Establishment of Biopredictive Dissolution and Bioequivalence Safe Space Using the Physiologically Based Biopharmaceutics Modeling for Tacrolimus Extended-Release Capsules.

Publisher: Springer Country of Publication: United States NLM ID: 100960111 Publication Model: Electronic Cited Medium: Internet ISSN: 1530-9932 (Electronic) Linking ISSN: 15309932 NLM ISO Abbreviation: AAPS PharmSciTech Subsets: MEDLINE

Publication: New York : Springer
Original Publication: Arlington, VA : American Association of Pharmaceutical Scientists, c2000-

Therapeutic Equivalency* ; Tacrolimus*/pharmacokinetics ; Tacrolimus*/administration & dosage ; Tacrolimus*/chemistry ; Delayed-Action Preparations*/pharmacokinetics ; Capsules* ; Drug Liberation* ; Solubility*; Humans ; Chemistry, Pharmaceutical/methods ; Biopharmaceutics/methods ; Models, Biological ; Drugs, Generic/pharmacokinetics ; Drugs, Generic/administration & dosage ; Drugs, Generic/chemistry ; Drugs, Generic/standards

A slight variation in in vivo exposure for tacrolimus extended-release (ER) capsules, which have a narrow therapeutic index (NTI), significantly affects the pharmacodynamics of the drug. Generic drug bioequivalence (BE) standards are stricter, necessitating accurate assessment of the rate and extent of drug release. Therefore, an in vitro dissolution method with high in vivo predictive power is crucial for developing generic drugs. In this study, physiologically based biopharmaceutics modeling (PBBM) for 5 mg tacrolimus ER capsules was developed and validated. The reference and non-BE test formulations were assessed using the Flow-Through Cell apparatus (USP IV) with biorelevant media to establish a biopredictive dissolution method. Using PBBM, virtual bioequivalence trials with virtual batches were conducted to propose a BE safe space. These criteria can identify formulations that pass the internal quality control test but are likely non-BE. This study highlights the benefits of developing biopredictive dissolution methods that are based on biorelevant dissolution. The PBBM, constructed by integrating various drug parameters, combined with the developed biopredictive dissolution methods, is a convenient approach for BE evaluation of NTI drugs and a practical tool for developing new drugs.
Competing Interests: Declarations. Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper.
(© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Yu L, Jiang W, Zhang X, Lionberger R, Makhlouf F, Schuirmann D, et al. Novel bioequivalence approach for narrow therapeutic index drugs. Clin Pharmacol Ther. 2015;97:286–91. https://doi.org/10.1002/cpt.28 . (PMID: 10.1002/cpt.2825669762)
Paixão P, Silva N, Guerreiro RB, Blake K, Bonelli M, Morais JAG, et al. Evaluation of a proposed approach for the determination of the bioequivalence acceptance range for narrow therapeutic index drugs in the European Union. Pharmaceutics. 2022;14:2349. https://doi.org/10.3390/pharmaceutics14112349 . (PMID: 10.3390/pharmaceutics14112349363651669697618)
Gozzo L, Caraci F, Drago F. Bioequivalence, drugs with narrow therapeutic index and the phenomenon of biocreep: A critical analysis of the system for generic substitution. Healthc Basel Switz. 2022;10:1392. https://doi.org/10.3390/healthcare10081392 . (PMID: 10.3390/healthcare10081392)
Cheng Z-Z, Hu X, Li Y-L, Zhang L. Predicting bioequivalence and developing dissolution bioequivalence safe space in vitro for warfarin using a Physiologically-Based pharmacokinetic absorption model. Eur J Pharm Biopharm. 2023;191:12–25. https://doi.org/10.1016/j.ejpb.2023.08.004 . (PMID: 10.1016/j.ejpb.2023.08.00437567396)
Jiang W, Makhlouf F, Schuirmann DJ, Zhang X, Zheng N, Conner D, et al. A bioequivalence approach for generic narrow therapeutic index drugs: Evaluation of the reference-scaled approach and variability comparison criterion. AAPS J. 2015;17:891–901. https://doi.org/10.1208/s12248-015-9753-5 . (PMID: 10.1208/s12248-015-9753-5258408834476992)
Draft Guidance on Warfarin Sodium. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Warfarin_Sodium_tab_09218_RC12-12.pdf . accessed 16 Jul 2023.
