Development and Application of a Physiologically-Based Pharmacokinetic Model to Predict the Pharmacokinetics of Therapeutic Proteins from Full-term Neonates to Adolescents

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides an integrated framework to predict the disposition of small molecule drugs in children and is increasingly being used for dose recommendation and optimal design of paediatric studies and in regulatory submissions. Existing paediatric PBPK models can be adopted to describe the disposition of therapeutic proteins (TPs) in children by incorporating information on age-related changes of additional physiological and biological parameters (e.g. endogenous IgG, neonatal Fc receptor, lymph flow). In this study, physiological parameters were collated from literature and evaluated for any age-dependent trends. The age-dependent physiological parameters were used to construct a paediatric PBPK model for TPs. The model was then used to predict the pharmacokinetics of recombinant human erythropoietin (EPO), infliximab, etanercept, basiliximab, anakinra and enfuvirtide in paediatric subjects. The developed paediatric PBPK model predicted the drug concentration-time profiles reasonably well in full-term neonates (clinical PK data only available for EPO), infants, children and adolescents with the ratios of predicted over observed clearance values within 1.5-fold and 25 out of 26 clearance predictions were within 0.8- to 1.25-fold of the observed values. The clinically reported data are required to further assess the predictive accuracy of PK for Fc-containing proteins in term-born children younger than 2 months. This study demonstrates the ability of PBPK models accounting for age-dependent changes in relevant parameters to predict the pharmacokinetics of different types of TPs in paediatrics. The information gained from the PBPK models described here can facilitate our understanding of the complexities of TPs’ disposition during growth and development.

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Data Availability

The Simcyp Simulator is freely available, following completion of the relevant workshop, to approved members of academic institutions and other non-profit organisations for research and teaching purposes.

References

  1. 1.

    Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet. 2009;24:53–75.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45:931–56.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet. 2006;45:683–704.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Reichert JM. Marketed therapeutic antibodies compendium. MAbs. 2012;4:413–5.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Xu Z, Davis HM, Zhou H. Rational development and utilization of antibody-based therapeutic proteins in pediatrics. Pharmacol Ther. 2013;137:225–47.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev. 1993;73:1–78.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Rippe B, Haraldsson B. Fluid and protein fluxes across small and large pores in the microvasculature. Application of two-pore equations. Acta Physiol Scand. 1987;131:411–28.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Brambell F, Hemmings W, Morris I. A theoretical model of γ-globulin catabolism. Nature. 1963;203:1352–5.

    Article  Google Scholar 

  10. 10.

    Wang W, Lu P, Fang Y, Hamuro L, Pittman T, Carr B, et al. Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. Drug Metab Disposition. 2011;39:1469–77.

    CAS  Article  Google Scholar 

  11. 11.

    Malik P, Edginton A. Pediatric physiology in relation to the pharmacokinetics of monoclonal antibodies. Expert Opin Drug Metab Toxicol. 2018;14:585–99.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Gill KL, Gardner I, Li L, Jamei M. A bottom-up whole-body physiologically based pharmacokinetic model to mechanistically predict the tissue distribution and the rate of subcutaneous absorption of therapeutic proteins. AAPS J. 2015;18:156–70.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Li L, Gardner I, Dostalek M, Jamei M. Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model. AAPS J. 2014;16:1097–109.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Ohlson M, Sorensson J, Haraldsson B. A gel-membrane model of glomerular charge and size selectivity in series. Am J Physiol Renal Physiol. 2001;280:F396–405.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Deen WM, Bridges CR, Brenner BM, Myers BD. Heteroporous model of glomerular size selectivity: application to normal and nephrotic humans. Am J Phys. 1985;249:F374–89.

    CAS  Google Scholar 

  16. 16.

    Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol. 2005;45:490–7.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Food and Drug Administration. BLA99-1490 (anakinra, Kineret™) clinical pharmacology review. 2000. Available from: www.accessdata.fda.gov/drugsatfda_docs/nda/2001/103950-0_Kineret_Biopharmr.PDF.

  18. 18.

    Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, et al. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol. 2010;184:1968–76.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Sawada K, Krantz SB, Sawyer ST, Civin CI. Quantitation of specific binding of erythropoietin to human erythroid colony-forming cells. J Cell Physiol. 1988;137:337–45.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Kaymakcalan Z, Sakorafas P, Bose S, Scesney S, Xiong L, Hanzatian DK, et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin Immunol. 2009;131:308–16.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem. 2006;281:2024–32.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Stepensky D. Local versus systemic anti-tumour necrosis factor-alpha effects of adalimumab in rheumatoid arthritis: pharmacokinetic modelling analysis of interaction between a soluble target and a drug. Clin Pharmacokinet. 2012;51:443–55.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics. J Clin Pharmacol. 2012;52:54S–62S.

    PubMed  Article  Google Scholar 

  24. 24.

    Mager DE, Krzyzanski W. Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res. 2005;22:1589–96.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28:507–32.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Krzyzanski W, Wyska E. Pharmacokinetics and pharmacodynamics of erythropoietin receptor in healthy volunteers. Naunyn Schmiedeberg’s Arch Pharmacol. 2008;377:637–45.

    CAS  Article  Google Scholar 

  27. 27.

    Fisher J, Nakashima J. The role of hypoxia in renal production of erythropoietin. Cancer. 1992;70:928–39.

    CAS  PubMed  Google Scholar 

  28. 28.

    Aksu G, Genel F, Koturoglu G, Kurugol Z, Kutukculer N. Serum immunoglobulin (IgG, IgM, IgA) and IgG subclass concentrations in healthy children: a study using nephelometric technique. Turk J Pediatr. 2006;48:19–24.

    PubMed  Google Scholar 

  29. 29.

    Allansmith M, McClellan B, Butterworth M, Maloney J. The development of immunoglobulinlevels in man. J Pediatr. 1968;72:276–90.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Isaacs D, Altman D, Tidmarsh C, Valman H, Webster A. Serum immunoglobulin concentrations in preschool children measured by laser nephelometry: reference ranges for IgG, IgA. IgM J Clin Pathol. 1983;36:1193–6.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Jazayeri MH, Pourfathollah AA, Rasaee MJ, Porpak Z, Jafari ME. The concentration of total serum IgG and IgM in sera of healthy individuals varies at different age intervals. Biomedicine & Aging Pathology. 2013;3:241–5.

    CAS  Article  Google Scholar 

  32. 32.

    Jolliff C, Cost K, Stivrins P, Grossman PP, Nolte CR, Franco S, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem. 1982;28:126–8.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Kardar G, Oraei M, Shahsavani M, Namdar Z, Kazemisefat G, Ashtiani MH, et al. Reference intervals for serum immunoglobulins IgG, IgA, IgM and complements C3 and C4 in Iranian healthy children. Iran J Public Health. 2012;41:59–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Lau Y, Jones B, Ng K, Yeung C. Percentile ranges for serum IgG subclass concentrations in healthy Chinese children. Clin Exp Immunol. 1993;91:337–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Lepage N, Huang S-HS, Nieuwenhuys E, Filler G. Pediatric reference intervals for immunoglobulin G and its subclasses with Siemens immunonephelometric assays. Clin Biochem. 2010;43:694–6.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Malvy D, Poveda J, Debruyne M, Montagnon B, Burtschy B, Herbert C, et al. Laser immunonephelometry reference intervals for eight serum proteins in healthy children. Clin Chem. 1992;38:394–9.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Sitcharungsi R, Ananworanich J, Vilaiyuk S, Apornpong T, Bunupuradah T, Pornvoranunt A, Nouanthong P, Phasomsap C, Khupulsup K, Pancharoen C, Puthanakit T, Shearer WT, Benjaponpitak S, on behalf of the HIV-NAT 108 Study Group Nephelometry determined serum immunoglobulin isotypes in healthy Thai children aged 2–15 years. Microbiol Immunol 2012;56:117–122.

  38. 38.

    Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1–110.

    CAS  PubMed  Google Scholar 

  39. 39.

