• 1
    Mathis L, Rodriguez W. Drug therapy in pediatrics: a developing field. Dermatol Ther 2009; 22: 257261.
  • 2
    Rose K, Della PO. Development of paediatric medicines: concepts and principles. Handb Exp Pharmacol 2011; 205: 111124.
  • 3
    Rodriguez W, Selen A, Avant D, Chaurasia C, Crescenzi T, Gieser G, Di Giacinto J, Huang S-M, Lee P, Mathis L, Murphy D, Murphy S, Roberts R, Sachs HC, Suarez S, Tandon V, Uppoor RS. Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics 2008; 121: 530539.
  • 4
    van den Berg H, Tak N. Licensing and labelling of drugs in a paediatric oncology ward. Br J Clin Pharmacol 2011; 72: 474481.
  • 5
    van den Berg H, van den Anker JN, Beijnen JH. Cytostatic drugs in infants: a review on pharmacokinetic data in infants. Cancer Treat Rev 2012; 38: 326.
  • 6
    Boklan J. Little patients, losing patience: pediatric cancer drug development. Mol Cancer Ther 2006; 5: 19051908.
  • 7
    Aleksa K, Koren G. Ethical issues in including pediatric cancer patients in drug development trials. Paediatr Drugs 2002; 4: 257265.
  • 8
    Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. E. 2006. Available at (last accessed 12 October 2010).
  • 9
    FDAAA. Title IV: Pediatric Research Equity Act of 2007 (PREA) and Title V: Best Pharmaceuticals for Children Act of 2007 (BPCA). 2007. September 27, 2007 (Public Law No. 110-85).
  • 10
    Guidance for industry exposure-response relationships – study design, data analysis, and regulatory applications. U.S. Department of Health and Human Services Food and Drug Administration. 2003. Available at (last accessed 10 October 2012).
  • 11
    Pizzo P, Poplack D. Chapter 1. Epidemiology of childhood cancer. In: Principles and Practice of Pediatric Oncology, 6th edn. ed. Pine JW Jr . Philadelphia, PA: Lippincott Williams & Wilkins, 2011.
  • 12
    Simone J, Lyons J. Superior cancer survival in children compared to adults: a superior system of cancer care? 1998. Available at (last accessed 4 October 2012).
  • 13
    Manolis E, Pons G. Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Br J Clin Pharmacol 2009; 68: 493501.
  • 14
    van den Broek MPH, Huitema ADR, van Hasselt JGC, Groenendaal F, Toet MC, Egberts TCG, de Vries LS, Rademaker CMA. Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. Clin Pharmacokinet 2011; 50: 461469.
  • 15
    van den Broek MPH, Groenendaal F, Toet M, van Straaten H, van Hasselt J, Huitema A, de Vries L, Egberts A, Rademaker C. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin Pharmacokinet 2012; 51: 671679.
  • 16
    Lo YL, van Hasselt JGC, Heng SC, Lim CT, Lee TC, Charles BG. Population pharmacokinetics of vancomycin in premature Malaysian neonates: identification of predictors for dosing determination. Antimicrob Agents Chemother 2010; 54: 26262632.
  • 17
    van Hasselt JGC, Andrew MA, Hebert MF, Tarning J, Vicini P, Mattison DR. The status of pharmacometrics in pregnancy: highlights from the 3rd American Conference on Pharmacometrics. Br J Clin Pharmacol 2012; 74: 932939.
  • 18
    Bellanti F, Della PO. Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol 2011; 67: (Suppl. 1): 7586.
  • 19
    Meibohm B, Läer S, Panetta JC, Barrett JS. Population pharmacokinetic studies in pediatrics: issues in design and analysis. AAPS J 2005; 7: E475487.
  • 20
    Cella M, Gorter de Vries F, Burger D, Danhof M, Della PO. A model-based approach to dose selection in early pediatric development. Clin Pharmacol Ther 2010; 87: 294302.
  • 21
    Marsoni S, Ungerleider RS, Hurson SB, Simon RM, Hammershaimb LD. Tolerance to antineoplastic agents in children and adults. Cancer treatment reports 1985; 69: 12631269.
  • 22
    van Hasselt JGC, Green B, Morrish GA. Leveraging physiological data from literature into a pharmacokinetic model to support informative clinical study design in pregnant women. Pharm Res 2012; 29: 16091617.
