The AAPS Journal

, Volume 18, Issue 4, pp 933–947 | Cite as

Using Physiologically Based Pharmacokinetic (PBPK) Modelling to Gain Insights into the Effect of Physiological Factors on Oral Absorption in Paediatric Populations

  • Angela Villiger
  • Cordula Stillhart
  • Neil Parrott
  • Martin Kuentz
Research Article


Paediatric pharmaceutics has become an important topic, but currently, there is an incomplete knowledge of paediatric gastrointestinal physiology and adequate biopharmaceutical tools still have to be developed. The present study aimed to increase the understanding of oral drug absorption in paediatric populations by using physiologically based pharmacokinetic (PBPK) modelling and in vitro dissolution testing. The oral absorption of two model compounds, sotalol and paracetamol, was studied by collection of reported pharmacokinetic profiles from adult and paediatric subjects. A PBPK model based on input parameters collected from the literature was first developed and validated in adults before being extrapolated to paediatric age groups. The accuracy of the model simulations was assessed by comparison to the observed pharmacokinetic profiles, and in the case of discrepancy, further investigations were made via parameter sensitivity analysis and in vitro dissolution testing. The PBPK models accurately predicted sotalol and paracetamol exposure in adult populations. An accurate simulation was also obtained after model extrapolation to children older than 2 years of age. However, the simulation in infants and newborns resulted in a discrepancy, which was further analysed. Dissolution testing suggested no significant difference in the drug release rate between paediatric and adult age groups. In contrast, mean gastric emptying time seemed to be underestimated in infants and newborns, and optimisation of this input parameter improved the prediction of the model. Considering age-specific differences in gastrointestinal tract physiology should improve prediction of drug absorption in paediatric patients.


in vitro dissolution mean gastric transit time oral drug absorption paediatric gastrointestinal physiology paediatric PBPK modelling 



