Abstract
The current review addresses the following 3 frequently encountered challenges in the design and analysis of population pharmacokinetic studies in pediatrics: (1) body size adjustments during the development of pharmacostatistical models, (2) design and validation of limited sampling strategies, and (3) the integration of historical priors in data analysis and trial simulation. Size adjustments with empiric approaches based on body weight or body surface area have frequently proven as a pragmatic tool to overcome large size differences in a pediatric study population. Allometric size adjustments, however, provide a more mechanistic, physiologically based approach that, if used a priori, allows delineation of the effect of size from that of other covariates that show a high degree of collinearity. The frequent lack of dense data sets in pediatric clinical pharmacology because of ethical and logistic constraints in study design can be overcome with the application of D-optimality-based limited sampling schemes in combination with Bayesian and nonlinear mixed-effects modeling approaches. Empirically based dose selection and clinical trial designs for pediatric clinical pharmacology studies can be improved by applying clinical trial simulation techniques, especially if they integrate adult and pediatric in vitro and/or in vivo data as historic priors. Although integration of these concepts and techniques in population pharmacokinetic analyses is not only limited to pediatric research, their application allows researchers to overcome some major hurdles frequently encountered in pharmacokinetic studies in pediatrics and, thus, provides the basis for additional clinical pharmacology research in this previously insufficiently studied fraction of the general population.
Similar content being viewed by others
References
Grasela TH, Sheiner LB, Rambeck B, et al. Steady-state pharmacokinetics of phenytoin from routinely collected patient data.Clin Pharmacokinet. 1983;8:355–364.
Grasela TH Jr, Donn SM. Neonatal population pharmacokinetics of phenobarbital derived from routine clinical data.Dev Pharmacol Ther. 1985;8:374–383.
Kelman AW, Thomson AH, Whiting B, et al. Estimation of gentamicin elearance and volume of distribution in neonates and young children.Br J Clin Pharmacol. 1984;18:685–692.
Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labeling: improving the safety and efficacy of pediatric therapies.JAMA. 2003;290:905–911.
CDER/FDA. General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products—Draft Guidance. Rockville: Food and Drug Administration, Center for Drug Evaluation and Research, 1998.
Rajagopalan P, Gastonguay MR. Population pharmacokinetics of ciprofloxacin in pediatric patients.J Clin Pharmacol. 2003;43:698–710.
Chatelut E, Boddy AV, Peng B, et al. Population pharmacokinetics of carboplatin in children.Clin Pharmacol Ther. 1996;59:436–443.
Ette EI, Ludden TM. Population pharmacokinetic modeling: the importance of informative graphics.Pharm Res. 1995;12:1845–1855.
Ette EI, Williams P, Fadiran E, Ajayi FO, Onyiah LC. The process of knowledge discovery from large pharmacokinetic data sets.J Clin Pharmacol. 2001;41:25–34.
Bonate PL. The effect of collinearity on parameter estimates in nonlinear mixed effect models.Pharm Res. 1999;16:709–717.
Gusella M, Toso S, Ferrazzi E, Ferrari M, Padrini R. Relationships between body composition parameters and fluorouracil pharmacokinetics.Br J Clin Pharmacol. 2002;54:131–139.
Kanamori M, Takahashi H, Echizen H. Developmental changes in the liver weight-and body weight-normalized clearance of theophylline, phenytoin and cyclosporine in children.Int J Clin Pharmacol Ther. 2002;40:485–492.
Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese?.Br J Clin Pharmacol. 2004;58:119–133.
Mahmood I. Allometric issues in drug development.J Pharm Sci. 1999;88:1101–1106.
Bonate PL, Howard D. Prospective allometric scaling: does the emperor have clothes?.J Clin Pharmacol. 2000;40:335–340.
Mahmood I. Interspecies scaling: predicting oral clearance in humans.Am J Ther. 2002;9:35–42.
West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms.Science. 1999;284:1677–1679.
West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology.Science. 1997;276:122–126.
Weibel ER. Physiology: the pitfalls of power laws.Nature. 2002;417:131–132.
Holford NH. A size standard for pharmacokinetics.Clin Pharmacokinet. 1996;30:329–332.
