生理药代动力学建模在药剂学中的应用
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摘要
生理药代动力学(physiologically based pharmacokinetics,PBPK)模型是药物研究的一种重要数学建模方法。它可以利用临床前数据预测药物在人体内的药代动力学行为,也可以探索年龄、种族或疾病状态等各种生理参数对人体药代动力学的影响,指导给药剂量和用药方案,以及评估药物-药物相互作用。近十几年来,PBPK建模在学术界和医药界迅速发展,已被广泛运用于药物研发的各个阶段。本文简要介绍了PBPK建模的基本概念与方法 ,从药物处方前研究、剂型开发、食物效应、群体药代动力学及仿制药的生物等效性等方面讨论了其在药物制剂研发中的应用及前景。
Physiologically based pharmacokinetics(PBPK) model is an important mathematical modeling method for drug research. It can predict the pharmacokinetic behaviors of drugs in the human by using preclinical data,explore the impacts of various physiological parameters, such as age, race or disease status on human pharmacokinetics,guide on dosage and dosing regimens and evaluate drug-drug interactions. PBPK modeling has developed rapidly in the last decade within both the fields of academia and the pharmaceutical industry, which has been widely used in all stages of drug development. In this article, the concept and methodology of PBPK modeling are briefly introduced. Several cases are discussed on its application and prospect in the research and development of pharmaceutics, including preformulation,dosage form development, food effect, prediction of population pharmacokinetics, bioequivalence of generic drugs, etc.
Physiologically based pharmacokinetics(PBPK) model is an important mathematical modeling method for drug research. It can predict the pharmacokinetic behaviors of drugs in the human by using preclinical data,explore the impacts of various physiological parameters, such as age, race or disease status on human pharmacokinetics,guide on dosage and dosing regimens and evaluate drug-drug interactions. PBPK modeling has developed rapidly in the last decade within both the fields of academia and the pharmaceutical industry, which has been widely used in all stages of drug development. In this article, the concept and methodology of PBPK modeling are briefly introduced. Several cases are discussed on its application and prospect in the research and development of pharmaceutics, including preformulation,dosage form development, food effect, prediction of population pharmacokinetics, bioequivalence of generic drugs, etc.
引文
[1] BOUZOM F, BALL K, PERDAEMS N, et al.Physiologically based pharmacokinetic(PBPK)modelling tools:how to fit with our needs?[J]. Biopharm Drug Dispos, 2012,33(2):55-71.
[2] SAGER J E, YU J, RAGUENEAU-MAJLESSI I, et al.Physiologically based pharmacokinetic(PBPK)modeling and simulation approaches:A systematic review of published models, applications, and model verification[J]. Drug Metab Dispos, 2015, 43(11):1823-1837.
[3] UPTON R N, FOSTER D J, ABUHELWA A Y. An introduction to physiologically-based pharmacokinetic models[J]. Paediatr Anaesth, 2016, 26(11):1036-1046.
[4] LIN L, WONG H. Predicting oral drug absorption:mini review on physiologically-based pharmacokinetic models[J]. Pharm, 2017, 9(4):E41.
[5] JONES H M,MAYAWALA K,POULIN P. Dose selection based on physiologically based pharmacokinetic(PBPK)approaches[J]. AAPS J, 2013, 15(2):377-387.
[6] KOSTEWICZ E S, AARONS L, BERGSTRAND M, et al.PBPK models for the prediction of in vivo performance of oral dosage forms[J]. Eur J Pharm Sci, 2014, 57(1):300-321.
[7] BERGSTROM C A, HOLM R, JφRGENSEN S A, et al.Early pharmaceutical profiling to predict oral drug absorption:current status and unmet needs[J]. Eur J Pharm Sci, 2014,57(1):173-199.
[8] ZHUANG X, LU C. PBPK modeling and simulation in drug research and development[J]. Acta Pharm Sin B, 2016,6(5):430-440.