    Antohe F, Rădulescu LA, Gafencu A, Ghetie V, Simionescu M. Expression of functionally active FcRn and the differentiated bidirectional transport of IgG in human placental endothelial cells. Hum Immunol. 2001;62:93–105.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Morell A, Skvaril F, Wu H, Barandun S. IgG subclasses: development of the serum concentrations in “normal” infants and children. J Pediatr. 1972;80:960–4.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Barr M, Glenny AT, Randall KJ. Concentration of diphtheria antitoxin in cord blood and rate of loss in babies. Lancet. 1949;2:324–6.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Birke G, Liljedahl SO, Olhagen B, Plantin LO, Ahlinder S. Catabolism and distribution of gamma-globulin. A preliminary study with 131 I-labelled gammaglobulin. Acta Med Scand. 1963;173:589–603.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Black FL, Berman LL, Borgono JM, Capper RA, Carvalho AA, Collins C, et al. Geographic variation in infant loss of maternal measles antibody and in prevalence of rubella antibody. Am J Epidemiol. 1986;124:442–52.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Da Silva MM, Prem KA, Johnson EA, McKelvey JL, Syverton JT. Response of pregnant women and their infants to poliomyelitis vaccine: distribution of poliovirus antibody in pregnant women before and after vaccination; transfer, persistence, and induction of antibodies in infants. J Am Med Assoc. 1958;168:1–5.

    Article  Google Scholar 

  45. 45.

    Neil JM, Gaspari EL, Richardson LV, Sugg JY. Diphtheria antibodies transmitted from mother to child. J Immunol. 1932;22:117–24.

    Google Scholar 

  46. 46.

    Noya FJ, Rench MA, Garcia-Prats JA, Jones TM, Baker CJ. Disposition of an immunoglobulin intravenous preparation in very low birth weight neonates. J Pediatr. 1988;112:278–83.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Sarvas H, Seppälä I, Kurikka S, Siegberg R, Mäkelä O. Half-life of the maternal IgG1 allotype in infants. J Clin Immunol. 1993;13:145–51.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Sato H, Albrecht P, Reynolds DW, Stagno S, Ennis FA. Transfer of measles, mumps, and rubella antibodies from mother to infant. Its effect on measles, mumps, and rubella immunization. Am J Dis Child. 1979;133:1240–3.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Solomon A, Waldmann TA, Fahey JL. Clinical and experimental metabolism of normal 6.6s gamma-globulin in normal subjects and in patients with macroglobulinemia and multiple myeloma. J Lab Clin Med. 1963;62:1–17.

    CAS  PubMed  Google Scholar 

  50. 50.

    Stiehm ER, Vaerman JP, Fudenberg HH. Plasma infusions in immunologic deficiency states: metabolic and therapeutic studies. Blood. 1966;28:918–37.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Strean GJ, Gelfand MM, Pavilanis V, Sternberg J. Maternal-fetal relationships: placental transmission of poliomyelitis antibodies in newborn. Can Med Assoc J. 1957;77:315–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Vaisberg A, Alvarez JO, Hernandez H, Guillen D, Chu P, Colarossi A. Loss of maternally acquired measles antibodies in well-nourished infants and response to measles vaccination. Peru Am J Public Health. 1990;80:736–8.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Waldmann TA, Schwab PJ. Igg (7 S gamma globulin) metabolism in hypogammaglobulinemia: studies in patients with defective gamma globulin synthesis, gastrointestinal protein loss, or both. J Clin Invest. 1965;44:1523–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Weisman LE, Fischer GW, Hemming VG, Peck CC. Pharmacokinetics of intravenous immunoglobulin (sandoglobulin) in neonates. Pediatr Infect Dis J. 1986;5:S185–S8.

    CAS  Article  Google Scholar 

  55. 55.

    Wiener AS. The half-life of passively acquired antibody globulin molecules in infants. J Exp Med. 1951;94:213–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Fan Y-Y, Avery LB, Wang M, O’Hara DM, Leung S, Neubert H. Tissue expression profile of human neonatal Fc receptor (FcRn) in Tg32 transgenic mice. MAbs. 2016;8:848–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Israel E, Taylor S, Wu Z, Mizoguchi E, Blumberg R, Bhan A, et al. Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology. 1997;92:69–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Cianga C, Cianga P, Plamadeala P, Amalinei C. Nonclassical major histocompatibility complex I-like Fc neonatal receptor (FcRn) expression in neonatal human tissues. Hum Immunol. 2011;72:1176–87.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Luscieti P, Hubschmid T, Cottier H, Hess M, Sobin L. Human lymph node morphology as a function of age and site. J Clin Pathol. 1980;33:454–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Vierordt H. Anatomische, physiologische und physikalische Daten und Tabellen zum Gebrauche für Mediziner: Jena: G: Fischer; 1888.