  • 23
    Barrett JS, Della CAO, Läer S, Meibohm B. Physiologically Based Pharmacokinetic (PBPK) modeling in children. Clin Pharmacol Ther 2012; 92: 4049. Available at (last accessed 20 July 2012).
  • 24
    Kersting G, Willmann S, Würthwein G, Lippert J, Boos J, Hempel G. Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children. Cancer Chemother Pharmacol 2011; 69: 397405.
  • 25
    Evans WE, Crom WR, Tsiatis A, Green AA, Hayes FA, Pratt CB. Pharmacokinetic modeling of cisplatin disposition in children and adolescents with cancer. Cancer Chemother Pharmacol 1982; 10: 2226.
  • 26
    Leong R, Vieira MLT, Zhao P, Mulugeta Y, Lee C, Huang S-M, Burckart GJ. Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials. Clin Pharmacol Ther 2012; 91: 926931. Available at (last accessed 23 April 2012).
  • 27
    Khalil F, Läer S. Physiologically based pharmacokinetic modeling: methodology, applications, and limitations with a focus on its role in pediatric drug development. J Biomed Biotechnol 2011; 2011: 113.
  • 28
    Kleiber M. Body size and metabolism. Hilgardia 1932; 6: 315351.
  • 29
    Holford NHG. A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30: 329332.
  • 30
    Anderson BJ, Allegaert K, Holford NHG. Population clinical pharmacology of children: modelling covariate effects. Eur J Pediatr 2006; 165: 819829.
  • 31
    Mahmood I. Theoretical versus empirical allometry: facts behind theories and application to pharmacokinetics. J Pharm Sci 2010; 99: 29272933. Available at (last accessed 26 November 2012).
  • 32
    McLeay SC, Morrish GA, Kirkpatrick CMJ, Green B. The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007. Clin Pharmacokinet 2012; 51: 319330.
  • 33
    Trame MN, Bergstrand M, Karlsson MO, Boos J, Hempel G. Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children. Clin Cancer Res 2011; 17: 68676877.
  • 34
    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: 195203.
  • 35
    Teitelbaum Z, Lave T, Freijer J, Cohen AF. Risk assessment in extrapolation of pharmacokinetics from preclinical data to humans. Clin Pharmacokinet 2010; 49: 619632. Available at (last accessed 29 August 2012).
  • 36
    Booth BP, Rahman A, Dagher R, Griebel D, Lennon S, Fuller D, Sahajwalla C, Mehta M, Gobburu JVS. Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients. J Clin Pharmacol 2007; 47: 101111.
  • 37
    Nguyen L. Integration of modelling and simulation into the development of intravenous busulfan in paediatrics: an industrial experience. Fundam Clin Pharmacol 2008; 22: 599604.
  • 38
    Sheiner L, Wakefield J. Population modelling in drug development. Stat Methods Med Res 1999; 8: 183193.
  • 39
    Foo LK, Duffull S. Adaptive optimal design for bridging studies with an application to population pharmacokinetic studies. Pharm Res 2012; 29: 15301543.
  • 40
    Duffull SB. Design of clinical pharmacology trials. Clin Exp Pharmacol Physiol 2001; 28: 905912.
  • 41
    Ueckert S, Nyberg J, Hooker A. Explicit optimization of clinical trials for statistical power. Abstracts of the Annual Meeting of the Population Approach Group in Europe 2011: 2251.
  • 42
    Green B, Duffull SB. Prospective evaluation of a d-optimal designed population pharmacokinetic study. J Pharmacokinet Pharmacodyn 2003; 30: 145161.
  • 43
    Maloney A, Karlsson MO, Simonsson USH. Optimal adaptive design in clinical drug development: a simulation example. J Clin Pharmacol 2007; 47: 12311243.
  • 44
    Jamsen KM, Duffull SB, Tarning J, Lindegardh N, White NJ, Simpson JA. Optimal designs for population pharmacokinetic studies of oral artesunate in patients with uncomplicated falciparum malaria. Malar J 2011; 10: 181.
  • 45
    Ogungbenro K, Matthews I, Looby M, Kaiser G, Graham G, Aarons L. Population pharmacokinetics and optimal design of paediatric studies for famciclovir. Br J Clin Pharmacol 2009; 68: 546560.