Anderson BJ, Woollard GA, Holford NH. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children.Br J Clin Pharmacol. 2000;50:125–134.
Hu TM, Hayton WL. Allometric scaling of xenobiotic clearance: uncertainty versus universality.AAPS PharmSci. 2001;3:E29.
Boxenbaum H. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics.J Pharmacokinet Biopharm. 1982;10:201–227.
Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients.Clin Pharmacokinet. 1997;33:313–327.
Kleiber M. Body size and metabolism.Hilgardia. 1932;6315–6353.
McMahon T. Size and shape in biology.Science. 1973;179:1201–1204.
Anderson BJ, Holford NH, Woollard GA, chan PL. Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children.Br J Clin Pharmacol. 1998;46:237–243.
Agutter PS, Wheatley DN. Metabolic scaling: consensus or controversy?Theor Biol Med Model. 2004:1–13.
Darveau CA, Suarez RK, Andrews RD, Hochachka PW. Allometric cascade as a unifying principle of body mass effects on metabolism.Nature. 2002;417:166–170.
Rodman JH. Pharmacokinetic variability in the adolescent: implications of body size and organ function for dosage regimen design.J Adolesc Health. 1994;15:654–662.
Bailey JM, Hoffman TM, Wessel DL, et al. A population pharmacokinetic analysis of milrinone in pediatric patients after cardiac surgery.J Pharmacokinet Pharmacodyn. 2004;31:43–59.
Martin-Suarez A, Falcao AC, Outeda M, et al. Population pharmacokinetics of digoxin in pediatric patients.Ther Drug Monit. 2002;24:742–745.
Schaefer HG, Stass H, Wedgwood J, et al. Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.Antimicrob Agents Chemother. 1996;40:29–34.
Christensen ML, Mottern RK, Jabbour JT, Fuseau E. Pharmacokinetics of sumatriptan nasal spray in children.J Clin Pharmacol. 2004;44:359–367.
Dubois D, Dubois E. A formula to estimate the approximate surface area if height and weight be known.Arch Int Med. 1916;17863–17871.
Gehan EA, George SL. Estimation of human body surface area from height and weight.Cancer Chemother Rep. 1970;54:225–235.
Mosteller RD. Simplified calculation of body-surface area.N Engl J Med. 1987;317:1098.
Shi J, Ludden TM, Melikian AP, Gastonguay MR, Hinderling PH. Population pharmacokinetics and pharmacodynamics of sotalol in pediatric patients with supraventricular or ventricular tachyarrhythmia.J Pharmacokinet Pharmacodyn. 2001;28:555–575.
Sallas WM, Milosavljev S, D'Souza J, Hossain M. Pharmacokinetic drug interactions in children taking oxcarbazepine.Clin Pharmacol Ther. 2003;74:138–149.
Reilly JJ, Workman P. Normalisation of anti-cancer drug dosage using body weight and surface area: is it worthwhile? A review of theoretical and practical considerations.Cancer Chemother Pharmacol. 1993;32:411–418.
Yukawa E, Satou M, Nonaka T, et al. Pharmacoepidemiologic investigation of clonazepam relative clearance by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.J Clin Pharmacol. 2002;42:81–88.
Mandema JW, Verotta D, Sheiner LB. Building population pharmacokinetic-pharmacodynamic models. I. Models for covariate effects.J Pharmacokinet Biopharm. 1992;20:511–528.
Capparelli EV, Englund JA, Connor JD, et al. Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children.J Clin Pharmacol. 2003;43:133–140.
Panetta JC, Iacono LC, Adamson PC, Stewart CF. The importance of pharmacokinetic limited sampling models for childhood cancer drug development.Clin Cancer Res. 2003;9:5068–5077.
Desoize B, Marechal F, Cattan A. Clinical pharmacokinetics of etoposide during 120 hours continuous infusions in solid tumours.Br J Cancer. 1990;62:840–841.
Kobayashi K, Ratain MJ. Pharmacodynamics and long-term toxicity of etoposide.Cancer Chemother Pharmacol. 1994;34(suppl):S64-S68.