Gantar K, Škerget K, Mochkin I, Bajc A. Meeting regulatory requirements for drugs with a narrow therapeutic index: Bioequivalence studies of generic once-daily tacrolimus. Drug Healthc Patient Saf. 2020;12:151–60. https://doi.org/10.2147/DHPS.S256455 . (PMID: 10.2147/DHPS.S256455329824667489937)
Venkataramanan R, Swaminathan A, Prasad T. Jain Ashok, Zuckerman Sheila. Clinical Pharmacokinetics of Tacrolimus: Clin Pharmacokinet. 1995;29:404–30. https://doi.org/10.2165/00003088-199529060-00003 . (PMID: 10.2165/00003088-199529060-000038787947)
Andrews LM, Li Y, De Winter BCM, Shi Y-Y, Baan CC, Van Gelder T, et al. Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients. Expert Opin Drug Metab Toxicol. 2017;13:1225–36. https://doi.org/10.1080/17425255.2017.1395413 . (PMID: 10.1080/17425255.2017.139541329084469)
Tamura S, Ohike A, Ibuki R, Amidon GL, Yamashita S. Tacrolimus is a class II low-solubility high-permeability drug: The effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats. J Pharm Sci. 2002;91:719–29. https://doi.org/10.1002/jps.10041 . (PMID: 10.1002/jps.1004111920757)
Mackie C, Arora S, Seo P, Moody R, Rege B, Pepin X, et al. Physiologically based biopharmaceutics modeling (PBBM): Best practices for drug product quality, regulatory and industry perspectives: 2023 workshop summary report. Mol Pharm. 2024 acs.molpharmaceut.4c00202. https://doi.org/10.1021/acs.molpharmaceut.4c00202 .
Kollipara S, Martins FS, Sanghavi M, Santos GML, Saini A, Ahmed T. Role of physiologically based biopharmaceutics modeling (PBBM) in fed bioequivalence study waivers: Regulatory outlook, case studies and future perspectives. J Pharm Sci. 2024;113:345–58. https://doi.org/10.1016/j.xphs.2023.11.030 . (PMID: 10.1016/j.xphs.2023.11.03038043684)
Huzjak T, Jakasanovski O, Berginc K, Puž V, Zajc-Kreft K, Jeraj Ž, et al. Overcoming drug impurity challenges in amorphous solid dispersion with rational development of biorelevant dissolution-permeation method. Eur J Pharm Sci. 2024;192:106655. https://doi.org/10.1016/j.ejps.2023.106655 . (PMID: 10.1016/j.ejps.2023.10665538016626)
Han M, Xu J, Lin Y. Approaches of formulation bridging in support of orally administered drug product development. Int J Pharm. 2022;629:122380. https://doi.org/10.1016/j.ijpharm.2022.122380 . (PMID: 10.1016/j.ijpharm.2022.12238036368608)
Kollipara S, Bhattiprolu AK, Boddu R, Ahmed T, Chachad S. Best Practices for Integration of Dissolution Data into Physiologically Based Biopharmaceutics Models (PBBM): A Biopharmaceutics Modeling Scientist Perspective. AAPS PharmSciTech. 2023;24:59. https://doi.org/10.1208/s12249-023-02521-y . (PMID: 10.1208/s12249-023-02521-y36759492)
Wu D, Li M. Current state and challenges of physiologically based biopharmaceutics modeling (PBBM) in oral drug product development. Pharm Res. 2023;40:321–36. https://doi.org/10.1007/s11095-022-03373-0 . (PMID: 10.1007/s11095-022-03373-036076007)
Zhang X, Lionberger RA, Davit BM, Yu LX. Utility of physiologically based absorption modeling in implementing quality by design in drug development. AAPS J. 2011;13:59–71. https://doi.org/10.1208/s12248-010-9250-9 . (PMID: 10.1208/s12248-010-9250-9212072163032086)
Kesisoglou F, Chung J, Van Asperen J, Heimbach T. Physiologically based absorption modeling to impact biopharmaceutics and formulation strategies in drug development—industry case studies. J Pharm Sci. 2016;105:2723–34. https://doi.org/10.1016/j.xphs.2015.11.034 . (PMID: 10.1016/j.xphs.2015.11.03426886317)
FDA expectations in building a safe space to gain regulatory flexibility based on Physiologically Based Biopharmaceutics Modeling (PBBM). https://cersi.umd.edu/sites/cersi.umd.edu/files/Day%203-1%20Zhao%20Suarez%20LM.pdf . Accessed cited 20 Apr 2024.