Active pharmaceutical ingredient


Area under the curve


Blood to plasma concentration ratio


Body surface area


Centers for Disease Control and Prevention


Maximal concentration of the plasma concentration-time curve




Fasted state simulated intestinal fluid


Fed state simulated intestinal fluid


Fraction unbound


European Medicines Agency


Mean gastric transit time




Hydrochloric acid


High-performance liquid chromatography


International Conference on Harmonisation




Potassium dihydrogen phosphate


Partition coefficient


Molecular weight


Sodium chloride


Sodium dihydrogen phosphate monohydrate


Sodium hydroxide


Physiologically based pharmacokinetic




Acid dissociation constant






Parameter sensitivity analysis


Observed to predicted ratio


Standard deviation


Simulated gastric fluid without pepsin


Small intestine


Small intestinal transit time


Trifluoroacetic acid


Time to reach the maximal concentration


Volume of distribution at steady state


  1. 1.
    International Conference of Harmonization. ICH Topic E 11. Clinical investigation of medicinal products in the pediatric population, London. 2001.Google Scholar
  2. 2.
    Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane AR, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ. 2000;320(7227):79–82. doi: 10.1136/bmj.320.7227.79.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Breitkreutz J. European perspectives on pediatric formulations. Clin Ther. 2008;30(11):2146–54. doi: 10.1016/j.clinthera.2008.11.016.CrossRefPubMedGoogle Scholar
  4. 4.
    Dunne J. The European Regulation on medicines for paediatric use. Paediatr Respir Rev. 2007;8(2):177–83. doi: 10.1016/j.prrv.2007.04.004.CrossRefPubMedGoogle Scholar
  5. 5.
    Kaye JL. Review of paediatric gastrointestinal physiology data relevant to oral drug delivery. Int J Clin Pharm. 2011;33(1):20–4. doi: 10.1007/s11096-010-9455-0.CrossRefPubMedGoogle Scholar
  6. 6.
    Mooij MG, de Koning BAE, Huijsman ML, de Wildt SN. Ontogeny of oral drug absorption processes in children. Expert Opin Drug Metab Toxicol. 2012;8(10):1293–303. doi: 10.1517/17425255.2012.698261.CrossRefPubMedGoogle Scholar
  7. 7.
    Dickinson PA, Lee WW, Stott PW, Townsend AI, Smart JP, Ghahramani P, et al. Clinical relevance of dissolution testing in quality by design. AAPS J. 2008;10(2):380–90. doi: 10.1208/s12248-008-9034-7.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Batchelor HK, Kendall R, Desset-Brethes S, Alex R, Ernest TB. Application of in vitro biopharmaceutical methods in development of immediate release oral dosage forms intended for paediatric patients. Eur J Pharm Biopharm. 2013;85(3):833–42. doi: 10.1016/j.ejpb.2013.04.015.
  9. 9.
    Batchelor HK, Fotaki N, Klein S. Paediatric oral biopharmaceutics: key considerations and current challenges. Adv Drug Deliver Rev. 2014;73:102–26. doi: 10.1016/j.addr.2013.10.006.CrossRefGoogle Scholar
  10. 10.
    Galia E, Nicolaides E, Horter D, Lobenberg R, Reppas C, Dressman JB. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res. 1998;15(5):698–705. doi: 10.1023/a:1011910801212.CrossRefPubMedGoogle Scholar
  11. 11.
    Vertzoni M, Fotaki N, Kostewicz E, Stippler E, Leuner C, Nicolaides E, et al. Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects. J Pharm Pharmacol. 2004;56(4):453–62. doi: 10.1211/0022357022935.CrossRefPubMedGoogle Scholar
  12. 12.
    Documenta Geigy. Wissenschaftliche Tabellen. Basel: J.R. Geigy AG., Red. K. Diem; 1969.Google Scholar
  13. 13.
    Hanyok JJ. Clinical pharmacokinetics of sotalol. Am J Cardiol. 1993;72(4):19a–26a.CrossRefPubMedGoogle Scholar
  14. 14.
    Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982;7(2):93–107.CrossRefPubMedGoogle Scholar
  15. 15.
    PubChem Compound Database; CID = 5253. U.S. National Center for Biotechnology Information. National Library of Medicine, 8600 Rockville Pike. 2005. Accessed 03 Jul 2014.
  16. 16.
    Khalil F, Laeer S. Physiologically based pharmacokinetic models in the prediction of oral drug exposure over the entire pediatric age range-sotalol as a model drug. AAPS J. 2014;16(2):226–39. doi: 10.1208/s12248-013-9555-6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jiang XL, Zhao P, Barrett JS, Lesko LJ, Schmidt S. Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children. CPT Pharmacometrics Syst Pharmacol. 2013;2:e80-e. doi: 10.1038/psp.2013.55.CrossRefGoogle Scholar
  18. 18.
    DrugBank Version 4.3. Canadian Institutes of Health Research, Alberta. 2013. Accessed 13 Dec 2014.
  19. 19.
    Yang Y, Faustino PJ, Volpe DA, Elllison CD, Lyon RC, Yu LX. Biopharmaceutics classification of selected beta-blockers: solubility and permeability class membership. Mol Pharm. 2007;4(4):608–14. doi: 10.1021/mp070028I.CrossRefPubMedGoogle Scholar
  20. 20.
    Rodgers T, Rowland M. Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm Res. 2007;24(5):918–33. doi: 10.1007/s11095-006-9210-3.CrossRefPubMedGoogle Scholar
  21. 21.
    Tjandramaga TB. Altered pharmacokinetics of beta-adrenoceptor blocking drugs in patients with renal insufficiency. Arch Int Pharmacod T. 1980;Suppl:38–53.Google Scholar
  22. 22.
    McDevitt DG. Comparison of pharmacokinetic properties of beta-adrenoceptor blocking drugs. Eur Heart J. 1987;8:9–14.CrossRefPubMedGoogle Scholar
  23. 23.
    Pery ARR, Brochot C, Zeman FA, Mombelli E, Desmots S, Pavan M, et al. Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: a case study with acetaminophen. Toxicol Lett. 2013;220(1):26–34. doi: 10.1016/j.toxlet.2013.03.032.CrossRefPubMedGoogle Scholar
  24. 24.
    Blair AD, Burgess ED, Maxwell BM, Cutler RE. Sotalol kinetics in renal insufficiency. Clin Pharmacol Ther. 1981;29(4):457–63.CrossRefPubMedGoogle Scholar
  25. 25.
    Clements JA, Critchley J, Prescott LF. The role of sulfate conjugation in the metabolism and disposition of oral and intravenous paracetamol in man. Brit J Clin Pharmacol. 1984;18(4):481–5.CrossRefGoogle Scholar
  26. 26.
    Alt A, Potthast H, Moessinger J, Sickmuller B, Oeser H. Biopharmaceutical characterization of sotalol-containing oral immediate release drug products. EurJ Pharm Biopharm. 2004;58(1):145–50. doi: 10.1016/j.ejpb.2004.02.007.CrossRefGoogle Scholar
  27. 27.
    Liu W, Okochi H, Benet LZ, Zhai S-D. Sotalol permeability in cultured-cell, rat intestine, and PAMPA system. Pharm Res. 2012;29(7):1768–74. doi: 10.1007/s11095-012-0699-3.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lennernas H. Human in vivo regional intestinal permeability: importance for pharmaceutical drug development. Mol Pharmaceut. 2014;11(1):12–23. doi: 10.1021/mp4003392.CrossRefGoogle Scholar
  29. 29.
    Levitt DG. Quantitation of small intestinal permeability during normal human drug absorption. BMC Pharmacol Tox. 2013;14. doi:  10.1186/2050-6511-14-34.
  30. 30.
    Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57. doi: 10.1002/jps.20502.CrossRefPubMedGoogle Scholar
  31. 31.
    Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005;94(6):1259–76. doi: 10.1002/jps.20322.CrossRefPubMedGoogle Scholar
  32. 32.
    Simulations Plus I. GastroPlus Manual—simulation software for drug discovery and development. 2013;Version 8.5.Google Scholar
  33. 33.
    Anttila M, Arstila M, Pfeffer M, Tikkanen R, Vallinkoski V, Sundquist H. Human pharmacokinetics of sotalol. Acta Pharmacol Tox. 1976;39(1):118–28.CrossRefGoogle Scholar
