Concept and utility of population pharmacokinetic and pharmacokinetic/ pharmacodynamic models in drug development and clinical practice

  • Maša Roganović University of Belgrade – Faculty of Pharmacy, Department of Pharmacokinetic and Clinical Pharmacy
  • Ana Homšek University of Belgrade – Faculty of Pharmacy, Department of Pharmacokinetic and Clinical Pharmacy
  • Marija Jovanović University of Belgrade – Faculty of Pharmacy, Department of Pharmacokinetic and Clinical Pharmacy
  • Valentina Topić Vučenović University of Banja Luka - Faculty of Medicine, Department of Pharmacy
  • Milica Ćulafić University of Belgrade – Faculty of Pharmacy, Department of Pharmacokinetic and Clinical Pharmacy
  • Branislava Miljković University of Belgrade – Faculty of Pharmacy, Department of Pharmacokinetic and Clinical Pharmacy
  • Katarina Vučićević University of Belgrade – Faculty of Pharmacy, Department of Pharmacokinetic and Clinical Pharmacy
Keywords: pharmacometrics, population analysis, pharmacokinetics, pharmacokinetic-pharmacodynamic modelling

Abstract


Due to frequent clinical trial failures and consequently fewer new drug approvals, the need for improvement in drug development has, to a certain extent, been met using model-based drug development. Pharmacometrics is a part of pharmacology that quantifies drug behaviour, treatment response and disease progression based on different models (pharmacokinetic - PK, pharmacodynamic - PD, PK/PD models, etc.) and simulations. Regulatory bodies (European Medicines Agency, Food and Drug Administration) encourage the use of modelling and simulations to facilitate decision-making throughout all drug development phases. Moreover, the identification of factors that contribute to variability provides a basis for dose individualisation in routine clinical practice. This review summarises current knowledge regarding the application of pharmacometrics in drug development and clinical practice with emphasis on the population modelling approach.

References

Hill RG. Drug discovery and development: Technology in transition: Elsevier Health Sciences; 2012. 368 p.

Turner JR. New drug development: An introduction to clinical trials. New York: Springer; 2010. 256 p.

Salazar DE, Gormley G. Modern drug discovery and development. In: Robertson D, Williams G, editors. Clinical and translational science: Principles of human research. London: Elsevier; 2017. p. 719-43.

Marchenko OV, Katenka NV. Quantitative methods in pharmaceutical research and development: Concepts and applications: Springer; 2020. 445 p.

Kimko H, Pinheiro J. Model-based clinical drug development in the past, present and future: A commentary. Br J Clin Pharmacol. 2015;79(1):108-16.

Milligan PA, Brown MJ, Marchant B, Martin SW, van der Graaf PH, Benson N, et al. Model-based drug development: A rational approach to efficiently accelerate drug development. Clin Pharmacol Ther. 2013;93(6):502-14.

U.S. Food and Drug Administration. Innovation or stagnation: Challenge and opportunity on the critical path to new medical products 2004. Available from: https://www.fda.gov/science-research/science-and-research-special-topics/critical-path-initiative.

Bhattaram VA, Bonapace C, Chilukuri DM, Duan JZ, Garnett C, Gobburu JV, et al. Impact of pharmacometric reviews on new drug approval and labeling decisions-a survey of 31 new drug applications submitted between 2005 and 2006. Clin Pharmacol Ther. 2007;81(2):213-21.

Bhattaram VA, Booth BP, Ramchandani RP, Beasley BN, Wang Y, Tandon V, et al. Impact of pharmacometrics on drug approval and labeling decisions: A survey of 42 new drug applications. AAPS J. 2005;7(3):E503-12.

Lee JY, Garnett CE, Gobburu JV, Bhattaram VA, Brar S, Earp JC, et al. Impact of pharmacometric analyses on new drug approval and labelling decisions: A review of 198 submissions between 2000 and 2008. Clin Pharmacokinet. 2011;50(10):627-35.

Wang Y, Bhattaram AV, Jadhav PR, Lesko LJ, Madabushi R, Powell JR, et al. Leveraging prior quantitative knowledge to guide drug development decisions and regulatory science recommendations: Impact of FDA pharmacometrics during 2004-2006. J Clin Pharmacol. 2008;48(2):146-56.