Minami H, Ratain MJ, Ando Y, Shimokata K. Pharmacodynamic modeling of prolonged administration of etoposide.Cancer Chemother Pharmacol. 1996;39:61–66.
Relling MV, McLeod H, Bowman L, Santana VM. Etoposide pharmacokinetics and pharmacodynamics after acute and chronic exposure to cisplatin.Clin Pharmacol Ther. 1994;56:503–511.
Sonnichsen DS, Ribeiro RC, Luo X, Mathew P, Relling MV. Pharmacokinetics and pharmacodynamics of 21-day continuous oral etoposide in pediatric patients with solid tumors.Clin Pharmacol Ther. 1995;58:99–107.
Panetta JC, Wilkinson M, Pui CH, Relling MV. Limited and optimal sampling strategies for etoposide and etoposide catechol in children with leukemia.J Pharmacokinet Pharmacodyn. 2002;29:171–188.
Kirstein MN, Panetta JC, Gajjar A, et al. Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC.Cancer Chemother Pharmacol. 2005;55:433–438.
D'Argenio DZ. Optimal sampling times for pharmacokinetic experiments.J Pharmacokinet Biopharm. 1981;9:739–756.
D'Argenio DZ. Incorporating prior parameter uncertainty in the design of sampling schedules for pharmacokinetic parameter estimation experiments.Math Biosci. 1990;99:105–118.
D'Argenio DZ, Schumitzky A.ADAPT II User's Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Resource; 1997.
Steimer JL, Mallet A, Golmard JL, Boisvieux JF. Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model.Drug Metab Rev. 1984;15:265–292.
Retout S, Duffull S, Mentre F. Development and implementation of the population Fischer information matrix for the evaluation of population pharmacokinetic designs.Comput Methods Programs Biomed. 2001;65:141–151.
Sheiner LB, Beal SL. Some suggestions for measuring predictive performance.J Pharmacokinet Biopharm. 1981;9:503–512.
Stewart CF, Iacono LC, Chintagumpala M, et al. Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor.J Clin Oncol. 2004;22:3357–3365.
Santana VM, Zamboni WC, Kirstein MN, et al. A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors.Clin Cancer Res. 2003;9:633–640.
Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia.N Engl J Med. 1998;338:499–505.
Wilson JT. An update on the therapeutic orphan.Pediatrics. 1999;104:585–590.
Lockwood PA, Cook JA, Ewy WE, Mandema JW. The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain.Pharm Res. 2003;20:1752–1759.
Anderson JJ, Bolognese JA, Felson DT. Comparison of rheumatoid arthritis clinical trial outcome measures: a simulation study.Arthritis Rheum. 2003;48:3031–3038.
Blesch KS, Gieschke R, Tsukamoto Y, Reigner BG, Burger HU, Steimer JL. Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.Invest New Drugs. 2003;21:195–223.
Thall PF, Lee SJ. Practical model-based dose-finding in phase I clinical trials: methods based on toxicity.Int J Gynecol Cancer. 2003;13:251–261.
Hausheer FH, Kochat H, Parker AR, et al. New approaches to drug discovery and development: a mechanism-based approach to pharmaceutical research and its application to BNP7787, a novel chemoprotective agent.Cancer Chemother Pharmacol. 2003;52:1S3–1S15.
Konski A, Sherman E, Krahn M, et al. Monte Carlo simulation of a Markov model for a phase III clinical trial evaluating the addition of total androgen suppression (TAS) to radiation versus radiation alone for locally advanced prostate cancer (RTOG 86-10).Int J Radiat Oncol Biol Phys. 2003;57:S215-S216.
Jumbe N, Yao B, Rovetti R, Rossi G, Heatherington AC. Clinical trial simulation of a 200-microg fixed dose of darbepoetin alfa in chemotherapy-induced anemia.Oncology (Huntingt). 2002;16:37–44.
Veyrat-Follet C, Bruno R, Olivares R, Rhodes GR, Chaikin P. Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization.Clin Pharmacol Ther. 2000;68:677–687.
Nestorov I, Graham G, Duffull S, Aarons L, Fuseau E, Coates P. Modeling and stimulation for clinical trial design involving a categorical response: a phase II case study with naratriptan.Pharm Res. 2001;18:1210–1219.