  34. 34.
    Salazar DE, Much DR, Nichola PS, Seibold JR, Shindler D, Slugg PH. A pharmacokinetic-pharmacodynamic model of d-sotalol Q-Tc prolongation during intravenous administration to healthy subjects. J Clin Pharmacol. 1997;37(9):799–809.CrossRefPubMedGoogle Scholar
  35. 35.
    Somberg JC, Preston RA, Ranade V, Molnar J. Developing a safe intravenous sotalol dosing regimen. Am J Ther. 2010;17(4):365–72. doi: 10.1097/MJT.0b013e3181ea3184.CrossRefPubMedGoogle Scholar
  36. 36.
    Poirier JM, Jaillon P, Lecocq B, Lecocq V, Ferry A, Cheymol G. The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers. Eur J Clin Pharmacol. 1990;38(6):579–82. doi: 10.1007/bf00278585.
  37. 37.
    Laer S, Neumann J, Scholz H. Interaction between sotalol and an antacid preparation. Brit J Clin Pharma. 1997;43(3):269–72. doi: 10.1111/j.1365-2125.1997.00506.x.CrossRefGoogle Scholar
  38. 38.
    Uematsu T, Kanamaru M, Nakashima M. Comparative pharmacokinetic and pharmacodynamic properties of oral and intravenous (+)-sotalol in healthy volunteers. J Pharm Pharmacol. 1994;46(7):600–5.Google Scholar
  39. 39.
    Kahela P, Anttila M, Tikkanen R, Sundquist H. Effect of food, food constituents and fluid volume on the bioavailability of sotalol. Acta Pharmacol Tox. 1979;44(1):7–12.CrossRefGoogle Scholar
  40. 40.
    Rawlins MD, Henderson DB, Hijab AR. Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral-administration. Eur J Clin Pharmacol. 1977;11(4):283–6. doi: 10.1007/bf00607678.CrossRefPubMedGoogle Scholar
  41. 41.
    Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012;12(7):523–32. doi: 10.1111/j.1533-2500.2012.00556.x.CrossRefPubMedGoogle Scholar
  42. 42.
    Douglas AP, Savage RL, Rawlins MD. Paracetamol (acetaminophen) kinetics in patients with Gilber’s syndrome. Eur J Clin Pharmacol. 1978;13(3):209–12. doi: 10.1007/bf00609984.
  43. 43.
    Liukas A, Kuusniemi K, Aantaa R, Virolainen P, Niemi M, Neuvonen PJ, et al. Pharmacokinetics of intravenous paracetamol in elderly patients. Clin Pharmacokinet. 2011;50(2):121–9. doi: 10.2165/11537240-000000000-00000.CrossRefPubMedGoogle Scholar
  44. 44.
    Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Brit J Clin Pharmacol. 1980;10:S291–S8.CrossRefGoogle Scholar
  45. 45.
    Perucca E, Richens A. Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs. Brit J Clin Pharmaco. 1979;7(2):201–6.CrossRefGoogle Scholar
  46. 46.
    Kamali F, Edwards C, Rawlins MD. The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics. Brit J Clin Pharmacol. 1992;33(3):309–12.Google Scholar
  47. 47.
    Prescott LF, Speirs GC, Critchley J, Temple RM, Winney RJ. Paracetamol disposition and metabolite kinetics in patients with chronic renal failure. Eur J Clin Pharmacol. 1989;36(3):291–7. doi: 10.1007/bf00558162.
  48. 48.
    Zapater P, de la Vega MCL, Horga JF, Such J, Frances R, Esteban A, et al. Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status. Aliment Pharm Ther. 2004;20(1):29–36. doi: 10.1111/j.1365-2036.2004.02022.x.CrossRefGoogle Scholar
  49. 49.
    Albert KS, Sedman AJ, Wilkinson P, Stoll RG, Murray WJ, Wagner JG et al. Bioavailability studies of acetaminophen and nitrofurantoin. J Clin Pharmacol. 1974:264–70.Google Scholar
  50. 50.
    Baraka OZ, Truman CA, Ford JM, Roberts CJC. The effect of propranolol on paracetamol metabolism in man. Brit J Clin Pharmacol. 1990;29(2):261–4.CrossRefGoogle Scholar
  51. 51.
    Critchley J, Critchley LAH, Anderson PJ, Tomlinson B. Differences in the single-oral-dose pharmacokinetics and urinary excretion of paracetamol and its conjugates between Hong Kong Chinese and Caucasian subjects. J Clin Pharm Ther. 2005;30(2):179–84. doi: 10.1111/j.1365-2710.2004.00626.x.CrossRefPubMedGoogle Scholar