[9] MOSS D M, MARZOLINI C, RAJOLI R K, et al.Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies[J]. Expert Opin Drug Metab Toxicol, 2015, 11(8):1203-1217.
[10] KHOT A, TIBBITTS J, ROCK D, et al. Development of a translational physiologically based pharmacokinetic model for antibody-drug conjugates:a case study with T-DM1[J].AAPS J, 2017, 19(6):1715-1734.
[11] JAMEI M. Recent advances in development and application of physiologically-based pharmacokinetic(PBPK)models:a transition from academic curiosity to regulatory acceptance[J]. Curr Pharmacol Rep, 2016, 2:161-169.
[12] SAEHENG T, NA-BANGCHANG K, KARBWANG J.Utility of physiologically based pharmacokinetic(PBPK)modeling in oncology drug development and its accuracy:a systematic review[J]. Eur J Clin Pharmacol, 2018,74(11):1365-1376.
[13] CHIANG P C, WONG H. Incorporation of physiologically based pharmacokinetic modeling in the evaluation of solubility requirements for the salt selection process:a case study using phenytoin[J]. AAPS J, 2013, 15(4):1109-1118.
[14] PARROTT N, LAVE T. Applications of physiologically based absorption models in drug discovery and development[J]. Mol Pharm, 2008, 5(5):760-775.
[15] CHOW E C, TALATTOF A, TSAKALOZOU E, et al.Using physiologically based pharmacokinetic(PBPK)modeling to evaluate the impact of pharmaceutical excipients on oral drug absorption:Sensitivity analyses[J]. AAPS J,2016,18(6):1500-1511.
[16] BROBERG M L, HOLM R, T(?)NSBERG H, et al. Function and expression of the proton-coupled amino acid transporter PAT1 along the rat gastrointestinal tract:implications for intestinal absorption of gaboxadol[J]. Br J Pharmacol,2012,167(3):654-665.
[17] KESISOGLOU F,BALAKRISHNAN A,MANSER K.Utility of PBPK absorption modeling to guide modified release formulation development of gaboxadol, a highly soluble compound with region-dependent absorption[J]. J Pharm Sci, 2016,105(2):722-728.
[18] WANG B L, LIU Z H, LI D, et al. Application of physiologically based pharmacokinetic modeling in the prediction of pharmacokinetics of bicyclol controlled-release formulation in human[J]. Eur J Pharm Sci, 2015, 77:265-272.
[19] LI M, ZOU P, TYNER K, et al. Physiologically based pharmacokinetic(PBPK)modeling of pharmaceutical nanoparticles[J]. AAPS J, 2016,19(1):26-42.
[20] DONG D, WANG X, WANG H, et al. Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model:a case study with the anticancer agent SNX-2112[J]. Int J Nanomedicine, 2015, 10:2521-2535.
[21] RAJOLI R K, BACK D J, RANNARD S, et al.Physiologically based pharmacokinetic modelling to inform development of intramuscular long-acting nanoformulationsfor HIV[J]. Clin Pharmacokinet, 2015, 54(6):639-650.
[22] LAOMETTACHIT T, PURI I K, LIANGRUKSA M. A twostep model of TiO2 nanoparticle toxicity in human liver tissue[J]. Toxicol Appl Pharmacol, 2017, 334:47-54.
[23] SALAR-BEHZADI S, WU S, MERCURI A, et al. Effect of the pulmonary deposition and in vitro permeability on the prediction of plasma levels of inhaled budesonide formulation[J]. Int J Pharm, 2017, 532(1):337-344.
[24] BACKMAN P, ARORA S, COUET W, et al. Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs[J]. Eur J Pharm Sci, 2018, 113:41-52.
[25] BACKMAN P, TEHLER U, OLSSON B. Predicting exposure after oral inhalation of the selective glucocorticoid receptor modulator, AZD5423, based on dose, deposition pattern,and mechanistic modeling of pulmonary disposition[J]. J Aerosol Med Pulm Drug Deliv, 2017, 30(2):108-117.