McAllister M, Flanagan T, Cole S, Abend A, Kotzagiorgis E, Limberg J, et al. Developing clinically relevant dissolution specifications (CRDSs) for oral drug products: Virtual webinar series. Pharmaceutics. 2022;14:1010. https://doi.org/10.3390/pharmaceutics14051010 . (PMID: 10.3390/pharmaceutics14051010356315959148161)
Wu F, Mousa Y, Raines K, Bode C, Tsang YC, Cristofoletti R, et al. Regulatory utility of physiologically-based pharmacokinetic modeling to support alternative bioequivalence approaches and risk assessment: A workshop summary report. CPT Pharmacomet Syst Pharmacol. 2023;12:585–97. https://doi.org/10.1002/psp4.12907 . (PMID: 10.1002/psp4.12907)
Pawar G, Wu F, Zhao L, Fang L, Burckart GJ, Feng K, et al. Integration of biorelevant pediatric dissolution methodology into PBPK modeling to predict in vivo performance and bioequivalence of generic drugs in pediatric populations: A carbamazepine case study. AAPS J. 2023;25:67. https://doi.org/10.1208/s12248-023-00826-1 . (PMID: 10.1208/s12248-023-00826-137386339)
Mondal S, Kollipara S, Chougule M, Bhatia A, Ahmed T. Biopredictive dissolutions for conventional oral IR, MR and non-oral formulations – current status and future opportunities. J Drug Deliv Sci Technol. 2024;97:105807. https://doi.org/10.1208/S1773224724004763 . (PMID: 10.1208/S1773224724004763)
Tsunashima D, Yamashita K, Ogawara K-I, Sako K, Hakomori T, Higaki K. Development of extended-release solid dispersion granules of tacrolimus: evaluation of release mechanism and human oral bioavailability. J Pharm Pharmacol. 2017;69:1697–706. https://doi.org/10.1111/jphp.12804 . (PMID: 10.1111/jphp.1280428872687)
Yoshida H, Teruya K, Abe Y, Furuishi T, Fukuzawa K, Yonemochi E, et al. Altered media flow and tablet position as factors of how air bubbles affect dissolution of disintegrating and non-disintegrating tablets using a USP 4 Flow-Through Cell Apparatus. AAPS PharmSciTech. 2021;22:227. https://doi.org/10.1208/s12249-021-02117-4 . (PMID: 10.1208/s12249-021-02117-434431011)
Fang JB, Robertson VK, Rawat A, Flick T, Tang ZJ, Cauchon NS, et al. Development and application of a biorelevant dissolution method using USP apparatus 4 in early phase formulation development. Mol Pharm. 2010;7:1466–77. https://doi.org/10.1021/mp100125b . (PMID: 10.1021/mp100125b20701327)
Jiang W. FDA drug topics: Understanding generic narrow therapeutic index drugs. https://www.fda.gov/media/162779/download . Accessed 10 Jul 2024.
Laisney M, Heimbach T, Mueller-Zsigmondy M, Blumenstein L, Costa R, Ji Y. Physiologically based biopharmaceutics modeling to demonstrate virtual bioequivalence and bioequivalence safe-space for ribociclib which has permeation rate-controlled absorption. J Pharm Sci. 2022;111:274–84. https://doi.org/10.1016/j.xphs.2021.10.017 . (PMID: 10.1016/j.xphs.2021.10.01734678270)
Möller A, Iwasaki K, Kawamura A, Teramura Y, Shiraga T, Hata T, et al. The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects. Drug Metab Dispos. 1999;27:633–6. https://dmd.aspetjournals.org/content/27/6/633 . Accessed 25 Jan 2023.
