phkineticaФармакокинетика и ФармакодинамикаPharmacokinetics and Pharmacodynamics2587-78362686-8830ООО «Издательство ОКИ»10.37489/2587-7836-2021-3-36-51phkinetica-292Research ArticleПОПУЛЯЦИОННАЯ ФАРМАКОКИНЕТИКАPOPULATION PHARMACOKINETICSПопуляционный фармакокинетический анализ в программе Lixoft MonolixPopulation pharmacokinetics analysis in Lixoft Monolix softwareshttps://orcid.org/0000-0002-9682-4623ПлатоваА. И.PlatovaA. I.

Платова Ангелина Игоревна - м. н. с. лаборатории фармакокинетикиSPIN-код: 6656-2194

Москва

Platova Angelina I. - Research assistant of pharmacokinetics laboratorySPIN code: 6656-2194

Moscow

platova@psychiatry.ruФедеральное государственное бюджетное научное учреждение «Научный центр психического здоровья»РоссияThe Mental Health Research Center (MHRC)Russian Federation202114022022033651Copyright © Платова А.И., 20222022Платова А.И.Platova A.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacokinetica.ru/jour/article/view/292

В статье рассматривается пошаговый алгоритм построения популяционных фармакокинетических моделей в программе Lixoft Monolix. Описаны особенности методологии популяционных фармакокинетических исследований. Отдельное внимание уделяется преимуществам камерного подхода и нелинейного моделирования смешанных эффектов в изучении фармакокинетики. Описаны методы оценивания популяционных фармакокинетических параметров и их реализация в программном обеспечении.

The article has discussed a step-by-step algorithm for developing population pharmacokinetics models in the Lixoft Monolix software. Features of population pharmacokinetics study’s methodology have described. Special attention is paid to the advantages of the compartmental approach and nonlinear mixed effects modeling in study of pharmacokinetics. Methods for estimating population pharmacokinetic parameters and its implementation in software are described.