European Medicines Agency. Guideline on reporting the results of population pharmacokinetic analyses 2007. Available from: https://www.ema.europa.eu/en/reporting-results-population-pharmacokinetic-analyses.

U.S. Food and Drug Administration. Guidance for industry population pharmacokinetics 1999. Available from: https://www.fda.gov/media/71364/download.

U.S. Food and Drug Administration. Population pharmacokinetics guidance for industry; draft guidance 2019. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/population-pharmacokinetics.

EFPIA MID3 Workgroup, Marshall SF, Burghaus R, Cosson V, Cheung SY, Chenel M, et al. Good practices in model-informed drug discovery and development: Practice, application, and documentation. CPT Pharmacometrics Syst Pharmacol. 2016;5(3):93-122.

U.S. Food and Drug Administration. Exposure-response relationships - study design, data analysis, and regulatory applications 2003. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/exposure-response-relationships-study-design-data-analysis-and-regulatory-applications.

Gobburu JV. Pharmacometrics 2020. J Clin Pharmacol. 2010;50(9 Suppl):151S-7S.

Gobburu JV, Lesko LJ. Quantitative disease, drug, and trial models. Annu Rev Pharmacol Toxicol. 2009;49:291-301.

Barrett JS, Fossler MJ, Cadieu KD, Gastonguay MR. Pharmacometrics: A multidisciplinary field to facilitate critical thinking in drug development and translational research settings. J Clin Pharmacol. 2008;48(5):632-49.

Ette EI, Williams PJ. Pharmacometrics: The science of quantitative pharmacology. Hoboken: Wiley; 2007.

Xu Y, Kimko H. Pharmacometrics: A quantitative decision-making tool in drug development. In: Marchenko O, Katenka N, editors. Quantitative methods in pharmaceutical research and development. 1 ed: Springer; 2020. p. 71-104.

Lala M, Gobburu JV. Pharmacometrics: Concepts and applications to drug development. In: Kaplan B, Burckart GJ, Lakkis FG, editors. Immunotherapy in transplantation: Principles and practice. 1 ed: Wiley-Blackwell; 2012. p. 114-32.

Kim TH, Shin S, Shin BS. Model-based drug development: Application of modeling and simulation in drug development. J Pharm Investig. 2018;48(4):431-41.

Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacometrics Syst Pharmacol. 2012;1(9):e6.

Upton RN, Mould DR. Basic concepts in population modeling, simulation, and model-based drug development: Part 3-introduction to pharmacodynamic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2014;3:e88.

Derendorf H, Meibohm B. Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: Concepts and perspectives. Pharm Res. 1999;16(2):176-85.

Holford N. A time to event tutorial for pharmacometricians. CPT Pharmacometrics Syst Pharmacol. 2013;2:e43.

Aarons L. Population pharmacokinetics: Theory and practice. Br J Clin Pharmacol. 1991;32(6):669-70.

Ette EI, Williams PJ. Population pharmacokinetics II: Estimation methods. Ann Pharmacother. 2004;38(11):1907-15.

Kiang TK, Sherwin CM, Spigarelli MG, Ensom MH. Fundamentals of population pharmacokinetic modelling: Modelling and software. Clin Pharmacokinet. 2012;51(8):515-25.

Sheiner LB, Rosenberg B, Melmon KL. Modelling of individual pharmacokinetics for computer-aided drug dosage. Comput Biomed Res. 1972;5(5):411-59.

De Cock RF, Piana C, Krekels EH, Danhof M, Allegaert K, Knibbe CA. The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol. 2011;67 Suppl 1:5-16.

Duffull SB, Wright DF, Winter HR. Interpreting population pharmacokinetic-pharmacodynamic analyses - a clinical viewpoint. Br J Clin Pharmacol. 2011;71(6):807-14.

Nguyen TH, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC, et al. Model evaluation of continuous data pharmacometric models: Metrics and graphics. CPT Pharmacometrics Syst Pharmacol. 2017;6(2):87-109.

Beal S SL, Boeckmann A, Bauer RJ. Nonmem user´s guides. Ellicott City: Icon Development Solutions; 1989-2018.