Mathew P, Mandal J, Patel K, Soni K, Tangudu G, Patel R, et al. Bioequivalence of two Tacrolimus formulations under fasting conditions in healthy male subjects. Clin Ther. 2011;33:1105–19. https://doi.org/10.1016/j.clinthera.2011.07.010 . (PMID: 10.1016/j.clinthera.2011.07.01021840601)
Ting FX, Jing J, Tong HY. Pharmacokinetics and clinical consistency of tacrolimus capsules in healthy Chinese volunteers. Chin J Pharm Anal. 2021;41:613–8. https://doi.org/10.16155/j.0254-1793.2021.04.07 . (PMID: 10.16155/j.0254-1793.2021.04.07)
Park K, Kim YS, Kwon K, Park MS, Lee YJ, Kim KH. A randomized, open-label, two-period, crossover bioavailability study of two oral formulations of tacrolimus in healthy Korean adults. Clin Ther. 2007;29:154–62. https://doi.org/10.1016/j.clinthera.2007.01.016 . (PMID: 10.1016/j.clinthera.2007.01.01617379055)
Lainesse A, Hussain S, Monif T, Reyar S, Tippabhotla S, Madan A, Thudi N. Bioequivalence Studies of Tacrolimus Capsule under Fasting and Fed Conditions in Healthy Male and Female Subjects. Arzneimittelforschung. 2011;58(05):242–7. https://doi.org/10.1055/s-0031-1296500 . (PMID: 10.1055/s-0031-1296500)
Dutta S, Qiu Y, Samara E, Cao G, Granneman GR. Once-a-day extended-release dosage form of divalproex sodium III: development and validation of a Level A in vitro-in vivo correlation (IVIVC). J Pharm Sci. 2005;94:1949–56. https://doi.org/10.1002/jps.20387 . (PMID: 10.1002/jps.2038716052544)
Zhang F, Jia R, Gao H, Wu X, Liu B, Wang H. In silico modeling and simulation to guide bioequivalence testing for oral drugs in a virtual population. Clin Pharmacokinet. 2021;60:1373–85. https://doi.org/10.1007/s40262-021-01045-7 . (PMID: 10.1007/s40262-021-01045-734191255)
Wang M, Heimbach T, Zhu W, Wu D, Reuter KG, Kesisoglou F. Physiologically based biopharmaceutics modeling for gefapixant IR formulation development and defining the bioequivalence dissolution safe space. AAPS J. 2024;26:69. https://doi.org/10.1208/s12248-024-00938-2 . (PMID: 10.1208/s12248-024-00938-238862807)
Tamura S, Tokunaga Y, Ibuki R, Amidon GL, Sezaki H, Yamashita S. The site-specific transport and metabolism of Tacrolimus in rat small intestine. J Pharmacol Exp Ther. 2003;306:310–6. https://doi.org/10.1124/jpet.103.050716 . (PMID: 10.1124/jpet.103.05071612676880)
Wojnowski L, Kamdem LK. Clinical implications of CYP3A polymorphisms. Expert Opin Drug Metab Toxicol. 2006;2:171–82. https://doi.org/10.1517/17425255.2.2.171 . (PMID: 10.1517/17425255.2.2.17116866606)
Kourentas A, Gajewska M, Lin W, Dhareshwar SS, Steib-Lauer C, Kulkarni S, et al. Establishing the safe space via physiologically based biopharmaceutics modeling. Case study: Fevipiprant/QAW039. AAPS J. 2023;25:25. https://doi.org/10.1208/s12248-023-00787-5 . (PMID: 10.1208/s12248-023-00787-536788163)
Pepin XJH, Flanagan TR, Holt DJ, Eidelman A, Treacy D, Rowlings CE. Justification of drug product dissolution rate and drug substance particle size specifications based on absorption PBPK modeling for lesinurad immediate release tablets. Mol Pharm. 2016;13:3256–69. https://doi.org/10.1021/acs.molpharmaceut.6b00497 . (PMID: 10.1021/acs.molpharmaceut.6b0049727438964)
Dos SantosMiranda E, Ferraz HG, Issa MG, Duque MD. Development of extended-release formulations containing cyclobenzaprine based on physiologically based biopharmaceutics modeling and bioequivalence safe space. J Pharm Sci. 2023;112:3131–40. https://doi.org/10.1016/j.xphs.2023.07.012 . (PMID: 10.1016/j.xphs.2023.07.012)
Mercuri A, Wu S, Stranzinger S, Mohr S, Salar-Behzadi S, Bresciani M, et al. In vitro and in silico characterisation of Tacrolimus released under biorelevant conditions. Int J Pharm. 2016;515:271–80. https://doi.org/10.1016/j.ijpharm.2016.10.020 . (PMID: 10.1016/j.ijpharm.2016.10.02027737809)
Loer HLH, Feick D, Rüdesheim S, Selzer D, Schwab M, et al. Physiologically Based Pharmacokinetic Modeling of Tacrolimus for Food-Drug and CYP3A Drug-Drug-Gene Interaction Predictions. CPT Pharmacomet Syst Pharmacol. 2023;12(5):724–38. https://doi.org/10.1002/psp4.12946 . (PMID: 10.1002/psp4.12946)
APPLICATION NUMBER: 204096Orig1s000; Tacrolimus Pharmacology Review(s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204096Orig1s000PharmR.pdf . Accessed 5 Aug 2022.
