83

    PubMed  CAS  Article  Google Scholar 

  26. Benson JM, Nahata MC. Pharmacokinetics of amphotericin B in children. Antimicrob Agents Chemother 1989; 33: 1989–93

    PubMed  CAS  Article  Google Scholar 

  27. Starke JR, Mason Jr EO, Kramer WG, et al. Pharmacokinetics of amphotericin B in infants and children. J Infect Dis 1987; 155: 766–74

    PubMed  CAS  Article  Google Scholar 

  28. Koren G, Lau A, Klein J, et al. Pharmacokinetics and adverse effects of amphotericin B in infants and children. J Pediatr 1988; 113: 559–63

    PubMed  CAS  Article  Google Scholar 

  29. Harrison MP, Moss SR, Featherstone A, et al. The disposition and metabolism of meropenem in laboratory animals and man. J Antimicrob Chemother 1989; 24Suppl. A: 265–77

    PubMed  CAS  Article  Google Scholar 

  30. van Enk JG, Touw DJ, Lafeber HN. Pharmacokinetics of meropenem in preterm neonates. Ther Drug Monit 2001; 23: 198–201

    PubMed  Article  Google Scholar 

  31. Blumer JL, Reed MD, Kearns GL, et al. Sequential, single-dose pharmacokinetic evaluation of meropenem in hospitalized infants and children. Antimicrob Agents Chemother 1995; 39: 1721–5

    PubMed  CAS  Article  Google Scholar 

  32. Bonati M, Latini R, Tognoni G. Interspecies comparison of in vivo caffeine pharmacokinetics in man, monkey, rabbit, rat, and mouse. Drug Metab Rev 1984–85; 15: 1355–83

    PubMed  CAS  Article  Google Scholar 

  33. Duthu GS. Interspecies correlation of the pharmacokinetics of erythromycin, oleandomycin, and tylosin. J Pharm Sci 1985; 74: 943–6

    PubMed  CAS  Article  Google Scholar 

  34. Patamasucon P, Kaojarern S, Kusmiesz H, et al. Pharmacokinetics of erythromycin ethylsuccinate and estolate in infants under 4 months of age. Antimicrob Agents Chemother 1981; 19: 736–9

    PubMed  CAS  Article  Google Scholar 

  35. Bjorkman S, Redke F. Clearance of fentanyl, alfentanil, methohexitone, thiopentone and ketamine in relation to estimated hepatic blood flow in several animal species: application to prediction of clearance in man. J Pharm Pharmacol 2000; 52: 1065–74

    PubMed  CAS  Article  Google Scholar 

  36. Jacqz-Aigrain E, Burtin P. Clinical pharmacokinetics ofsedatives in neonates. Clin Pharmacokinet 1996; 31: 423–43

    PubMed  CAS  Article  Google Scholar 

  37. Goresky GV, Koren G, Sabourin MA, et al. The pharmacokinetics of alfentanil in children. Anesthesiology 1987; 67: 654–9

    PubMed  CAS  Article  Google Scholar 

  38. Kaplan SL, Mason Jr EO, Garcia H, et al. Pharmacokinetics and cerebrospinal fluid penetration of moxalactam in children with bacterial meningitis. J Pediatr 1981; 98: 152–7

    PubMed  CAS  Article  Google Scholar 

  39. Schaad UB, McCracken Jr GH, Threlkeld N, et al. Clinical evaluation of a new broad-spectrum oxa-beta-lactam antibiotic, moxalactam, in neonates and infants. J Pediatr 1981; 98: 129–36

    PubMed  CAS  Article  Google Scholar 

  40. Mandema JW, Tukker E, Danhof M. Pharmacokinetic-pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration. Br J Pharmacol 1991; 102: 663–8

    PubMed  CAS  Article  Google Scholar 

  41. Kuroha M, Azumano A, Kuze Y, et al. Effect of multiple dosing of ketoconazole on pharmacokineticsof midazolam, a cytochrome P-4503Asubstrate in beagle dogs. Drug Metab Dispos 2002; 30: 63–8

    PubMed  CAS  Article  Google Scholar 

  42. Jacqz-Aigrain E, Wood C, Robieux I. Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol 1990; 39: 191–2

    PubMed  CAS  Article  Google Scholar 

  43. Peeters MY, Prins SA, Knibbe CA, et al. Pharmacokinetics and pharmacodynamics of midazolam and metabolites in nonventilated infants after craniofacial surgery. Anesthesiology 2006; 105: 1135–46