[26] VULOVIC A, SUSTERSIC T, CVIJIC S, et al. Coupled in silico platform:Computational fluid dynamics(CFD)and physiologically-based pharmacokinetic(PBPK)modelling[J]. EurJPharm Sci, 2018,113:171-184.
[27] KALLURI H V, ZHANG H, CARITIS S N, et al. A physiologically based pharmacokinetic modelling approach to predict buprenorphine pharmacokinetics following intravenous and sublingual administration[J]. Br J Clin Pharmacol, 2017, 83(11):2458-2473.
[28] ROWLAND M, PECK C, TUCKER G. Physiologicallybased phamiacokinetics in drug development and regulatory science[J]. Annu Rev Pharmacol Toxicol, 2011, 51:45-73.
[29] POLAK S, GHOBADI C, MISHRA H, et al. Prediction of concentration-time profile and its inter-individual variability following the dermal drug absorption[J]. J Pharm Sci,2012,101(7):2584-2595.
[30] ANDREAS C J, PEPIN X, MARKOPOULOS C, et al.Mechanistic investigation of the negative food effect of modified release zolpidem[J]. Eur J Pharm Sci, 2017, 102:284-298.
[31] ZHANG H, XIA B, SHENG J, et al. Application of physiologically based absorption modeling to formulation development of a low solubility, low permeability weak base:mechanistic investigation of food effect[J].AAPS Pharm SciTech, 2014, 15(2):400-406.
[32] KOHLMANN P, STILLHART C, KUENTZ M, et al.Investigating oral absorption of carbamazepine in pediatric populations[J]. AAPS J, 2017,19(6):1864-1877.
[33] KESISOGLOU F. The role of physiologically based oral absorption modelling in formulation development under a quality by design paradigm[J]. JPharm Sci, 2017,106(4):944-949.
[34] SCHLENDER J F, MEYER M, THELEN K, et al.Development of a whole-body physiologically based pharmacokinetic approach to assess the pharmacokinetics of drugs in elderly individuals[J]. Clin Pharmacokinet, 2016,55(12):1573-1589.
[35] DUAN P, FISHER J W, YOSHIDA K, et al.Physiologically based pharmacokinetic prediction of linezolid and emtricitabine in neonates and infants[J]. Clin Pharmacokinet, 2017, 56(4):383-394.
[36] CRISTOFOLETTI R,PATEL N,DRESSMAN J B.Assessment of bioequivalence of weak base formulations under various dosing conditions using physiologically based pharmacokinetic simulations in virtual populations. Case examples:ketoconazole and posaconazole[J]. JPharm Sci,2017,106(2):560-569.
[37] DOKI K, DARWICH AS, PATEL N, et al. Virtual bioequivalence for achlorhydric subjects:The use of PBPK modelling to assess the formulation-dependent effect of achlorhydria[J]. EurJPharm Sci, 2017,109:111-120.
[38] PUROHIT H S, TRASI N S, SUN D D, et al. Investigating the impact of drug crystallinity in amorphous tacrolimus capsules on pharmacokinetics and bioequivalence using discriminatory in vitro dissolution testing and physiologically based pharmacokinetic modeling and simulation[J]. J Pharm Sci, 2018,107(5):1330-1341.
[2] SAGER J E, YU J, RAGUENEAU-MAJLESSI I, et al.Physiologically based pharmacokinetic(PBPK)modeling and simulation approaches:A systematic review of published models, applications, and model verification[J]. Drug Metab Dispos, 2015, 43(11):1823-1837.
[3] UPTON R N, FOSTER D J, ABUHELWA A Y. An introduction to physiologically-based pharmacokinetic models[J]. Paediatr Anaesth, 2016, 26(11):1036-1046.
[4] LIN L, WONG H. Predicting oral drug absorption:mini review on physiologically-based pharmacokinetic models[J]. Pharm, 2017, 9(4):E41.
[5] JONES H M,MAYAWALA K,POULIN P. Dose selection based on physiologically based pharmacokinetic(PBPK)approaches[J]. AAPS J, 2013, 15(2):377-387.