MonolixNLMEMSAEMMCMCбайесовский функционалММПФКПФКMonolixNLMEMSAEMMCMCBayesian functionalMLEPKPPKReferencesGuideline on reporting the results of population pharmacokinetic analyses. Doc. Ref. CHMP/EWP/185990/06. 21 June, 2007. Electronic resourse. European Medicines Agency Official website. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003067.pdf (accessed: 13.12.2020).Guideline on reporting the results of population pharmacokinetic analyses. Doc. Ref. CHMP/EWP/185990/06. 21 June, 2007. Electronic resourse. European Medicines Agency Official website. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003067.pdf (accessed: 13.12.2020).Owen JS, Fiedler-Kelly J. Introduction to population pharmacokinetic / pharmacodynamic analysis with nonlinear mixed effects models. Hoboken, New Jersey: John Wiley & Sons; 2014. 301 p.Owen JS, Fiedler-Kelly J. Introduction to population pharmacokinetic / pharmacodynamic analysis with nonlinear mixed effects models. Hoboken, New Jersey: John Wiley & Sons; 2014. 301 p.Lavielle M, Mentre F. Estimation of population pharmacokinetic parameters of saquinavir in HIV patients with the MONOLIX software. J Pharmacokinet Pharmacodyn. 2007;34(2):229–249. DOI:10.1007/s10928-006-9043-z.Lavielle M, Mentre F. Estimation of population pharmacokinetic parameters of saquinavir in HIV patients with the MONOLIX software. J Pharmacokinet Pharmacodyn. 2007;34(2):229–249. DOI:10.1007/s10928-006-9043-z.Дедов И.И., Тюльпаков А.Н., Чехонин В. П., Баклаушев В.П., Арчаков А.И., Мошковский С.А. Персонализированная медицина: современное состояние и перспективы. Вестник РАМН. 2012;(12):4–12.Dedov II, Tyul’pakov AN, Chekhonin VP, Baklaushev VP, Archakov AI, Moshkovskii SA. Personalized medicine: State-of-the-art and prospects. Vestnik RAMN. 2012;(12):4–12. (In Russ).Sheiner LB. The population approach to pharmacokinetic data analysis: rationale and standard data analysis methods. Drug Metab Rev. 1984; 15(1-2):153–171. DOI:10.3109/03602538409015063.Sheiner LB. The population approach to pharmacokinetic data analysis: rationale and standard data analysis methods. Drug Metab Rev. 1984; 15(1-2):153–171. DOI:10.3109/03602538409015063.Guidance for Industry. Population Pharmacokinetics. FDA. CDER. CBER. February, 1999. Electronic resource. US. Food and Drug Administration (FDA). Official website. URL: http://www.fda.gov/downloads/Drugs/Guidances/UCM072137.pdf (accessed:13.12.2020).Guidance for Industry. Population Pharmacokinetics. FDA. CDER. CBER. February, 1999. Electronic resource. US. Food and Drug Administration (FDA). Official website. URL: http://www.fda.gov/downloads/Drugs/Guidances/UCM072137.pdf (accessed:13.12.2020).Терапевтический лекарственный мониторинг: инструмент персонализированной медицины (методические рекомендации) / под ред. акад. РАМН В.Г. Кукеса (Россия) и проф. Д. Берри (Великобритания). М.: Изд-во Автономной некоммерческой организации «Международная ассоциация клинических фармакологов и фармацевтов»; 2013: 48 с.Terapevticheskij lekarstvennyj monitoring: instrument personalizirovannoj mediciny (metodicheskie rekomendacii) / Pod red. akad. RAMN V. G. Kukesa (Rossiya) i prof. D. Berri (Velikobritaniya). Moscow: Izd-vo Avtonomnoj nekommercheskoj organizacii «Mezhdunarodnaya associaciya klinicheskih farmakologov i farmacevtov»; 2013. (In Russ).Long-Boyle JR, Savic R, Yan S, et al. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit. 2015;37(2):236–245. DOI:10.1097/FTD.0000000000000131.Long-Boyle JR, Savic R, Yan S, et al. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit. 2015;37(2):236–245. DOI:10.1097/FTD.0000000000000131.Соловьев В.Н., Фирсов А.А., Филов В.А. Фармакокинетика. М.: Медицина; 1980. 494 с.Solov'ev VN, Firsov AA, Filov VA. Farmakokinetika. Moscow: Medicina; 1980. (In Russ).Каркищенко Н.Н., Хоронько В.В., Сергеева С.А., Каркищенко В.Н. Фармакокинетика. Ростов-на-Дону: Феникс; 2001. 384 с.Karkishchenko NN, Horon'ko VV, Sergeeva SA, Karkishchenko VN. Farmakokinetika. Rostov-na-Donu: Feniks. 2001. (In Russ).Сергиенко В.И., Джеллифф Р., Бондарева И.Б. Прикладная Фармакокинетика: основные положения и клиническое применение. М.: Издательство РАМН; 2003. 208 с.Sergienko VI, Dzhelliff R, Bondareva IB. Prikladnaya Farmakokinetika: osnovnye polozheniya i klinicheskoe primenenie. Moscow: Izdatel'stvo RAMN; 2003. (In Russ).Мирошниченко И.И. Рациональное дозирование и мониторинг лекарственных средств. М.: ООО Издательство Медицинское информационное агентство; 2011: 353–371.Miroshnichenko II. Racional'noe dozirovanie i monitoring lekarstvennyh sredstv. Moscow: OOO Izdatel'stvo Medicinskoe informacionnoe agentstvo; 2011. 353–371. (In Russ).Heeremans EH, Proost JH, Eleveld DJ, et al. Population pharmacokinetics and pharmacodynamics in anesthesia, intensive care and pain medicine. Curr Opin Anaesthesiol. 