Conclusion
An optimized PBPK model of TAC was successfully established in adults to evaluate DDI between TAC and VRCZ with different administration. Furthermore, the adult PBPK model had been successfully scaled to pediatrics population with different age groups for assessment of DDI between TAC and VRCZ. Both IV and oral VRCZ had a significant effect on PK of TAC in two population. For pediatrics at the age of 0-1, VRCZ presented a relative unremarkable effect on the PK of TAC compared with adults, and DDI was more pronounced when VRCZ was administered orally. The DDI progressed gradually as the age advances and finally equal to adults. Besides, TAC liposolubility was the most significant parameter on the DDI between TAC and VRCZ. In clinical practice, the concentration monitoring and dosage adjustment of TAC should be emphasized when co-administrated with VRCZ, especially in adult or in oral formulation.
1. Patel JN, Hamadeh IS. Pharmacogenetics and tacrolimus administration in stem cell transplantation. Pharmacogenomics 2020; 21: 419-26.
2. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004; 43: 623-53.
3. Schumacher L, Leino AD, Park JM. Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective. Pharmacotherapy 2021; 41: 103-18.
4. Bentata Y. Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity. Artif Organs 2020; 44: 140-52.
5. Zhang X, Lin G, Tan L, Li J. Current progress of tacrolimus dosing in solid organ transplant recipients: Pharmacogenetic considerations. Biomed Pharmacother 2018; 102: 107-14.
6. Marquet P, Cros F, Micallef L, Jacqz-Aigrain E, Woillard JB, Monchaud C, Saint-Marcoux F, Debord J. Tacrolimus Bayesian Dose Adjustment in Pediatric Renal Transplant Recipients. Ther Drug Monit 2021; 43: 472-80.
7. Vanhove T, Bouwsma H, Hilbrands L, Swen JJ, Spriet I, Annaert P, Vanaudenaerde B, Verleden G, Vos R, Kuypers DRJ. Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients. Am J Transplant 2017; 17: 2372-80.
8. Kadam RS, Van Den Anker JN. Pediatric Clinical Pharmacology of Voriconazole: Role of Pharmacokinetic/Pharmacodynamic Modeling in Pharmacotherapy. Clin Pharmacokinet 2016; 55: 1031-43.
9. Ota R, Hirata A, Noto K, Yokoyama S, Hosomi K, Takada M, Matsuoka H. Relationship between the blood concentrations of tacrolimus and voriconazole in hematopoietic stem cell transplant recipients
Int J Clin Pharmacol Ther 2019; 57: 561-66.
10. Hikasa S, Shimabukuro S, Osugi Y, Ikegame K, Kaida K, Fukunaga K, Higami T, Tada M, Tanaka K, Yanai M, Kimura T. Tacrolimus Concentration after Letermovir Initiation in Hematopoietic Stem Cell Transplantation Recipients Receiving Voriconazole: A Retrospective, Observational Study. Int J Med Sci 2020; 17: 859-64.
11. Mimura A, Yamaori S, Ikemura N, Katsuyama Y, Matsuzawa N, Ohmori S. Influence of azole antifungal drugs on blood tacrolimus levels after switching from intravenous tacrolimus to once-daily modified release tacrolimus in patients receiving allogeneic hematopoietic stem cell transplantation. J Clin Pharm Ther 2019; 44: 565-71.
12. Utano T, Kato M, Osumi T, Shioda Y, Kiyotani C, Terashima K, Tomizawa D, Matsumoto K, Yamatani A. Tacrolimus blood concentration increase depends on administration route when combined with voriconazole in pediatric stem cell transplant recipients. Pediatr Transplant 2020; 24: e13619.
13. Chie, Emoto, Trevor N, Johnson, David, Hahn, Uwe, Christians, Rita R, Alloway. A Theoretical Physiologically-Based Pharmacokinetic Approach to Ascertain Covariates Explaining the Large Interpatient Variability in Tacrolimus Disposition. CPT: pharmacometrics & systems pharmacology 2019.