  • 46
    Mizia-Malarz A, Sobol G, Janowska J, Wos H, Zahorska-Markiewicz B. Prognostic value of proangiogenic cytokines in children with lymphomas. Pediatr Blood Cancer 2009; 53: 11951199.
  • 47
    Gessi M, Bueren AO, Rutkowski S, Pietsch T. p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease. J Neurooncol 2011; 106: 135141.
  • 48
    Sandoval JA, Malkas LH, Hickey RJ. Clinical significance of serum biomarkers in pediatric solid mediastinal and abdominal tumors. Int J Mol Sci 2012; 13: 11261153. Available at (last accessed 2 October 2012).
  • 49
    van Dongen JJ, Seriu T, Panzer-Grümayer ER, Biondi A, Pongers-Willemse MJ, Corral L, Stolz F, Schrappe M, Masera G, Kamps WA, Gadner H, van Wering ER, Ludwig WD, Basso G, De Bruijn MA, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop WC, Riehm H, Bartram CR. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 17311738. Available at (last accessed 1 September 2012).
  • 50
    Keizer RJ, Funahashi Y, Semba T, Wanders J, Beijnen JH, Schellens JHM, Huitema ADR. Evaluation of α2-integrin expression as a biomarker for tumor growth inhibition for the investigational integrin inhibitor e7820 in preclinical and clinical studies. AAPS J 2011; 13: 230239.
  • 51
    Lindauer A, Di Gion P, Kanefendt F, Tomalik-Scharte D, Kinzig M, Rodamer M, Dodos F, Sörgel F, Fuhr U, Jaehde U. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin Pharmacol Ther 2010; 87: 601608. Available at (last accessed 15 July 2012).
  • 52
    Bruno R, Claret L. On the use of change in tumor size to predict survival in clinical oncology studies: toward a new paradigm to design and evaluate phase II studies. Clin Pharmacol Ther 2009; 86: 136138.
  • 53
    Claret L, Girard P, Hoff PM, van Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R. Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. J Clin Oncol 2009; 27: 41034108.
  • 54
    Bonate PL, Cunningham CC, Gaynon P, Jeha S, Kadota R, Lam GN, Razzouk B, Rytting M, Steinherz P, Weitman S. Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer. Cancer Chemother Pharmacol 2011; 67: 875890.
  • 55
    Bonate PL, Craig A, Gaynon P, Gandhi V, Jeha S, Kadota R, Lam GN, Plunkett W, Razzouk B, Rytting M, Steinherz P, Weitman S. Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia. J Clin Pharmacol 2004; 44: 13091322.
  • 56
    Pession A, Masetti R, Kleinschmidt K, Martoni A. Use of clofarabine for acute childhood leukemia. Biologics 2010; 4: 111118.
  • 57
    Holford N, Ma SC, Ploeger BA. Clinical trial simulation: a review. Clin Pharmacol Ther 2010; 88: 166182.
  • 58
    Hawwa AF, Collier PS, Millership JS, McCarthy A, Dempsey S, Cairns C, McElnay JC. Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia. Br J Clin Pharmacol 2008; 66: 826837.
  • 59
    Sandström M, Karlsson MO, Ljungman P, Hassan Z, Jonsson EN, Nilsson C, Ringden O, Oberg G, Bekassy A, Hassan M. Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients. Bone Marrow Transplant 2001; 28: 657664.
  • 60
    Cremers S, Schoemaker R, Bredius R, Den Hartigh J, Ball L, Twiss I, Vermeij P, Vossen J. Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation. Br J Clin Pharmacol 2002; 53: 386389.
  • 61
    McCune JS, Salinger DH, Vicini P, Oglesby C, Blough DK, Park JR. Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the Children's Oncology Group. J Clin Pharmacol 2009; 49: 88102.
  • 62
    Thompson PA, Rosner GL, Matthay KK, Moore TB, Bomgaars LR, Ellis KJ, Renbarger J, Berg SL. Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study. Cancer Chemother Pharmacol 2009; 64: 243251.