  52. 52.
    Shinoda S, Aoyama T, Aoyama Y, Tomioka S, Matsumoto Y, Ohe Y. Pharmacokinetics/pharmacodynamics of acetaminophen analgesia in Japanese patients with chronic pain. Biol Pharm Bull. 2007;30(1):157–61. doi: 10.1248/bpb.30.157.CrossRefPubMedGoogle Scholar
  53. 53.
    Saul JP, Schaffer MS, Karpawich PP, Erickson CC, Epstein MR, Melikian AP, et al. Single-dose pharmacokinetics of sotalol in a pediatric population with supraventricular and/or ventricular tachyarrhythmia. J Clin Pharmacol. 2001;41(1):35–43.CrossRefPubMedGoogle Scholar
  54. 54.
    Mooij MG, Van Duijn E, Knibbe CA, Windhorst AD, Hendrikse NH, Vaes WH. Pediatric microdose study of [14C] paracetamol to study drug metabolism using accelerated mass spectrometry: proof of concept. Clin Pharmacol Ther. 2015;97:S97–S8.Google Scholar
  55. 55.
    Kelley MT, Walson PD, Edge JH, Cox S, Mortensen ME. Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children. Clin Pharmacol Ther. 1992;52(2):181–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Zuppa AF, Hammer GB, Barrett JS, Kenney BF, Kassir N, Mouksassi S, et al. Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or fever. J Pediat Pharmacol Therapeut. 2011;16(4):246–61. doi: 10.5863/1551-6776-16.4.246.
  57. 57.
    Hopkins CS, Underhill S, Booker PD. Pharmacokinetics of paracetamol after cardiac surgery. Arch Dis Child. 1990;65(9):971–6.Google Scholar
  58. 58.
    Palmer GM, Atkins M, Anderson BJ, Smith KR, Culnane TJ, McNally CM, et al. IV acetaminophen pharmacokinetics in neonates after multiple doses. Brit J Anaesth. 2008;101(4):523–30. doi: 10.1093/bja/aen208.CrossRefPubMedGoogle Scholar
  59. 59.
    Walson PD, Halvorsen M, Edge J, Casavant MJ, Kelley MT. 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. 2013;35(2):135–40. doi: 10.1016/j.clinthera.2012.12.016.CrossRefPubMedGoogle Scholar
  60. 60.
    Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliver Rev. 2001;50:S41–67. doi: 10.1016/s0169-409x(01)00179-x.CrossRefGoogle Scholar
  61. 61.
    Yalkowsky SH, He Y, Jain P. Handbook of aqueous solubility data. 2nd ed. Boca Raton: CRC Press; 2010.CrossRefGoogle Scholar
  62. 62.
    Yu LX, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm. 1999;186(2):119–25. doi: 10.1016/s0378-5173(99)00147-7.CrossRefPubMedGoogle Scholar
  63. 63.
    Wang C, Allegaert K, Tibboel D, Danhof M, van der Marel CD, Mathot RAA, et al. Population pharmacokinetics of paracetamol across the human age-range from (pre)term neonates, infants, children to adults. J Clin Pharmacol. 2014;54(6):619–29. doi: 10.1002/jcph.259.
  64. 64.
    Strougo A, Eissing T, Yassen A, Willmann S, Danhof M, Freijer J. First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development. J Pharmacokinet Pharmacodyn. 2012;39(2):195–203. doi: 10.1007/s10928-012-9241-9.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Mohammed BS, Engelhardt T, Cameron GA, Cameron L, Hawksworth GM, Hawwa AF, et al. Population pharmacokinetics of single-dose intravenous paracetamol in children. Brit J Anaesth. 2012;108(5):823–9. doi: 10.1093/bja/aes025.CrossRefPubMedGoogle Scholar
  66. 66.
    Anderson BJ, Pons G, Autret-Leca E, Allegaert K, Boccard E. Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis. Pediatr Anesth. 2005;15(4):282–92. doi: 10.1111/j.1460-9592.2005.01455.x.CrossRefGoogle Scholar
  67. 67.
    CDC growth chart stature-for-age and weight-for-age percentiles. Centers for Disease Control and Prevention, Atlanta. 2010. Accessed 16. Dec 2014.
  68. 68. The QMB Innovation Centre, London. 2011. Accessed 17. Dec 2014.