  61. 61.

    Johnson S, Vander Straten M, Parellada J, Schnakenberg W, Gest A. Thoracic duct function in fetal, newborn, and adult sheep. Lymphology. 1996;29:50–6.

    CAS  PubMed  Google Scholar 

  62. 62.

    Taylor PM, Boonyaprakob U, Waterman V, Watson D, Lopata E. Clearances of plasma proteins from pulmonary vascular beds of adult dogs and pups. Am J Phys. 1967;213:441–9.

    CAS  Article  Google Scholar 

  63. 63.

    Braun A, Ding R, Seidel C, Fies T, Kurtz A, Schärer K. Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to children with chronic renal failure. Pediatr Nephrol. 1993;7:61–4.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Kling PJ, Widness JA, Guillery EN, Veng-Pedersen P, Peters C, DeAlarcon PA. Pharmacokinetics and pharmacodynamics of erythropoietin during therapy in an infant with renal failure. J Pediatr. 1992;121:822–5.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Wu YW, Bauer LA, Ballard RA, Ferriero DM, Glidden DV, Mayock DE, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012;130:683–91.

    PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Adedokun OJ, Xu Z, Padgett L, Blank M, Johanns J, Griffiths A, et al. Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis. Inflamm Bowel Dis. 2013;19:2753–62.

    PubMed  Article  Google Scholar 

  67. 67.

    Baldassano R, Braegger CP, Escher JC, DeWoody K, Hendricks DF, Keenan GF, et al. Infliximab (REMICADE) therapy in the treatment of pediatric Crohn’s disease. Am J Gastroenterol. 2003;98:833–8.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Burns JC, Best BM, Mejias A, Mahony L, Fixler DE, Jafri HS, et al. Infliximab treatment of intravenous immunoglobulin–resistant Kawasaki disease. J Pediatr. 2008;153:833–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007;56:3096–106.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Li CR, Yang XQ, Shen J, Li YB, Jiang LP. Immunoglobulin G subclasses in serum and circulating immune complexes in patients with Kawasaki syndrome. Pediatr Infect Dis J. 1990;9:544–7.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Niu L, An XJ, Fu MY, He XH, Wang QW. Observation of Kawasaki disease-related indexes and the study of relationship between myocardial enzyme changes and coronary artery lesions. Eur Rev Med Pharmacol Sci. 2015;19:4407–10.

    CAS  PubMed  Google Scholar 

  72. 72.

    Choueiter NF, Olson AK, Shen DD, Portman MA. Prospective open-label trial of etanercept as adjunctive therapy for Kawasaki disease. J Pediatr. 2010;157:960–6.e1.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Yim D-S, Zhou H, Buckwalter M, Nestorov I, Peck CC, Lee H. Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis. J Clin Pharmacol. 2005;45:246–56.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Zhou SY, Shu C, Korth-Bradley J, Raible D, Palmisano M, Wadjula J, et al. Integrated population pharmacokinetics of etanercept in healthy subjects and in patients with rheumatoid arthritis ankylosing spondylitis. J Clin Pharmacol. 2011;51:864–75.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Kovarik JM, Offner G, Broyer M, Niaudet P, Loirat C, Mentser M, et al. A rational dosing algorithm for basiliximab (Simulect) in pediatric renal transplantation based on pharmacokinetic-dynamic evaluations. Transplantation. 2002;74:966–71.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Food and Drug Administration. BLA97-1251 (basiliximab, Simulect™) clinical pharmacology Review. 1998. Available from: www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm113364.pdf.

  77. 77.

    Urien S, Bardin C, Bader-Meunier B, Mouy R, Compeyrot-Lacassagne S, Foissac F, et al. Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes. BMC Pharmacol Toxicol. 2013;14:40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Ilowite N, Porras O, Reiff A, Rudge S, Punaro M, Martin A, et al. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol. 2008;28:129–37.

    PubMed  Article  Google Scholar 

  79. 79.

    Soy D, Aweeka FT, Church JA, Cunningham CK, Palumbo P, Kosel BW, et al. Population pharmacokinetics of enfuvirtide in pediatric patients with human immunodeficiency virus: searching for exposure-response relationships. Clin Pharmacol Ther. 2003;74:569–80.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Bellibas SE, Siddique Z, Dorr A, Bertasso A, Sista P, Kolis SJ, et al. Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy. Pediatr Infect Dis J. 2004;23:1137–41.