Monolix. 2020R1 version: Lixoft. Available from: https://lixoft.com/products/monolix/

Phoenix NLME. 8.3 version: Certara. Available from: https://www.certara.com/software/pkpd-modeling-and-simulation/phoenix-nlme/

The R project for statistical computing. R Core Team. Available from: https://www.r-project.org/

Pillai GC, Mentre F, Steimer JL. Non-linear mixed effects modeling - from methodology and software development to driving implementation in drug development science. J Pharmacokinet Pharmacodyn. 2005;32(2):161-83.

Byon W, Smith MK, Chan P, Tortorici MA, Riley S, Dai H, et al. Establishing best practices and guidance in population modeling: An experience with an internal population pharmacokinetic analysis guidance. CPT Pharmacometrics Syst Pharmacol. 2013;2:e51.

Owen JS, Fiedler-Kelly J. Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models. New Jersey: John Wiley & Sons; 2014. 320 p.

Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: Introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2013;2:e38.

Ette EI, Williams PJ. Population pharmacokinetics I: Background, concepts, and models. Ann Pharmacother. 2004;38(10):1702-6.

Jonsson EN, Karlsson MO. Automated covariate model building within NONMEM. Pharm Res. 1998;15(9):1463-8.

Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82(1):17-20.

Sherwin CM, Kiang TK, Spigarelli MG, Ensom MH. Fundamentals of population pharmacokinetic modelling: Validation methods. Clin Pharmacokinet. 2012;51(9):573-90.

Ette EI, Williams PJ, Lane JR. Population pharmacokinetics III: Design, analysis, and application of population pharmacokinetic studies. Ann Pharmacother. 2004;38(12):2136-44.

Bender G, Gosset J, Florian J, Tan K, Field M, Marshall S, et al. Population pharmacokinetic model of the pregabalin-sildenafil interaction in rats: Application of simulation to preclinical PK-PD study design. Pharm Res. 2009;26(10):2259-69.

Chen WJ, Zhou TY, Lu W. Population pharmacokinetics and its application in new drug research (abstract). Yao xue xue bao = Acta pharmaceutica Sinica. 2017;52(3):371-7.

Porzio S. Application of population pharmacokinetics for preclinical safety and efficacy studies. Bioanalysis. 2013;5(16):2053-69.

Holford N, Ma SC, Ploeger BA. Clinical trial simulation: A review. Clin Pharmacol Ther. 2010;88(2):166-82.

Bonate PL. Clinical trial simulation in drug development. Pharm Res. 2000;17(3):252-6.

Girard P. Clinical trial simulation: A tool for understanding study failures and preventing them. Basic Clin Pharmacol Toxicol. 2005;96(3):228-34.

Aarons L, Karlsson MO, Mentre F, Rombout F, Steimer JL, van Peer A, et al. Role of modelling and simulation in phase I drug development. Eur J Pharm Sci. 2001;13(2):115-22.

Bellanti F, van Wijk RC, Danhof M, Della Pasqua O. Integration of PKPD relationships into benefit-risk analysis. Br J Clin Pharmacol. 2015;80(5):979-91.

Standing JF. Understanding and applying pharmacometric modelling and simulation in clinical practice and research. Br J Clin Pharmacol. 2017;83(2):247-54.

Hourcade-Potelleret F, Lemenuel-Diot A, McIntyre C, Brewster M, Lum B, Bittner B. Use of a population pharmacokinetic approach for the clinical development of a fixed-dose subcutaneous formulation of trastuzumab. CPT Pharmacometrics Syst Pharmacol. 2014;3:e87, doi: 10.1038/psp.2013.63.

Wang YC, Wang Y, Schrieber SJ, Earp J, Thway TM, Huang SM, et al. Role of modeling and simulation in the development of novel and biosimilar therapeutic proteins. J Pharm Sci. 2019;108(1):73-7.

European Medicines Agency. Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population. 2007. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-role-pharmacokinetics-development-medicinal-products-paediatric-population_en.pdf

Suvarna V. Phase IV of drug development. Perspect Clin Res. 2010;1(2):57-60.