  • 63
    Kimura T, Kashiwase S, Makimoto A, Kumagai M, Taga T, Ishida Y, Ida K, Nagatoshi Y, Mugishima H, Kaneko M, Barrett JS. Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors. Int J Clin Pharmacol Ther 2010; 48: 327334.
  • 64
    Johnson L, Orchard PJ, Baker KS, Brundage R, Cao Q, Wang X, Langer E, Farag-El Maasah S, Ross JA, Remmel R, Jacobson PA. Glutathione S-transferase A1 genetic variants reduce busulfan clearance in children undergoing hematopoietic cell transplantation. J Clin Pharmacol 2008; 48: 10521062.
  • 65
    Ribbing J, Jonsson EN. Power, selection bias and predictive performance of the Population Pharmacokinetic Covariate Model. J Pharmacokinet Pharmacodyn 2004; 31: 109134.
  • 66
    Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Pharmacodyn 1993; 21: 735750.
  • 67
    Panetta JC, Sparreboom A, Pui C-H, Relling MV, Evans WE. Modeling mechanisms of in vivo variability in methotrexate accumulation and folate pathway inhibition in acute lymphoblastic leukemia cells. PLoS Comput Biol 2010; 6: 113.
  • 68
    Li J, Gwilt P. The effect of malignant effusions on methotrexate disposition. Cancer Chemother Pharmacol 2002; 50: 373382.
  • 69
    Berg SL, Blaney SM, Adamson PC, O'Brien M, Poplack DG, Arndt C, Blatt J, Balis FM. Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers. J Clin Oncol 1998; 16: 181186.
  • 70
    Sonnichsen DS, Hurwitz CA, Pratt CB, Shuster JJ, Relling MV. Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors. J Clin Oncol 1994; 12: 532538.
  • 71
    Zamboni WC, D'Argenio DZ, Stewart CF, MacVittie T, Delauter BJ, Farese AM, Potter DM, Kubat NM, Tubergen D, Egorin MJ. Pharmacodynamic model of topotecan-induced time course of neutropenia. Clin Cancer Res 2001; 7: 23012308.
  • 72
    Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 2002; 20: 47134721.
  • 73
    Panetta JC, Schaiquevich P, Santana VM, Stewart CF. Using pharmacokinetic and pharmacodynamic modeling and simulation to evaluate importance of schedule in topotecan therapy for pediatric neuroblastoma. Clin Cancer Res 2008; 14: 318325.
  • 74
    White-Koning M, Civade E, Geoerger B, Thomas F, Le Deley M-C, Hennebelle I, Delord J-P, Chatelut E, Vassal G. Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children. Clin Cancer Res 2011; 17: 48624871.
  • 75
    Buitenkamp TD, Mathôt RAA, de Haas V, Pieters R, Zwaan CM. Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica 2010; 95: 11061113.
  • 76
    Aquerreta I, Aldaz A, Giráldez J, Sierrasesúmaga L. Pharmacodynamics of high-dose methotrexate in pediatric patients. Ann Pharmacother 2002; 36: 13441350.
  • 77
    van Hasselt JGC, Schellens JHM, Mac Gillavry MR, Beijnen JH, Huitema ADR. Model-based evaluation and optimization of cardiac monitoring protocols for adjuvant treatment of breast cancer with trastuzumab. Pharm Res 2012; 29: 34993511.
  • 78
    van Hasselt JGC, Boekhout AH, Beijnen JH, Schellens JHM, Huitema ADR. Population pharmacokinetic-pharmacodynamic analysis of trastuzumab-associated cardiotoxicity. Clin Pharmacol Ther 2011; 90: 126132.
  • 79
    Jönsson P, Skärby T, Heldrup J, Schrøder H, Höglund P. High dose methotrexate treatment in children with acute lymphoblastic leukaemia may be optimised by a weight-based dose calculation. Pediatr Blood Cancer 2011; 57: 4146.
  • 80
    Martelli N, Mathieu O, Margueritte G, Bozonnat MC, Daurès J-P, Bressolle F, Hillaire-Buys D, Peyrière H. Methotrexate pharmacokinetics in childhood acute lymphoblastic leukaemia: a prognostic value? J Clin Pharm Ther 2011; 36: 237245.