    PubMed  Google Scholar 

  81. 81.

    Björkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol. 2005;59:691–704.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Johnson TN, Rostami-Hodjegan A. Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice. Pediatr Anesth. 2011;21:291–301.

    Article  Google Scholar 

  83. 83.

    Bouzom F, Walther B. Pharmacokinetic predictions in children by using the physiologically based pharmacokinetic modelling. Fundam Clin Pharmacol. 2008;22:579–87.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Cao Y, Balthasar JP, Jusko WJ. Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies. J Pharmacokinet Pharmacodyn. 2013;40:597–607.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Shah DK, Betts AM. Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J Pharmacokinet Pharmacodyn. 2012;39:67–86.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Bellini C, Boccardo F, Campisi C, Villa G, Taddei G, Traggiai C, et al. Lymphatic dysplasias in newborns and children: the role of lymphoscintigraphy. J Pediatr. 2008;152:587–9.

    PubMed  Article  Google Scholar 

  87. 87.

    Bellini C, Villa G, Sambuceti G, Traggiai C, Campisi C, Bellini T, et al. Lymphoscintigraphy patterns in newborns and children with congenital lymphatic dysplasia. Lymphology. 2014;47:28–39.

    CAS  PubMed  Google Scholar 

  88. 88.

    Hardiansyah D, Ng CM. Effects of the FcRn developmental pharmacology on the pharmacokinetics of therapeutic monoclonal IgG antibody in pediatric subjects using minimal physiologically-based pharmacokinetic modelling. MAbs. 2018;10:1144–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Akilesh S, Christianson GJ, Roopenian DC, Shaw AS. Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism. J Immunol. 2007;179:4580–8.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Chen X, DuBois DC, Almon RR, Jusko WJ. Biodistribution of etanercept to tissues and sites of inflammation in arthritic rats. Drug Metab Dispos. 2015;43:898–907.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Gómez-Mantilla JD, Trocóniz IF, Parra-Guillén Z, Garrido MJ. Review on modeling anti-antibody responses to monoclonal antibodies. J Pharmacokinet Pharmacodyn. 2014;41:523–36.

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Gorovits B, Baltrukonis DJ, Bhattacharya I, Birchler MA, Finco D, Sikkema D, et al. Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab. Clin Exp Immunol. 2018;192:348–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Strik AS, van den Brink GR, Ponsioen C, Mathot R, Lowenberg M, D’Haens GR. Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128–34.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Mahmood I. Interspecies scaling of protein drugs: prediction of clearance from animals to humans. J Pharm Sci. 2004;93:177–85.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Tang H, Mayersohn M. A global examination of allometric scaling for predicting human drug clearance and the prediction of large vertical allometry. J Pharm Sci. 2006;95:1783–99.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Hanke N, Kunz C, Thiemann M, Fricke H, Lehr T. Translational PBPK modeling of the protein therapeutic and CD95L inhibitor asunercept to develop dose recommendations for its first use in pediatric glioblastoma patients. Pharmaceutics. 2019;11:E152.

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Malik PRV, Edginton AN. Physiologically-based pharmacokinetic modelling versus allometric scaling for the prediction of infliximab pharmacokinetics in pediatric patients. CPT Pharmacometrics Syst Pharmacol. 2019;8:835–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgments

The authors thank Eleanor Savill for her assistance in the preparation and submission of the article and Dr. Mian Zhang for critical reading of the manuscript.

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Felix Stader has no conflict of interest to declare. Xian Pan, Khaled Abduljalil, Katherine L. Gill, Trevor N. Johnson, Iain Gardner and Masoud Jamei are employees of Certara UK Limited, Simcyp Division.

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Pan, X., Stader, F., Abduljalil, K. et al. Development and Application of a Physiologically-Based Pharmacokinetic Model to Predict the Pharmacokinetics of Therapeutic Proteins from Full-term Neonates to Adolescents. AAPS J 22, 76 (2020). https://doi.org/10.1208/s12248-020-00460-1

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KEY WORDS

  • paediatrics
  • monoclonal antibodies
  • therapeutic proteins
  • PBPK