Farahani P, Levine M, Gaebel K, Thabane L. Clinical data gap between phase III clinical trials (pre-marketing) and phase IV (post-marketing) studies: Evaluation of etanercept in rheumatoid arthritis. Can J Clin Pharmacol. 2005;12(3):e254-63.

Brzakovic B, Vucicevic K, Kovacevic SV, Miljkovic B, Prostran M, Martinovic Z, et al. Pharmacokinetics of lamotrigine in paediatric and young adult epileptic patients-nonlinear mixed effects modelling approach. Eur J Clin Pharmacol. 2014;70(2):179-85.

Jovanovic M, Sokic D, Grabnar I, Vovk T, Prostran M, Vucicevic K, et al. Population pharmacokinetics of topiramate in adult patients with epilepsy using nonlinear mixed effects modelling. Eur J Pharm Sci. 2013;50(3-4):282-9.

Vucicevic K, Jovanovic M, Golubovic B, Kovacevic SV, Miljkovic B, Martinovic Z, et al. Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients. Eur J Clin Pharmacol. 2015;71(2):183-90.

Vucicevic K, Miljkovic B, Pokrajac M, Prostran M, Martinovic Z, Grabnar I. The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling. Eur J Pharm Sci. 2009;38(5):512-8.

Vucicevic K, Miljkovic B, Velickovic R, Pokrajac M, Mrhar A, Grabnar I. Population pharmacokinetic model of carbamazepine derived from routine therapeutic drug monitoring data. Ther Drug Monit. 2007;29(6):781-8.

Golubovic B, Vucicevic K, Radivojevic D, Kovacevic SV, Prostran M, Miljkovic B. Total plasma protein effect on tacrolimus elimination in kidney transplant patients-population pharmacokinetic approach. Eur J Pharm Sci. 2014;52:34-40.

Golubovic B, Vucicevic K, Radivojevic D, Kovacevic SV, Prostran M, Miljkovic B. Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients - population pharmacokinetic approach. J Med Biochem. 2019;38(3):323-31.

Golubovic B, Prostran M, Miljkovic B, Vucicevic K, Radivojevic D, Grabnar I. Population pharmacokinetic approach of immunosuppressive therapy in kidney transplant patients. Curr Med Chem. 2016;23(19):1998-2011.

Jovanović M, Vučićević K, Miljković B. Understanding variability in the pharmacokinetics of atypical antipsychotics-focus on clozapine, olanzapine and aripiprazole population models. Drug Metab Rev. 2020;52(1):1-18.

Holford N. Pharmacodynamic principles and target concentration intervention. Transl Clin Pharmacol. 2018;26(4):150-4.

Darwich AS, Polasek TM, Aronson JK, Ogungbenro K, Wright DFB, Achour B, et al. Model-informed precision dosing: Background, requirements, validation, implementation, and forward trajectory of individualizing drug therapy. Annu Rev Pharmacol Toxicol. 2021;61:225-45.

Polasek TM, Shakib S, Rostami-Hodjegan A. Precision dosing in clinical medicine: Present and future. Expert Rev Clin Pharmacol. 2018;11(8):743-6.

Polasek TM, Kirkpatrick CM, Rostami-Hodjegan A. Precision dosing to avoid adverse drug reactions. Ther Adv Drug Saf. 2019; 10:2042098619894147, doi: 10.1177/2042098619894147.

Wright DFB, Martin JH, Cremers S. Spotlight commentary: Model-informed precision dosing must demonstrate improved patient outcomes. Br J Clin Pharmacol. 2019;85(10):2238-40.

Holford N, Ma G, Metz D. TDM is dead. Long live TCI! Br J Clin Pharmacol. 2020; doi: 10.1111/bcp.14434.

Wicha SG, Martson AG, Nielsen EI, Koch BCP, Friberg LE, Alffenaar JW, et al. From therapeutic drug monitoring to model-informed precision dosing for antibiotics. Clin Pharmacol Ther. 2021;109(4):928-41.

Abdulla A, Edwina AE, Flint RB, Allegaert K, Wildschut ED, Koch BCP, et al. Model-informed precision dosing of antibiotics in pediatric patients: A narrative review. Front Pediatr. 2021;9:624639.

Charles B. Population pharmacokinetics: An overview. Australian Prescriber. 2014;37(6):210-3.