[6] KOSTEWICZ E S, AARONS L, BERGSTRAND M, et al.PBPK models for the prediction of in vivo performance of oral dosage forms[J]. Eur J Pharm Sci, 2014, 57(1):300-321.
[7] BERGSTROM C A, HOLM R, JφRGENSEN S A, et al.Early pharmaceutical profiling to predict oral drug absorption:current status and unmet needs[J]. Eur J Pharm Sci, 2014,57(1):173-199.
[8] ZHUANG X, LU C. PBPK modeling and simulation in drug research and development[J]. Acta Pharm Sin B, 2016,6(5):430-440.
[9] MOSS D M, MARZOLINI C, RAJOLI R K, et al.Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies[J]. Expert Opin Drug Metab Toxicol, 2015, 11(8):1203-1217.
[10] KHOT A, TIBBITTS J, ROCK D, et al. Development of a translational physiologically based pharmacokinetic model for antibody-drug conjugates:a case study with T-DM1[J].AAPS J, 2017, 19(6):1715-1734.
[11] JAMEI M. Recent advances in development and application of physiologically-based pharmacokinetic(PBPK)models:a transition from academic curiosity to regulatory acceptance[J]. Curr Pharmacol Rep, 2016, 2:161-169.
[12] SAEHENG T, NA-BANGCHANG K, KARBWANG J.Utility of physiologically based pharmacokinetic(PBPK)modeling in oncology drug development and its accuracy:a systematic review[J]. Eur J Clin Pharmacol, 2018,74(11):1365-1376.
[13] CHIANG P C, WONG H. Incorporation of physiologically based pharmacokinetic modeling in the evaluation of solubility requirements for the salt selection process:a case study using phenytoin[J]. AAPS J, 2013, 15(4):1109-1118.
[14] PARROTT N, LAVE T. Applications of physiologically based absorption models in drug discovery and development[J]. Mol Pharm, 2008, 5(5):760-775.
[15] CHOW E C, TALATTOF A, TSAKALOZOU E, et al.Using physiologically based pharmacokinetic(PBPK)modeling to evaluate the impact of pharmaceutical excipients on oral drug absorption:Sensitivity analyses[J]. AAPS J,2016,18(6):1500-1511.
[16] BROBERG M L, HOLM R, T(?)NSBERG H, et al. Function and expression of the proton-coupled amino acid transporter PAT1 along the rat gastrointestinal tract:implications for intestinal absorption of gaboxadol[J]. Br J Pharmacol,2012,167(3):654-665.
[17] KESISOGLOU F,BALAKRISHNAN A,MANSER K.Utility of PBPK absorption modeling to guide modified release formulation development of gaboxadol, a highly soluble compound with region-dependent absorption[J]. J Pharm Sci, 2016,105(2):722-728.
[18] WANG B L, LIU Z H, LI D, et al. Application of physiologically based pharmacokinetic modeling in the prediction of pharmacokinetics of bicyclol controlled-release formulation in human[J]. Eur J Pharm Sci, 2015, 77:265-272.
[19] LI M, ZOU P, TYNER K, et al. Physiologically based pharmacokinetic(PBPK)modeling of pharmaceutical nanoparticles[J]. AAPS J, 2016,19(1):26-42.
[20] DONG D, WANG X, WANG H, et al. Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model:a case study with the anticancer agent SNX-2112[J]. Int J Nanomedicine, 2015, 10:2521-2535.
[21] RAJOLI R K, BACK D J, RANNARD S, et al.Physiologically based pharmacokinetic modelling to inform development of intramuscular long-acting nanoformulationsfor HIV[J]. Clin Pharmacokinet, 2015, 54(6):639-650.
[22] LAOMETTACHIT T, PURI I K, LIANGRUKSA M. A twostep model of TiO2 nanoparticle toxicity in human liver tissue[J]. Toxicol Appl Pharmacol, 2017, 334:47-54.