Wu F, Shah H, Li M, Duan P, Zhao P, Suarez S, et al. Biopharmaceutics applications of physiologically based pharmacokinetic absorption modeling and simulation in regulatory submissions to the U.S. Food and Drug Administration for new drugs. AAPS J. 2021;23:31. https://doi.org/10.1208/s12248-021-00564-2 . (PMID: 10.1208/s12248-021-00564-233619657)
Niu Y, Lan G, Wang J, Yan T, Jin P. Bioequivalence evaluation and blood concentration estimation of generic and branded tacrolimus in healthy subjects under fasting: A randomized, four-periods, two-sequences, complete repeated, crossover study. Transpl Immunol. 2023;81:101933. https://doi.org/10.1016/j.trim.2023.101933 . (PMID: 10.1016/j.trim.2023.10193337730184)
Jones H, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacomet Syst Pharmacol. 2013;2:e63. https://doi.org/10.1038/psp.2013.41 . (PMID: 10.1038/psp.2013.41)
Ibarra M, Schiavo A, Lesko LJ. Physiologically based pharmacokinetic (PBPK) modeling: model development and evaluation. In: Talevi A (ed) The ADME Encyclopedia. Springer, Cham; 2022. https://doi.org/10.1007/978-3-030-84860-6_168 .
Loisios-Konstantinidis I, Dressman J. Physiologically based pharmacokinetic/pharmacodynamic modeling to support waivers of in vivo clinical studies: Current status, challenges, and opportunities. Mol Pharm. 2021;18:1–17. https://doi.org/10.1021/acs.molpharmaceut.0c00903 . (PMID: 10.1021/acs.molpharmaceut.0c0090333320002)
Kim TH, Shin S, Shin BS. Model-based drug development: Application of modeling and simulation in drug development. J Pharm Investig. 2018;48:431–41. https://doi.org/10.1007/s40005-017-0371-3 . (PMID: 10.1007/s40005-017-0371-3)
Wu D, Sanghavi M, Kollipara S, Ahmed T, Saini AK, Heimbach T. Physiologically based pharmacokinetics modeling in biopharmaceutics: Case studies for establishing the bioequivalence safe space for innovator and generic drugs. Pharm Res. 2022. https://doi.org/10.1007/s11095-022-03319-6 . (PMID: 10.1007/s11095-022-03319-6363852169668393)
Jaiswal S, Ahmed T, Kollipara S, Bhargava M, Chachad S. Development, validation and application of physiologically based biopharmaceutics model to justify the change in dissolution specifications for DRL ABC extended release tablets. Drug Dev Ind Pharm. 2021;47:778–89. https://doi.org/10.1080/03639045.2021.1934870 . (PMID: 10.1080/03639045.2021.193487034082622)
Kato T, Nakagawa H, Mikkaichi T, Miyano T, Matsumoto Y, Ando S. Establishment of a clinically relevant specification for dissolution testing using physiologically based pharmacokinetic (PBPK) modeling approaches. Eur J Pharm Biopharm. 2020;151:45–52. https://doi.org/10.1016/j.ejpb.2020.03.012 . (PMID: 10.1016/j.ejpb.2020.03.01232298756)
Mitra A, Petek B, Bajc A, Velagapudi R, Legen I. Physiologically based absorption modeling to predict bioequivalence of controlled release and immediate release oral products. Eur J Pharm Biopharm. 2019;134:117–25. https://doi.org/10.1016/j.ejpb.2018.11.019 . (PMID: 10.1016/j.ejpb.2018.11.01930472143)
Wu D, Sanghavi M, Kollipara S, Ahmed T, Saini AK, Heimbach T. Physiologically based pharmacokinetics modeling in biopharmaceutics: Case studies for establishing the bioequivalence safe space for innovator and generic drugs. Pharm Res. 2023;40:337–57. https://doi.org/10.1007/s11095-022-03319-6 . (PMID: 10.1007/s11095-022-03319-635840856)
Pepin XJH, Sanderson NJ, Blanazs A, Grover S, Ingallinera TG, Mann JC. Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part I. Mechanistic modelling of drug product dissolution to derive a P-PSD for PBPK model input. Eur J Pharm Biopharm. 2019;142:421–34. https://doi.org/10.1016/j.ejpb.2019.07.014 . (PMID: 10.1016/j.ejpb.2019.07.01431306753)