2010;23(4):479–484. DOI:10.1097/ACO.0b013e32833a1d2f.Heeremans EH, Proost JH, Eleveld DJ, et al. Population pharmacokinetics and pharmacodynamics in anesthesia, intensive care and pain medicine. Curr Opin Anaesthesiol. 2010;23(4):479–484. DOI:10.1097/ACO.0b013e32833a1d2f.Watanabe-Uchida M, Watanabe T, Narukawa M. The Current State and Future Prospects of Population Pharmacokinetic Research in Postmarketing Clinical Studies in Japan. Yakugaku Zasshi. 2019;139(10):1297–1303. DOI:10.1248/yakushi.18-00227.Watanabe-Uchida M, Watanabe T, Narukawa M. The Current State and Future Prospects of Population Pharmacokinetic Research in Postmarketing Clinical Studies in Japan. Yakugaku Zasshi. 2019;139(10):1297–1303. DOI:10.1248/yakushi.18-00227.Beal SL, Sheiner LB. NONMEM users guides In EDS. Text data. San Francisco: NONMEM Project Group. University of California, CA; 1992 (CD-ROM).Beal SL, Sheiner LB. NONMEM users guides In EDS. Text data. San Francisco: NONMEM Project Group. University of California, CA; 1992 (CD-ROM).Холодов Л.Е., Яковлев В.П. Клиническая фармакокинетика. М.: Медицина; 1985. 464 с.Holodov LE, Yakovlev VP. Klinicheskaya farmakokinetika. Moscow: Medicina; 1985. (In Russ).Moon YJ, Wang L, DiCenzo R, Morris ME. Quercetin pharmacokinetics in humans. Biopharm Drug Dispos. 2008;29(4):205–217. DOI:10.1002/bdd.605.Moon YJ, Wang L, DiCenzo R, Morris ME. Quercetin pharmacokinetics in humans. Biopharm Drug Dispos. 2008;29(4):205–217. DOI:10.1002/bdd.605.Vonesh EF, Carter RL. Mixed-effects nonlinear regression for unbalanced repeated measures. Biometrics.1992;48(1):1–17.Vonesh EF, Carter RL. Mixed-effects nonlinear regression for unbalanced repeated measures. Biometrics.1992;48(1):1–17.Bauer RJ, Guzy S, Chee Ng. A survey of population analysis methods and software for complex pharmacokinetic and pharmacodynamic models with examples. AAPS J. 2007;9(1): E60-E83. DOI:10.1208/aapsj0901007.Bauer RJ, Guzy S, Chee Ng. A survey of population analysis methods and software for complex pharmacokinetic and pharmacodynamic models with examples. AAPS J. 2007;9(1): E60-E83. DOI:10.1208/aapsj0901007.Joerger M. Covariate pharmacokinetic model building in oncology and its potential clinical relevance. AAPS J. 2012;14(1):119–132. DOI:10.1208/s12248-012-9320-2.Joerger M. Covariate pharmacokinetic model building in oncology and its potential clinical relevance. AAPS J. 2012;14(1):119–132. DOI:10.1208/s12248-012-9320-2.Горьков В.А., Карамышева Е.И. Введение в фармакокинетику. Фармакокинетика и фармакодинамика. 2004;(1):2–4.Gor'kov VA, Karamysheva EI. Vvedenie v farmakokinetiku. Farmakokinetika i farmakodinamika. 2004;(1):2–4. (In Russ).WinNonlin® User’s Guide in EDS.: Pharsight Corporation. University of California, 800 West El Camino Real, Suite 200, Mountain View, California 94040, 2009. (CD-ROM).WinNonlin® User’s Guide in EDS.: Pharsight Corporation. University of California, 800 West El Camino Real, Suite 200, Mountain View, California 94040, 2009. (CD-ROM).Gibaldi M, Perrier D. Pharmacokinetics. New York: Marcell Decker; 1982.Gibaldi M, Perrier D. Pharmacokinetics. New York: Marcell Decker; 1982.Gabrielsson J, Weiner D. Pharmacokinetic and pharmacodynamic data analysis: concepts and applications. Stockholm: Swedish Pharmaceutical Press; 2000 (third edition), 925 р.Gabrielsson J, Weiner D. Pharmacokinetic and pharmacodynamic data analysis: concepts and applications. Stockholm: Swedish Pharmaceutical Press; 2000 (third edition), 925 р.Rosenbaum S. Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations. New Jersey: J. Wiley & Sons; 2011, 430 p.Rosenbaum S. Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations. New Jersey: J. Wiley & Sons; 2011, 430 p.Davda JP, Dodds MG, Gibbs MA, Wisdom W, Gibbs J. A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal firstin-human study design. MAbs. 2014;6(4):1094–1102. DOI:10.4161/mabs.29095.Davda JP, Dodds MG, Gibbs MA, Wisdom W, Gibbs J. A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal firstin-human study design. MAbs. 2014;6(4):1094–1102. DOI:10.4161/mabs.29095.Bonate PL, Howard DR. Compartmental models in pharmacokinetics in drug development: clinical study design and analysis. AAPS. 2004;1:291–362.Bonate PL, Howard DR. Compartmental models in pharmacokinetics in drug development: clinical study design and analysis. AAPS. 2004;1:291–362.Clifford AJ, Müller H-G. Mathematical modeling in experimental nutrition. New York: Plenum Press; 1998, 426 p.Clifford AJ, Müller H-G. Mathematical modeling in experimental nutrition. New York: Plenum Press; 1998, 426 p.Frommer A, Szyld DB. H-Splittings and two-stage iterative methods. Numerische Mathematik. 1992;63(1):345–356.Frommer A, Szyld DB. H-Splittings and two-stage iterative methods. Numerische Mathematik. 