    PubMed  CAS  Article  Google Scholar 

  44. Rey E, Delaunay L, Pons G, et al. Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration. Eur J Clin Pharmacol 1991; 41: 355–7

    PubMed  CAS  Article  Google Scholar 

  45. Payne K, Mattheyse FJ, Liebenberg D, et al. The pharmacokinetics of midazolam in pediatric patients. Eur J Clin Pharmacol 1989; 37: 267–72

    PubMed  CAS  Article  Google Scholar 

  46. Persson P, Nilsson A, Hartvig P, et al. Pharmacokinetics of midazolam in total IV anesthesia. Br J Anaesth 1987; 59: 548–56

    PubMed  CAS  Article  Google Scholar 

  47. Sano H, Sato H, Furuta S, et al. Pharmacokinetics of nizatidine in dogs and rats. Xenobiotica 1991; 21: 1257–64

    PubMed  CAS  Article  Google Scholar 

  48. Callaghan JT, Bergstrom RF, Rubin A, et al. A pharmacokinetic profile of nizatidine in man. Scand J Gastroenterol Suppl 1987; 136: 9–17

    PubMed  CAS  Article  Google Scholar 

  49. Abdel-Rahman SM, Johnson FK, Connor JD, et al. Developmental pharmacokinetics and pharmacodynamics of nizatidine. J Pediatr Gastroenterol Nutr 2004; 38: 442–51

    PubMed  CAS  Article  Google Scholar 

  50. Abdel-Rahman SM, Johnson FK, Manowitz N, et al. Single-dose pharmacokinetics of nizatidine (Axid) in children. J Clin Pharmacol 2002; 42: 1089–96

    PubMed  CAS  Article  Google Scholar 

  51. Zaghlol HA, Brown SA. Single- and multiple-dose pharmacokinetics of intravenously administered vancomycin in dogs. Am J Vet Res 1988; 49: 1637–40

    PubMed  CAS  Google Scholar 

  52. Engineer MS, Ho DH, Bodey Sr GP. Comparison of vancomycin disposition in rats with normal and abnormal renal functions. Antimicrob Agents Chemother 1981; 20(6): 718–22

    PubMed  CAS  Article  Google Scholar 

  53. Gardner SY, Papich MG. Comparison of cefepime pharmacokinetics in neonatal foals and adult dogs. J Vet Pharmacol Ther 2001; 24: 187–92

    PubMed  CAS  Article  Google Scholar 

  54. Forgue ST, Shyu WC, Gleason CR, et al. Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys. Antimicrob Agents Chemother 1987; 31: 799–804

    PubMed  CAS  Article  Google Scholar 

  55. Barbhaiya RH, Forgue ST, Gleason CR, et al. Pharmacokinetics of cefepime after single and multiple intravenous administrations in healthy subjects. Antimicrob Agents Chemother 1992; 36: 552–7

    PubMed  CAS  Article  Google Scholar 

  56. Reed MD, Yamashita TS, Knupp CK, et al. Pharmacokinetics of intravenously and intramuscularly administered cefepime in infants and children. Antimicrob Agents Chemother 1997; 41: 1783–7

    PubMed  CAS  Google Scholar 

  57. Dedrick RL, Bischoff KB, Zaharko DZ. Interspecies correlation of plasma concentration history of methotrexate (NSC-740). Cancer Chemother Rep (Part 1) 1970; 54: 95–101

    CAS  Google Scholar 

  58. Donelli MG, Zucchetti M, Robatto A, et al. Pharmacokinetics of HD-MTX in infants, children, and adolescents with non-B acute lymphoblastic leukemia. Med Pediatr Oncol 1995; 24: 154–9

    PubMed  CAS  Article  Google Scholar 

  59. Lonnerholm G, Valsecchi MG, De Lorenzo P, et al., Interfant-99 Study Group. Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia. Pediat Blood Cancer 2009; 52: 596–601

    Article  Google Scholar 

  60. Thompson PA, Murry DJ, Rosner GL, et al. Methotrexate pharmacokinetics in infants with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2007; 59: 847–53

    PubMed  CAS  Article  Google Scholar 

  61. Lee DY, Lee I, Lee MG. Pharmacokinetics of omeprazole after intravenous and oral administration to rats with liver cirrhosis induced by dimethylnitrosamine. Int J Pharm 2007; 330(1-2): 37–44

    PubMed  CAS  Article  Google Scholar 

  62. Jacqz-Aigrain E, Bellaich M, Faure C, et al. Pharmacokinetics of intravenous omeprazole in children. Eur J Clin Pharmacol 1994; 47: 181–5