Pepin X, McAlpine V, Moir A, Mann J. Acalabrutinib maleate tablets: The physiologically based biopharmaceutics model behind the drug product dissolution specification. Mol Pharm. 2023;20:2181–93. https://doi.org/10.1021/acs.molpharmaceut.3c00005 . (PMID: 10.1021/acs.molpharmaceut.3c0000536859819)
Ikuta S, Nakagawa H, Kai T, Sugano K. Development of bicarbonate buffer flow-through cell dissolution test and its application in prediction of in vivo performance of colon targeting tablets. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2023;180:106326. https://doi.org/10.1016/j.ejps.2022.106326 . (PMID: 10.1016/j.ejps.2022.106326)
Singh I, Aboul-Enein HY. Advantages of USP Apparatus IV (flow-through cell apparatus) in dissolution studies. J Iran Chem Soc. 2006;3:220–2. https://doi.org/10.1007/BF03247211 . (PMID: 10.1007/BF03247211)
Medina JR, Salazar DK, Hurtado M, Cortés AR, Domínguez-Ramírez AM. Comparative in vitro dissolution study of carbamazepine immediate-release products using the USP paddles method and the flow-through cell system. Saudi Pharm J SPJ Off Publ Saudi Pharm Soc. 2014;22:141–7. https://doi.org/10.1016/j.jsps.2013.02.001 . (PMID: 10.1016/j.jsps.2013.02.001)
Jantratid E, De Maio V, Ronda E, Mattavelli V, Vertzoni M, Dressman JB. Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form. Eur J Pharm Sci. 2009;37:434–41. https://doi.org/10.1016/j.ejps.2009.03.015 . (PMID: 10.1016/j.ejps.2009.03.01519491035)
Tsakiridou G, O’Dwyer PJ, Margaritis A, Box KJ, Vertzoni M, Kalantzi L, et al. On the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state. J Drug Deliv Sci Technol. 2022;69:102990. https://doi.org/10.1016/j.jddst.2021.102990 . (PMID: 10.1016/j.jddst.2021.102990)
Uppoor VRS. Regulatory perspectives on in vitro (dissolution)/in vivo (bioavailability) correlations. J Controlled Release. 2001;72:127–32. https://doi.org/10.1016/S0168-3659(01)00268-1 . (PMID: 10.1016/S0168-3659(01)00268-1)
Hottinger M, Liang BA. Deficiencies of the FDA in evaluating generic formulations: Addressing narrow therapeutic index drugs. Am J Law Med. 2012;38:667–89. https://doi.org/10.1177/009885881203800403 . (PMID: 10.1177/00988588120380040323356099)
Lennernäs H, Lindahl A, Van Peer A, Ollier C, Flanagan T, Lionberger R, et al. In vivo predictive dissolution (IPD) and biopharmaceutical modeling and simulation: Future use of modern approaches and methodologies in a regulatory context. Mol Pharm. 2017;14:1307–14. https://doi.org/10.1021/acs.molpharmaceut.6b00824 . (PMID: 10.1021/acs.molpharmaceut.6b0082428195732)
The impact and future of physiological based PK in biopharmaceutics modeling (PBBM) in support of drug product quality. https://cersi.umd.edu/sites/cersi.umd.edu/files/Day%201-1%20Paul%20Seo%20Final.pdf . Accessed Aug 4 2022.
The use of physiologically based pharmacokinetic analyses — biopharmaceutics applications for oral drug product development, manufacturing changes, and controls guidance for industry. https://www.fda.gov/media/142500/download . Accessed 7 Sep 2022.
Clinically relevant dissolution specifications: a biopharmaceutics’ risk based approach: an FDA perspective. https://www.apsgb.co.uk/wp-content/uploads/2021/05/Clinically-Relevant-Dissolution-Specifications-an-FDA-Perspective-Om-Anand.pdf . Accessed 27 Feb 2024.

Keywords: Narrow Therapeutic Index (NTI); Physiologically Based Biopharmaceutics Modeling (PBBM); biopredictive dissolution; flow-through cell apparatus; tacrolimus extended-release (ER) capsules

WM0HAQ4WNM (Tacrolimus)
0 (Delayed-Action Preparations)
0 (Capsules)
0 (Drugs, Generic)

Date Created: 20241217 Date Completed: 20241217 Latest Revision: 20241217

20241218

10.1208/s12249-024-03006-2

39690309