  • 81
    Barrett JS, Mondick JT, Narayan M, Vijayakumar K, Vijayakumar S. Integration of modeling and simulation into hospital-based decision support systems guiding pediatric pharmacotherapy. BMC Med Inform Decis Mak 2008; 8: 6.
  • 82
    Edwards AYZ, Skolnik JM, Dombrowsky E, Patel D, Barrett JS. Modeling and simulation approaches to evaluate pharmacokinetic sampling contamination from central venous catheters in pediatric pharmacokinetic studies of actinomycin-D: a report from the children's oncology group. Cancer Chemother Pharmacol 2012; 70: 8394. Available at (last accessed 1 October 2012).
  • 83
    Hempel G, Müller H-J, Lanvers-Kaminsky C, Würthwein G, Hoppe A, Boos J. A population pharmacokinetic model for pegylated-asparaginase in children. Br J Haematol 2010; 148: 119125.
  • 84
    Avramis VI, Spence SA. Clinical pharmacology of asparaginases in the United States: asparaginase population pharmacokinetic and pharmacodynamic (PK-PD) models (NONMEM) in adult and pediatric ALL patients. J Pediatr Hematol Oncol 2007; 29: 239247.
  • 85
    Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, Franklin J, Gaynon PS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holcenberg JS, Stork L. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 2002; 99: 19861994.
  • 86
    Borghorst S, Pieters R, Kuehnel H-J, Boos J, Hempel G. Population pharmacokinetics of native Escherichia coli asparaginase. Pediatr Hematol Oncol 2012; 29: 154165.
  • 87
    Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant 2004; 33: 979987.
  • 88
    Schiltmeyer B, Klingebiel T, Schwab M, Mürdter TE, Ritter CA, Jenke A, Ehninger G, Gruhn B, Würthwein G, Boos J, Hempel G. Population pharmacokinetics of oral busulfan in children. Cancer Chemother Pharmacol 2003; 52: 209216.
  • 89
    Hassan M, Fasth A, Gerritsen B, Haraldsson A, Syrůcková Z, van den Berg H, Sandström M, Karlsson M, Kumlien S, Vossen J. Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders. Bone Marrow Transplant 1996; 18: 843850.
  • 90
    Zwaveling J, Press RR, Bredius RGM, van Derstraaten TRJHM, den Hartigh J, Bartelink IH, Boelens JJ, Guchelaar H-J. Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients. Ther Drug Monit 2008; 30: 504510.
  • 91
    Nakamura H, Sato T, Okada K, Miura G, Ariyoshi N, Nakazawa K, Kitada M. Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation. Ther Drug Monit 2008; 30: 7583.
  • 92
    Bertholle-Bonnet V, Bleyzac N, Galambrun C, Mialou V, Bertrand Y, Souillet G, Aulagner G. Influence of underlying disease on busulfan disposition in pediatric bone marrow transplant recipients: a nonparametric population pharmacokinetic study. Ther Drug Monit 2007; 29: 177184.
  • 93
    Paci A, Vassal G, Moshous D, Dalle J-H, Bleyzac N, Neven B, Galambrun C, Kemmel V, Abdi ZD, Broutin S, Pétain A, Nguyen L. Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation. Ther Drug Monit 2012; 34: 198208.
  • 94
    Bartelink IH, Boelens JJ, Bredius RGM, Egberts ACG, Wang C, Bierings MB, Shaw PJ, Nath CE, Hempel G, Zwaveling J, Danhof M, Knibbe CAJ. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet 2012; 51: 331345.
  • 95
    Bartelink IH, van Kesteren C Boelens JJ, Egberts TCG, Bierings MB, Cuvelier GDE, Wynn RF, Slatter MA, Chiesa R, Danhof M, Knibbe CAJ. Predictive performance of a busulfan pharmacokinetic model in children and young adults. Ther Drug Monit 2012; 34: 574583.
  • 96
    Veal GJ, Nguyen L, Paci A, Riggi M, Amiel M, Valteau-Couanet D, Brock P, Ladenstein R, Vassal G. Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial. Eur J Cancer 2012; 48: 30633072. Available at (last accessed 1 October 2012).
  • 97
    Lindauer A, Eickhoff C, Kloft C, Jaehde U. Population pharmacokinetics of high-dose carboplatin in children and adults. Ther Drug Monit 2010; 32: 159168.