    PubMed  CAS  Google Scholar 

  63. Regardh CG, Gabrielsson M, Hoffman KJ, et al. Pharmacokinetics and metabolism of omeprazole in animals and man: an overview. Scand J Gastroenterol Suppl 1985; 108: 79–94

    PubMed  CAS  Article  Google Scholar 

  64. Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33: 313–27

    PubMed  CAS  Article  Google Scholar 

  65. Koehntop DE, Rodman JH, Brundage M, et al. Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986; 65: 227–32

    PubMed  CAS  Article  Google Scholar 

  66. Teng R, Girard D, Gootz TD, et al. Pharmacokinetics of trovafloxacin (CP-99,219), a new quinolone, in rats, dogs, and monkeys. Antimicrob Agents Chemother 1996; 40: 561–6

    PubMed  CAS  Google Scholar 

  67. Vincent J, Venitz J, Teng R, et al. Pharmacokinetics and safety of trovafloxacin in healthy male volunteers following administration of single intravenous doses of the prodrug, alatrofloxacin. J Antimicrob Chemother 1997; 39Suppl. B: 75–80

    PubMed  CAS  Article  Google Scholar 

  68. Bradley JS, Kearns GL, Reed MD, et al. Pharmacokinetics of a fluoronaphthyridone, trovafloxacin (CP 99,219), in infants and children following administration of a single intravenous dose of alatrofloxacin. Antimicrob Agents Chemother 2000; 44: 1195–9

    PubMed  CAS  Article  Google Scholar 

  69. Stalker DJ, Jungbluth GL, Hopkins NK, et al. Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. J Antimicrob Chemother 2003; 51: 1239–46

    PubMed  CAS  Article  Google Scholar 

  70. Slatter JG, Adams LA, Bush EC, et al. Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog. Xenobiotica 2002; 32: 907–24

    PubMed  CAS  Article  Google Scholar 

  71. Jungbluth GL, Welshman IR, Hopkins NK. Linezolid pharmacokinetics in pediatric patients: an overview. Pediatr Infect Dis J 2003; 22(9 Suppl.): S153–7

    PubMed  Google Scholar 

  72. Martín-Jiménez T, Riviere JE. Mixed effects modeling of the disposition of gentamicin across domestic animal species. J Vet Pharmacol Ther 2001; 24: 321–32

    PubMed  Article  Google Scholar 

  73. Tanira MO, Ali BH, Bashir AK. Effect of endotoxin on gentamicin pharmacokinetics in old and young adult rats. Life Sci 1997; 60: 413–24

    PubMed  CAS  Article  Google Scholar 

  74. Miline RW, Nation RL, Somogyi A. The disposition of morphine and its 3-and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. Drug Metab Rev 1996; 28: 345–72

    Article  Google Scholar 

  75. Olkkola KT, Maunuskela EL, Korpela R, et al. Kinetics and dynamics of postoperative intravenous morphine in children. Clin Pharmacol Ther 1988; 44: 128–36

    PubMed  CAS  Article  Google Scholar 

  76. Choonara IA, McKay P, Hain R, et al. Morphine metabolism in children. Br J Clin Pharmacol 1989; 28: 599–604

    PubMed  CAS  Article  Google Scholar 

  77. Mroszczak EJ, Lee FW, Combs D, et al. Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans. Drug Metab Dispos 1987; 15: 618–26

    PubMed  CAS  Google Scholar 

  78. Dsida RM, Wheeler M, Birmingham PK, et al. Age-stratified pharmacokinetics of ketorolac tromethamine in pediatric surgical patients. Anesth Analg 2002; 94: 266–70

    PubMed  CAS  Google Scholar 

  79. Jacobs RF, Maples HD, Aranda JV, et al. Pharmacokinetics of intravenously administered azithromycin in pediatric patients. Pediat Infect Dis J 2005; 24: 34–9

    Article  Google Scholar 

  80. Shepard RM, Falkner FC. Pharmacokinetics of azithromycin in rats and dogs. J Antimicrob Chemother 1990; 25Suppl. A: 49–60

    PubMed  CAS  Article  Google Scholar 

  81. Luke DR, Foulds G, Cohen SF, et al. Safety, toleration, and pharmacokinetics of intravenous azithromycin. Antimicrob Agents Chemother 1996; 40: 2577–81

    PubMed  CAS  Google Scholar 

  82. Servin F, Cockshott ID, Farinotti R, et al. Pharmacokinetics of propofol infusions in patients with cirrhosis. Br J Anaesth 1990; 65: 177–83