Uster DW, Stocker SL, Carland JE, Brett J, Marriott DJE, Day RO, et al. A model averaging/selection approach improves the predictive performance of model-informed precision dosing: Vancomycin as a case study. Clin Pharmacol Ther. 2021;109(1):175-83.

Sime FB, Roberts MS, Roberts JA. Optimization of dosing regimens and dosing in special populations. Clin Microbiol Infect. 2015;21(10):886-93.

Keizer RJ, Ter Heine R, Frymoyer A, Lesko LJ, Mangat R, Goswami S. Model-informed precision dosing at the bedside: Scientific challenges and opportunities. CPT Pharmacometrics Syst Pharmacol. 2018;7(12):785-7.

Kantasiripitak W, Van Daele R, Gijsen M, Ferrante M, Spriet I, Dreesen E. Software tools for model-informed precision dosing: How well do they satisfy the needs? Front Pharmacol. 2020;11:620.

Rybak MJ, Le J, Lodise T, Levine D, Bradley J, Liu C, et al. Executive summary: Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. J Pediatric Infect Dis Soc. 2020;9(3):281-4.

Grimsrud KN, Sherwin CM, Constance JE, Tak C, Zuppa AF, Spigarelli MG, et al. Special population considerations and regulatory affairs for clinical research. Clin Res Regul Aff. 2015;32(2):47-56.

Stillhart C, Vucicevic K, Augustijns P, Basit AW, Batchelor H, Flanagan TR, et al. Impact of gastrointestinal physiology on drug absorption in special populations-an UNGAP review. Eur J Pharm Sci. 2020;147:105280.

Krekels EHJ, van Hasselt JGC, van den Anker JN, Allegaert K, Tibboel D, Knibbe CAJ. Evidence-based drug treatment for special patient populations through model-based approaches. Eur J Pharm Sci. 2017;109S:S22-S6.

Momper JD, Mulugeta Y, Burckart GJ. Failed pediatric drug development trials. Clin Pharmacol Ther. 2015;98(3):245-51.

Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303-32.

Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941-52.

Germovsek E, Barker CI, Sharland M, Standing JF. Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful? Br J Clin Pharmacol. 2017;83(4):777-90.

Kos MK, Miksic M, Jovanovic M, Roskar R, Grosek S, Grabnar I. Maturation of midazolam clearance in critically ill children with severe bronchiolitis: A population pharmacokinetic analysis. Eur J Pharm Sci. 2020;141:105095.

Kovacevic T, Miljkovic B, Kovacevic P, Dragic S, Momcicevic D, Avram S, et al. Population pharmacokinetic model of vancomycin based on therapeutic drug monitoring data in critically ill septic patients. J Crit Care. 2020;55:116-21.

Wallender E, Vucicevic K, Jagannathan P, Huang L, Natureeba P, Kakuru A, et al. Predicting optimal dihydroartemisinin-piperaquine regimens to prevent malaria during pregnancy for human immunodeficiency virus-infected women receiving efavirenz. J Infect Dis. 2018;217(6):964-72.

Grimstein M, Yang Y, Zhang X, Grillo J, Huang SM, Zineh I, et al. Physiologically based pharmacokinetic modeling in regulatory science: An update from the U.S. Food and Drug Administration's office of Clinical Pharmacology. J Pharm Sci. 2019;108(1):21-5.

Jones HM, Gardner IB, Watson KJ. Modelling and PBPK simulation in drug discovery. AAPS J. 2009;11(1):155-66.

Huang W, Nakano M, Sager J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic model of the CYP2D6 probe atomoxetine: Extrapolation to special populations and drug-drug interactions. Drug Metab Dispos. 2017;45(11):1156-65.

U.S. Food and Drug Administration. Physiologically based pharmacokinetic analyses - format and content guidance for industry 2018. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/physiologically-based-pharmacokinetic-analyses-format-and-content-guidance-industry.

U.S. Food and Drug Administration. In vitro drug interaction studies - cytochrome p450 enzyme- and transporter-mediated drug interactions guidance for industry 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.

European Medicines Agency. Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation 2018. Available from: https://www.ema.europa.eu/en/reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation.

Published
2021/08/27
Section
Review articles