[23] SALAR-BEHZADI S, WU S, MERCURI A, et al. Effect of the pulmonary deposition and in vitro permeability on the prediction of plasma levels of inhaled budesonide formulation[J]. Int J Pharm, 2017, 532(1):337-344.
[24] BACKMAN P, ARORA S, COUET W, et al. Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs[J]. Eur J Pharm Sci, 2018, 113:41-52.
[25] BACKMAN P, TEHLER U, OLSSON B. Predicting exposure after oral inhalation of the selective glucocorticoid receptor modulator, AZD5423, based on dose, deposition pattern,and mechanistic modeling of pulmonary disposition[J]. J Aerosol Med Pulm Drug Deliv, 2017, 30(2):108-117.
[26] VULOVIC A, SUSTERSIC T, CVIJIC S, et al. Coupled in silico platform:Computational fluid dynamics(CFD)and physiologically-based pharmacokinetic(PBPK)modelling[J]. EurJPharm Sci, 2018,113:171-184.
[27] KALLURI H V, ZHANG H, CARITIS S N, et al. A physiologically based pharmacokinetic modelling approach to predict buprenorphine pharmacokinetics following intravenous and sublingual administration[J]. Br J Clin Pharmacol, 2017, 83(11):2458-2473.
[28] ROWLAND M, PECK C, TUCKER G. Physiologicallybased phamiacokinetics in drug development and regulatory science[J]. Annu Rev Pharmacol Toxicol, 2011, 51:45-73.
[29] POLAK S, GHOBADI C, MISHRA H, et al. Prediction of concentration-time profile and its inter-individual variability following the dermal drug absorption[J]. J Pharm Sci,2012,101(7):2584-2595.
[30] ANDREAS C J, PEPIN X, MARKOPOULOS C, et al.Mechanistic investigation of the negative food effect of modified release zolpidem[J]. Eur J Pharm Sci, 2017, 102:284-298.
[31] ZHANG H, XIA B, SHENG J, et al. Application of physiologically based absorption modeling to formulation development of a low solubility, low permeability weak base:mechanistic investigation of food effect[J].AAPS Pharm SciTech, 2014, 15(2):400-406.
[32] KOHLMANN P, STILLHART C, KUENTZ M, et al.Investigating oral absorption of carbamazepine in pediatric populations[J]. AAPS J, 2017,19(6):1864-1877.
[33] KESISOGLOU F. The role of physiologically based oral absorption modelling in formulation development under a quality by design paradigm[J]. JPharm Sci, 2017,106(4):944-949.
[34] SCHLENDER J F, MEYER M, THELEN K, et al.Development of a whole-body physiologically based pharmacokinetic approach to assess the pharmacokinetics of drugs in elderly individuals[J]. Clin Pharmacokinet, 2016,55(12):1573-1589.
[35] DUAN P, FISHER J W, YOSHIDA K, et al.Physiologically based pharmacokinetic prediction of linezolid and emtricitabine in neonates and infants[J]. Clin Pharmacokinet, 2017, 56(4):383-394.
[36] CRISTOFOLETTI R,PATEL N,DRESSMAN J B.Assessment of bioequivalence of weak base formulations under various dosing conditions using physiologically based pharmacokinetic simulations in virtual populations. Case examples:ketoconazole and posaconazole[J]. JPharm Sci,2017,106(2):560-569.
[37] DOKI K, DARWICH AS, PATEL N, et al. Virtual bioequivalence for achlorhydric subjects:The use of PBPK modelling to assess the formulation-dependent effect of achlorhydria[J]. EurJPharm Sci, 2017,109:111-120.
[38] PUROHIT H S, TRASI N S, SUN D D, et al. Investigating the impact of drug crystallinity in amorphous tacrolimus capsules on pharmacokinetics and bioequivalence using discriminatory in vitro dissolution testing and physiologically based pharmacokinetic modeling and simulation[J]. J Pharm Sci, 2018,107(5):1330-1341.