    PubMed  CAS  Article  Google Scholar 

  83. Saint-Maurice C, Cockshott ID, Douglas EJ, et al. Pharmacokinetics of propofol in young children after a single dose. Br J Anaesth 1989; 63: 667–70

    PubMed  CAS  Article  Google Scholar 

  84. Allegaert K, de Hoon J, Verbesselt R, et al. Maturational pharmacokinetics of single intravenous bolus of propofol. Paediatr Anaesth 2007; 17: 1028–34

    PubMed  Article  Google Scholar 

  85. Davi H, Tronquet C, Miscoria G, et al. Disposition of irbesartan, an angiotensin II AT1-receptor antagonist, in mice, rats, rabbits, and macaques. Drug Metab Dispos 2000; 28: 79–88

    PubMed  CAS  Google Scholar 

  86. Marino MR, Langenbacher K, Ford NF, et al. Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects. J Clin Pharmacol 1998; 38: 246–55

    PubMed  CAS  Google Scholar 

  87. Sakarcan A, Tenney F, Wilson JT, et al. The pharmacokinetics of irbesartan in hypertensive children and adolescents. J Clin Pharmacol 2001; 41: 742–9

    PubMed  CAS  Article  Google Scholar 

  88. Gascon RA, Calvo B, Hernandez RM, etal. Interspecies scaling of cimetidinetheophylline pharmacokinetic interaction: interspecies scaling in pharmacokinetic interaction. Pharm Res 1994; 11: 945–50

    PubMed  CAS  Article  Google Scholar 

  89. Chiou WL, Choi YM. Unbound total (plasma) clearance approach in interspecies pharmacokinetics correlation: theophylline-cimetidine interaction. Pharm Res 1995; 12: 1238–9

    PubMed  CAS  Article  Google Scholar 

  90. Uniphyl® (theophylline) tablets: US prescribing information. Stamford (CT): Purdue Pharmaceutical Products LP, 2010 Mar 4 [online]. Available from URL: http://www.purduepharma.com/PI/Prescription/Uniphyl.pdf [Accessed 2010 May 17]

  91. Kaul S, Dandekar KA, Schilling BE, et al. Toxicokinetics of 2′,3′-didehydro-3′-deoxythymidine, stavudine (D4T). Drug Metab Dispos 1999; 27: 1–12

    PubMed  CAS  Google Scholar 

  92. Boucher FD, Modlin JF, Weller S, et al. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J Pediatr 1993; 122: 137–44

    PubMed  CAS  Article  Google Scholar 

  93. Mirochnick M, Capparelli E, Dankner W, et al. Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrob Agents Chemother 1998; 42: 808–12

    PubMed  CAS  Google Scholar 

  94. Hirai J, Miyazaki H, Taneike T. The pharmacokinetics and pharmacodynamics of furosemide in the anaesthetized dog. J Vet Pharmacol Ther 1992; 15: 231–9

    PubMed  CAS  Article  Google Scholar 

  95. Prandota J, Pruitt AW. Pharmacokinetic, biliary excretion, and metabolic studies of 14C furosemide in the rat. Xenobiotica 1991; 21: 725–36

    PubMed  CAS  Article  Google Scholar 

  96. Tuck S, Morselli P, Broquaire M, et al. Plasma and urinary kinetics of furosemide in newborn infants. J Pediatr 1983; 103: 481–5

    PubMed  CAS  Article  Google Scholar 

  97. Vert P, Broquaire M, Legagneur M, et al. Pharmacokinetics of furosemide in neonates. Eur J Clin Pharmacol 1982; 22: 39–45

    PubMed  CAS  Article  Google Scholar 

  98. Shin JH, Choi KY, Kim YC, et al. Dose-dependent pharmacokinetics of itraconazole after intravenous or oral administration to rats: intestinal firstpass effect. Antimicrob Agents Chemother 2004; 48: 1756–62

    PubMed  CAS  Article  Google Scholar 

  99. Yi Y, Yoon HJ, Kim BO, et al. A mixed polymeric micellar formulation of itraconazole: characteristics, toxicity and pharmacokinetics. J Control Release 2007; 117: 59–67

    PubMed  CAS  Article  Google Scholar 

  100. Abdel-Rahman SM, Jacobs RF, Massarella J, et al. Single-dose pharmacokinetics of intravenous itraconazole and hydroxypropyl-beta-cyclodextrin in infants, children, and adolescents. Antimicrob Agents Chemother 2007; 51: 2668–73