  • 98
    Urien S, Doz F, Namouni F, Bastian G. Pharmacokinetic modelling of total and unbound plasma carboplatin–a population study in 75 children. Int J Clin Pharmacol Ther 2002; 40: 270278.
  • 99
    Chatelut E, Boddy AV, Peng B, Rubie H, Lavit M, Dezeuze A, Pearson AD, Roché H, Robert A, Newell DR, Canal P. Population pharmacokinetics of carboplatin in children. Clin Pharmacol Ther 1996; 59: 436443.
  • 100
    Chinnaswamy G, Errington J, Foot A, Boddy AV, Veal GJ, Cole M. Pharmacokinetics of cyclophosphamide and its metabolites in paediatric patients receiving high-dose myeloablative therapy. Eur J Cancer 2011; 47: 15561563.
  • 101
    Periclou AP, Avramis VI. NONMEM population pharmacokinetic studies of cytosine arabinoside after high-dose and after loading bolus followed by continuous infusion of the drug in pediatric patients with leukemias. Cancer Chemother Pharmacol 1996; 39: 4250.
  • 102
    Hempel G, Reinhardt D, Creutzig U, Boos J. Population pharmacokinetics of liposomal daunorubicin in children. Br J Clin Pharmacol 2003; 56: 370377.
  • 103
    Hempel G, Relling MV, de Rossi G, Stary J, de Lorenzo P, Valsecchi MG, Barisone E, Boos J, Pieters R. Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol. Pediatr Blood Cancer 2010; 54: 355360.
  • 104
    Urien S, Doz F, Giraud C, Rey E, Gentet J-C, Chastagner P, Vassal G, Corradini N, Auvrignon A, Leblond P, Rubie H, Treluyer J-M. Developmental pharmacokinetics of etoposide in 67 children: lack of dexamethasone effect. Cancer Chemother Pharmacol 2011; 67: 597603.
  • 105
    Würthwein G, Klingebiel T, Krümpelmann S, Metz M, Schwenker K, Kranz K, Lanvers C, Boos J. Population pharmacokinetics of high-dose etoposide in children receiving different conditioning regimens. Anticancer Drugs 2002; 13: 101110.
  • 106
    Würthwein G, Boos J. Simulation tool for schedule-dependent etoposide exposure based on pharmacokinetic findings published in the literature. Anticancer Drugs 2001; 12: 151158.
  • 107
    Baheti G, McGuire TR, Davda JP, Manouilov KK, Wall D, Gwilt PR, Gordon BB. Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours. Xenobiotica 2012; DOI:10.3109/00498254.2012.713530.
  • 108
    Kerbusch T, de Kraker J, Mathjt RA, Beijnen JH. Population pharmacokinetics of ifosfamide and its dechloroethylated and hydroxylated metabolites in children with malignant disease: a sparse sampling approach. Clin Pharmacokinet 2001; 40: 615625.
  • 109
    Menon-Andersen D, Mondick JT, Jayaraman B, Thompson PA, Blaney SM, Bernstein M, Bond M, Champagne M, Fossler MJ, Barrett JS. Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother Pharmacol 2009; 63: 229238.
  • 110
    Thompson PA, Gupta M, Rosner GL, Yu A, Barrett J, Bomgaars L, Bernstein ML, Blaney SM, Mondick J. Pharmacokinetics of irinotecan and its metabolites in pediatric cancer patients: a report from the children's oncology group. Cancer Chemother Pharmacol 2008; 62: 10271037.
  • 111
    Veal GJ, Cole M, Errington J, Pearson ADJ, Foot ABM, Whyman G, Boddy AV. Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma – a study of the United Kingdom Children's Cancer Study Group. Br J Cancer 2007; 96: 424431.
  • 112
    Nath CE, Shaw PJ, Montgomery K, Earl JW. Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients. Br J Clin Pharmacol 2007; 64: 151164.
  • 113
    Faganel Kotnik B, Grabnar I, Bohanec Grabar P, Dolžan V, Jazbec J. Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 2011; 67: 9931006.
  • 114
    Zhang C, Zhai S, Yang L, Wu H, Zhang J, Ke X. Population pharmacokinetic study of methotrexate in children with acute lymphoblastic leukemia. Int J Clin Pharmacol Ther 2010; 48: 1121.