  69. 69.
    Baranowska I, Wilczek A. Simultaneous RP-HPLC determination of sotalol, metoprolol, alpha-hydroxymetoprolol, paracetamol and its glucuronide and sulfate metabolites in human urine. Anal Sci. 2009;25(6):769–72.Google Scholar
  70. 70.
    Altun ML. HPLC method for the analysis of paracetamol, caffeine and dipyrone. Turk J Chem. 2002;26:521–8.Google Scholar
  71. 71.
    Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, et al. Biowaiver monographs for immediate release solid oral dosage forms: Acetaminophen (paracetamol). J Pharm Sci. 2006;95(1):4–14. doi: 10.1002/jps.20477.
  72. 72.
    Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet. 2006;45(10):1013–34. doi: 10.2165/00003088-200645100-00005.CrossRefPubMedGoogle Scholar
  73. 73.
    Bagnall WE, Kelleher J, Walker BE, Losowsky MS. Gastro-intestinal absorption of paracetamol in the rat. J Pharm Pharmacol. 1979;31(3):157–60.CrossRefPubMedGoogle Scholar
  74. 74.
    Lebenthal E, Lee PC, Heitlinger LA. Impact of development of the gastrointestinal tract on infant feeding. J Pediatr. 1983;102(1):1–9. doi: 10.1016/s0022-3476(83)80276-5.CrossRefPubMedGoogle Scholar
  75. 75.
    Van Den Driessche M, Peeters K, Marien P, Ghoos Y, Devlieger H, Veereman-Wauters G. Gastric emptying in formula-fed and breast-fed infants measured with the 13C-octanoic acid breath test. J Pediatr Gastr Nutr. 1999;29(1):46–51. doi: 10.1097/00005176-199907000-00013.
  76. 76.
    Cavell B. Gastric emptying in infants fed human milk or infant formula.G. Acta Paediatr Scand. 1981;70(5):639–41.Google Scholar
  77. 77.
    Heimann G. Enteral absorption and bioavailability in children in relation to age. Eur J Clin Pharmacol. 1980;18(1):43–50. doi: 10.1007/bf00561477.CrossRefPubMedGoogle Scholar
  78. 78.
    Shaaban SY, Nassar MF, Sawaby AS, El-Masry H, Ghana AF. Ultrasonographic gastric emptying in protein energy malnutrition: effect of type of meal and nutritional recovery. Eur J Clin Nutr. 2004;58(6):972–8. doi: 10.1038/sj.ejcn.1601931.CrossRefPubMedGoogle Scholar
  79. 79.
    Garzi A, Messina M, Frati F, Carfagna L, Zagordo L, Belcastro M, et al. An extensively hydrolysed cow’s milk formula improves clinical symptoms of gastroesophageal reflux and reduces the gastric emptying time in infants. Allergol Immunopath. 2002;30(1):36–41.CrossRefGoogle Scholar
  80. 80.
    Marciani L, Gowland PA, Spiller RC, Manoj P, Moore RJ, Young P, et al. Effect of meal viscosity and nutrients on satiety, intragastric dilution, and emptying assessed by MRI. Am J Physiol Gastrointest Liver Physiol. 2001;280(6):G1227–G33.Google Scholar
  81. 81.
    Bonner JJ, Vajjah P, Abduljalil K, Jamei M, Rostami-Hodjegan A, Tucker GT, et al. Does age affect gastric emptying time? A model-based meta-analysis of data from premature neonates through to adults. Biopharm Drug Dispos. 2015;36(4):245–57. doi:  10.1002/bdd.1937.
  82. 82.
    Lange A, Funch-Jensen P, Thommesen P, Schiotz PO. Gastric emptying patterns of a liquid meal in newborn infants measured by epigastric impedance. Neurogastroent Motil. 1997;9(2):55–62. doi: 10.1046/j.1365-2982.1997.d01-20.x.

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Angela Villiger
    • 1
    • 3
  • Cordula Stillhart
    • 1
  • Neil Parrott
    • 2
  • Martin Kuentz
    • 3
  1. 1.Formulation Research & DevelopmentF. Hoffmann - La Roche Ltd.BaselSwitzerland
  2. 2.Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center BaselF. Hoffmann - La Roche Ltd.BaselSwitzerland
  3. 3.Institute of Pharmaceutical TechnologyUniversity of Applied Sciences and Arts Northwestern SwitzerlandMuttenzSwitzerland

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