    PubMed  CAS  Article  Google Scholar 

  101. Ginsberg G, Hattis D, Sonawane B. Incorporating pharmacokinetic differences between children and adults in assessing children’s risks to environmental toxicants. Toxicol Appl Pharmacol 2004; 198: 164–83

    PubMed  CAS  Article  Google Scholar 

  102. Ginsberg G, Hattis D, Russ A, et al. Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults: implications for assessing children’s risks from environmental agents. J Toxicol Environ Health A 2004; 67: 297–329

    PubMed  CAS  Article  Google Scholar 

  103. Mahmood I. Interspecies pharmacokinetic scaling: principles and application of allometric scaling. Rockville (MD): Pine House Publishers, 2005: 39–85

    Google Scholar 

  104. Kleiber M. Body size and metabolism. Hilgardia 1932; 6: 315

    CAS  Google Scholar 

  105. Mahmood I. Application of fixed exponent 0.75 to the prediction of human drug clearance: an inaccurate and misleading concept. Drug Metabol Drug Interact 2009; 24: 57–81

    PubMed  CAS  Article  Google Scholar 

  106. Haddad S, Restieri C, Krishnan K. Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. J Toxicol Environ Health A 2001; 64: 453–64

    PubMed  CAS  Article  Google Scholar 

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Acknowledgements

The views expressed in this article are those of the author and do not reflect the official policy of the US FDA. No official support or endorsement by the FDA is intended or should be inferred. No sources of funding were used in the preparation of this study. The author has no conflicts of interest that are directly relevant to the content of this study.

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    Iftekhar Mahmood

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Appendix A

Appendix A

Since simple allometry systematically (and unacceptably) overpredicted drug clearance, MLP was applied across all age groups, irrespective of the exponents of simple allometry. Although application of MLP produced comparatively lower prediction errors than simple allometry in most of the children, the net result was a systematic underprediction of clearance in children. Before application of MLP, irrespective of the exponents of simple allometry, MLP was only applied to those drugs whose exponent was >0.7, but this approach did not improve the prediction of drug clearance in children. It should be noted that application of MLP is a mathematical manipulation and is not based on any physiological consideration.

Since simple allometry systematically overpredicted drug clearance in children and MLP systematically underpredicted it, an empirical correction factor for MLP in equation 2 was sought that could balance the over- and underprediction of drug clearance in children.

To this end, the first approach was to evaluate if MLPs in neonates, infants and children at least 10 years of age would be different from those in adults. Based on the data shown in Appendix table A-I, it can be found that MLP will not vary across ages in humans. Although MLP was slightly lower in children aged 0.25 years than in adults and children aged ≥1 year, this may be by chance rather than a real occurrence. Logically, MLP in a given species will not be age dependent and will carry a constant value. This is quite evident from Appendix table A-I. Therefore, the search focused on finding a suitable denominator in equation 2 to improve the prediction by balancing the over- and underprediction.

Table A-I
figure Tab5

Maximum lifespan potential (MLP) values in humans of different ages

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Initially, approximately 50 observations were used to search for a suitable denominator in equation 2. The approaches used were the MLP values of 8.18 × 105, 6 × 105 and 4 × 105 hours. The MLP value of 6 × 105 hours was selected on the basis of the MLP value obtained from 0.25 year-old children (5.8 × 105 hours, which was rounded to 6 × 105). The application of 4 × 105 hours in equation 2 was chosen on the basis of the results of 8.18 × 105 and 6 × 105 hours, and was somewhat arbitrary. Then the ratio of the predicted/observed was calculated for simple allometry and the three aforementioned MLP values. The means of these ratios were 2.17, 0.52, 0.76 and 1.06 for simple allometry and 8.18 × 105, 6 × 105 and 4 × 105 hours for MLP, respectively. Based on these observations, 4 × 105 hours was considered a suitable denominator for equation 2. Further analysis of the data confirmed that the MLP value of 4 × 105 hours appears to be suitable as a denominator in equation 2; hence the choice of 4 × 105 hours as an empirical correction factor in equation 2. It must be recognized that although for some observations, the prediction error was less by simple allometry, MLP and the exponent of 0.75 than by MLPECF, overall prediction accuracy for most of the observations remained superior with MLPECF compared with the three aforementioned approaches.

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Mahmood, I. Interspecies Scaling for the Prediction of Drug Clearance in Children. Clin Pharmacokinet 49, 479–492 (2010). https://doi.org/10.2165/11531830-000000000-00000

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Keywords

  • Pharmacokinetic Parameter
  • Prediction Error
  • Drug Clearance
  • Allometric Equation
  • Allometric Scaling