  • 115
    Colom H, Farré R, Soy D, Peraire C, Cendros J-M, Pardo N, Torrent M, Domenech J, Mangues M-A. Population pharmacokinetics of high-dose methotrexate after intravenous administration in pediatric patients with osteosarcoma. Ther Drug Monit 2009; 31: 7685.
  • 116
    Plard C, Piard C, Bressolle F, Fakhoury M, Zhang D, Yacouben K, Rieutord A, Jacqz-Aigrain E. A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2007; 60: 609620.
  • 117
    Aumente D, Buelga DS, Lukas JC, Gomez P, Torres A, García MJ. Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia. Clin Pharmacokinet 2006; 45: 12271238.
  • 118
    Odoul F, Le Guellec C, Lamagnère JP, Breilh D, Saux MC, Paintaud G, Autret-Leca E. Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach. Fundam Clin Pharmacol 1999; 13: 595604.
  • 119
    Fouladi M, Stewart CF, Olson J, Wagner LM, Onar-Thomas A, Kocak M, Packer RJ, Goldman S, Gururangan S, Gajjar A, Demuth T, Kun LE, Boyett JM, Gilbertson RJ. Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Clin Oncol 2011; 29: 35293534.
  • 120
    Neville K, Blaney S, Bernstein M, Thompson P, Adams D, Aleksic A, Berg S. Pharmacokinetics of O(6)-benzylguanine in pediatric patients with central nervous system tumors: a pediatric oncology group study. Clin Cancer Res 2004; 10: 50725075.
  • 121
    Thompson P, Balis F, Serabe BM, Berg S, Adamson P, Klenke R, Aiken A, Packer R, Murry DJ, Jakacki R, Blaney SM. Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer. Cancer Chemother Pharmacol 2003; 52: 417423.
  • 122
    Petersen KB, Jusko WJ, Rasmussen M, Schmiegelow K. Population pharmacokinetics of prednisolone in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2003; 51: 465473.
  • 123
    Panetta JC, Kirstein MN, Gajjar A, Nair G, Fouladi M, Heideman RL, Wilkinson M, Stewart CF. Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors. Cancer Chemother Pharmacol 2003; 52: 435441.
  • 124
    Kirstein MN, Panetta JC, Gajjar A, Nair G, Iacono LC, Freeman BB, Stewart CF. Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC. Cancer Chemother Pharmacol 2005; 55: 433438.
  • 125
    Kitchen BJ, Balis FM, Poplack DG, O'Brien M, Craig CE, Adamson PC. A pediatric phase I trial and pharmacokinetic study of thioguanine administered by continuous i.v. infusion. Clin Cancer Res 1997; 3: 713717.
  • 126
    Schaiquevich P, Panetta JC, Iacono LC, Freeman BB, Santana VM, Gajjar A, Stewart CF. Population pharmacokinetic analysis of topotecan in pediatric cancer patients. Clin Cancer Res 2007; 13 (22 Pt 1): 67036711.
  • 127
    Freeman BB, Iacono LC, Panetta JC, Gajjar A, Stewart CF. Using plasma topotecan pharmacokinetics to estimate topotecan exposure in cerebrospinal fluid of children with medulloblastoma. Neuro-oncol 2006; 8: 8995.
  • 128
    Baker SD, Heideman RL, Crom WR, Kuttesch JF, Gajjar A, Stewart CF. Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 1996; 37: 195202.
  • 129
    Guilhaumou R, Simon N, Quaranta S, Verschuur A, Lacarelle B, Andre N, Solas C. Population pharmacokinetics and pharmacogenetics of vincristine in paediatric patients treated for solid tumour diseases. Cancer Chemother Pharmacol 2011; 68: 11911198.
  • 130
    Groninger E, Meeuwsen-de Boar T, Koopmans P, Uges D, Sluiter W, Veerman A, Kamps W, De Graaf S. Pharmacokinetics of vincristine monotherapy in childhood acute lymphoblastic leukemia. Pediatr Res 2002; 52: 113118.
  • 131
    de Graaf SS, Bloemhof H, Vendrig DE, Uges DR. Vincristine disposition in children with acute lymphoblastic leukemia. Med Pediatr Oncol 1995; 24: 235240.