1992;63(1):345–356.Tatarinova T, Neely M, Bartroff J, et al. Two general methods for population pharmacokinetic modeling: non-parametric adaptive grid and non-parametric Bayesian. J Pharmacokinet Pharmacodyn. 2013;40(2):189–199. DOI:10.1007/s10928-013-9302-8.Tatarinova T, Neely M, Bartroff J, et al. Two general methods for population pharmacokinetic modeling: non-parametric adaptive grid and non-parametric Bayesian. J Pharmacokinet Pharmacodyn. 2013;40(2):189–199. DOI:10.1007/s10928-013-9302-8.Jelliffe RW, Schumitzky A. Modeling, adaptive control, and optimal drug therapy. Med Prog Technol. 1990;16(1-2)95–110.Jelliffe RW, Schumitzky A. Modeling, adaptive control, and optimal drug therapy. Med Prog Technol. 1990;16(1-2)95–110.Savic RM, Mentré F, Lavielle M. Implementation and evaluation of the SAEM algorithm for longitudinal ordered categorical data with an illustration in pharmacokinetics – pharmacodynamics. AAPS J. 2011;13(1):44–53. DOI:10.1208/s12248-010-9238-5.Savic RM, Mentré F, Lavielle M. Implementation and evaluation of the SAEM algorithm for longitudinal ordered categorical data with an illustration in pharmacokinetics – pharmacodynamics. AAPS J. 2011;13(1):44–53. DOI:10.1208/s12248-010-9238-5.Urien C, Bardin C, Bader-Meunier B et al. Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes. BMC Pharmacol Toxicol. 2013;14:40. doi:10.1186/2050-6511-14-40.Urien C, Bardin C, Bader-Meunier B et al. Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes. BMC Pharmacol Toxicol. 2013;14:40. doi:10.1186/2050-6511-14-40.Karlsson MO, Beal SL, Sheiner LB. Three new residual error models for population PK/PD analyses. J Pharmacokinetics Biopharm. 1995;23(6):651–672. DOI:10.1007/BF02353466.Karlsson MO, Beal SL, Sheiner LB. Three new residual error models for population PK/PD analyses. J Pharmacokinetics Biopharm. 1995;23(6):651–672. DOI:10.1007/BF02353466.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(4):e38. DOI:10.1038/psp.2013.14.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(4):e38. DOI:10.1038/psp.2013.14.Мирошниченко И.И., Платова А.И. Проблемы персонализации психофармакотерапии. Психиатрия. 2015;(3):85–94.Miroshnichenko II, Platova AI. Personalized psychopharmacotherapy: State of problem. Psikhiatriya. 2015;(3):85–94. (In Russ).Gatsonis C, Sampson AR. Multiple correlation: exact power and sample size calculations. Psycholl Bull. 1989;106(3):516–524. DOI:10.1037/0033-2909.106.3.516.Gatsonis C, Sampson AR. Multiple correlation: exact power and sample size calculations. Psycholl Bull. 1989;106(3):516–524. DOI:10.1037/0033-2909.106.3.516.Kang D, Schwartz JB, Verotta D. Sample size computation method for non-linear mixed effects models with applications to pharmacokinetics models. Stat Med. 2004;23(16): 2551–2566. DOI:10.1002/sim.1695.Kang D, Schwartz JB, Verotta D. Sample size computation method for non-linear mixed effects models with applications to pharmacokinetics models. Stat Med. 2004;23(16): 2551–2566. DOI:10.1002/sim.1695.Samson A, Lavielle M, Mentré F. The SAEM algorithm for group comparison tests in longitudinal data analysis based on non-linear mixedeffects model. Stat Med. 2007;26(27):4860–4875. DOI:10.1002/sim.2950.Samson A, Lavielle M, Mentré F. The SAEM algorithm for group comparison tests in longitudinal data analysis based on non-linear mixedeffects model. Stat Med. 2007;26(27):4860–4875. DOI:10.1002/sim.2950.Retout S, Comets E, Samson A, Mentré F. Design in nonlinear mixed effects models: optimization using the Fedorov–Wynn algorithm and power of the Wald test for binary covariates. Stat Med. 2007;26(28):5162–5179. DOI:10.1002/sim.2910.Retout S, Comets E, Samson A, Mentré F. Design in nonlinear mixed effects models: optimization using the Fedorov–Wynn algorithm and power of the Wald test for binary covariates. Stat Med. 2007;26(28):5162–5179. DOI:10.1002/sim.2910.Bertrand J, Comets E, Laffont CM, Chenel M, Mentré F. Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm. J Pharmacokinet Pharmacodyn. 2009;36(4):317–339. DOI:10.1007/s10928-009-9124-x.Bertrand J, Comets E, Laffont CM, Chenel M, Mentré F. Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm. J Pharmacokinet Pharmacodyn. 2009;36(4):317–339. DOI:10.1007/s10928-009-9124-x.Combes FP, Retout S, Frey N, Mentré F. Powers of the likelihood ratio test and the correlation test using empirical bayes estimates for various shrinkages in population pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2014;3(4):e109. DOI:10.1038/psp.2014.5.Combes FP, Retout S, Frey N, Mentré F. Powers of the likelihood ratio test and the correlation test using empirical bayes estimates for various shrinkages in population pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2014;3(4):e109. DOI:10.1038/psp.2014.5.

The authors declare that there are no conflicts of interest present.