Chabaud S, Girard P, Nony P, Boissel JP. Clinical trial simulation using therapeutic effect modeling: application to ivabradine efficacy in patients with angina pectoris.J Pharmacokinet Pharmacodyn. 2002;29:339–363.
Holford NH, Kimko HC, Monteleone JP, Peck CC. Simulation of clinical trials.Annu Rev Pharmacol Toxicol. 2000;40:209–234.
Ette EI, Sun H, Ludden TM. Balanced designs in longitudinal population pharmacokinetic studies.J Clin Pharmacol. 1998;38:417–423.
Ette EI, Sun H, Ludden TM. Ignorability and parameter estimation in longitudinal pharmacokinetic studies.J Clin Pharmacol. 1998;38:221–226.
Fernandez de Gatta MM, Tamayo M, Garcia MJ, et al. Prediction of imipramine serum levels in enuretic children by a Bayesian method: comparison with two other conventional dosing methods.Ther Drug Monit. 1989;11:637–641.
Kraus DM, Dusik CM, Rodvold KA, Campbell MM, Kecskes SA. Bayesian forecasting of gentamicin pharmacokinetics in pediatric intensive care unit patients.Pediatr Infect Dis J. 1993;12:713–718.
el Desoky E, Ghazal MH, Mohamed MA, Klotz U. Disposition of intravenous theophylline in asthmatic children: Bayesian approach vs direct pharmacokinetic calculations.Jpn J Pharmacol. 1997;75:13–20.
Lares-Asseff I, Lugo-Goytia G, Perez-Guille MG, Flores-Perez J, Juarez-Olguin H, Raquel Moreno MA. Cefuroxime Bayesian pharmacokinetics in severely ill septic children.Rev Invest Clin. 1998;50:311–316.
Lares-Asseff I, Lugo-Goytia G, Perez-Guille MG, et al. Bayesian prediction of chloramphenicol blood levels in children with sepsis and malnutrition.Rev Invest Clin. 1999;51:159–165.
Wrishko RE, Levine M, Khoo D, Abbott P, Hamilton D. Vancomycin pharmacokinetics and Bayesian estimation in pediatric patients.Ther Drug Monit. 2000;22:522–531.
Bressolle F, Gouby A, Martinez JM, et al. Population pharmacokinetics of amikacin in critically ill patients.Antimicrob Agents Chemother. 1996;40:1682–1689.
Barrett JS, Gibiansky E, Hull RD, et al. Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis.Int J Clin Pharmacol Ther. 2001;39:431–446.
Andrew MV, Mitchell DJ, Barrett JS, Hainer JW. Design aspects of dose-finding trials in pediatric patients with severe TE: Tinzaparin pediatric study [abstract].Thromb Heamostasis. 2001;86.
Gastonguay MR, Gibiansky E, Gibiansky L, Barrett JS. Optimizing a Bayesian dose-adjustment scheme for a pediatric trial: a simulation study. In: Kimko HC, Duffull SB, eds.Simulation for Designing Clinical Trials. New York: Marcel Dekker; 2002;369–390.
Willis C, Staatz CE, Tett SE. Bayesian forcasting and prediction of tacrolimus concentrations in pediatric liver and adult renal transplant recipients.Ther Drug Monit. 2003;25:158–166.
de Wildt SN, de Hoog M, Vinks AA, van der Giesen E, van den Anker JN. Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients.Crit Care Med. 2003;31:1952–1958.
CDER/FDA.Innovation and Stagnation: Challenge and Opportunity on the Critical Path to New Medicinal Products. Rockville, MD: Food and Drug administration, Center for Drug Evaluation and Research, 2004.
Schwartz GJ, Haycock GB, Spitzer A. Plasma creatinine and urea concentration in children: normal values for age and sex.J Pediatr. 1976;88:828–830.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published: October 5, 2005
Rights and permissions
About this article
Cite this article
Meibohm, B., Läer, S., Panetta, J.C. et al. Population pharmacokinetic studies in pediatrics: Issues in design and analysis. AAPS J 7, 48 (2005). https://doi.org/10.1208/aapsj070248
Received:
Accepted:
DOI: https://doi.org/10.1208/aapsj070248