14. Zeiser S, Treijtel N, Spaans E. Whole-Body PBPK Modeling of Tacrolimus in Healthy Volunteers.
15. He Q, Bu F, Zhang H, Wang Q, Tang Z, Yuan J, Lin HS, Xiang X. Investigation of the Impact of CYP3A5 Polymorphism on Drug–Drug Interaction between Tacrolimus and Schisantherin A/Schisandrin A Based on Physiologically-Based Pharmacokinetic Modeling. Multidisciplinary Digital Publishing Institute 2021.
16. Xin HW, Wu XC, Li Q, Yu AR, Zhu M, Shen Y, Su D, Xiong L. Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. Br J Clin Pharmacol 2007; 64: 469-75.
17. Hasegawa A, Takahashi K, Ito K, Oshima S, Uchida K, Sonoda T. Optimal use of tacrolimus in living donor renal transplantation in children. Transplant Proc 2002; 34: 1939-41.
18. Dong J, Liu SB, Rasheduzzaman JM, Huang CR, Miao LY. Development of Physiology Based Pharmacokinetic Model to Predict the Drug Interactions of Voriconazole and Venetoclax. Pharmaceutical Research 2022; 39: 1921-33.
19. Frechen S, Junge L, Saari TI, Suleiman AA, Rokitta D, Neuvonen PJ, Olkkola KT, Fuhr U. A semiphysiological population pharmacokinetic model for dynamic inhibition of liver and gut wall cytochrome P450 3A by voriconazole. Clin Pharmacokinet 2013; 52: 763-81.
20. Damle B, Varma MV, Wood N. Pharmacokinetics of voriconazole administered concomitantly with fluconazole and population-based simulation for sequential use. Antimicrob Agents Chemother 2011; 55: 5172-7.
21. Lee S, Kim BH, Nam WS, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS. Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers. J Clin Pharmacol 2012; 52: 195-203.
22. Walsh TJ, Driscoll T, Milligan PA, Wood ND, Schlamm H, Groll AH, Jafri H, Arrieta AC, Klein NJ, Lutsar I. Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children. Antimicrob Agents Chemother 2010; 54: 4116-23.
23. Hohmann N, Kocheise F, Carls A, Burhenne J, Weiss J, Haefeli WE, Mikus G. Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole. Clin Pharmacokinet 2016; 55: 1535-45.
24. Driscoll TA, Yu LC, Frangoul H, Krance RA, Nemecek E, Blumer J, Arrieta A, Graham ML, Bradfield SM, Baruch A, Liu P. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults. Antimicrob Agents Chemother 2011; 55: 5770-9.
25. Huang W, Lin YS, McConn DJ, 2nd, Calamia JC, Totah RA, Isoherranen N, Glodowski M, Thummel KE. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos 2004; 32: 1434-45.
26. Hines RN. Ontogeny of human hepatic cytochromes P450. J Biochem Mol Toxicol 2007; 21: 169-75.
27. Strougo A, Yassen A, Monnereau C, Danhof M, Freijer J. Predicting the ”First dose in children” of CYP3A-metabolized drugs: Evaluation of scaling approaches and insights into the CYP3A7-CYP3A4 switch at young ages. J Clin Pharmacol 2014; 54: 1006-15.
28. Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol 2003; 17: 281-99.
29. Stevens JC. New perspectives on the impact of cytochrome P450 3A expression for pediatric pharmacology. Drug Discov Today 2006; 11: 440-5.
30. Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT. Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Clin Pharmacol Ther 2006; 79: 362-70.
31. Monostory K, Tóth K, Kiss Á, Háfra E, Csikány N, Paulik J, Sárváry E, Kóbori L. Personalizing initial calcineurin inhibitor dosing by adjusting to donor CYP3A-status in liver transplant patients. Br J Clin Pharmacol 2015; 80: 1429-37.
32. Liu Y, Zhang C, Li L, Ou B, Yuan L, Zhang T, Fan J, Peng Z. Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function. Front Genet 2019; 10: 528.
33. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 ”pie”. Drug Metab Dispos 2006; 34: 880-6.
34. Liu P, Mould DR. Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis. Antimicrob Agents Chemother 2014; 58: 4727-36.
35. Suetsugu K, Mori Y, Yamamoto N, Shigematsu T, Miyamoto T, Egashira N, Akashi K, Masuda S. Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation. Int J Mol Sci 2019; 20.
36. Moorthy GS, Vedar C, Zane N, Prodell JL, Zuppa AF. Development and validation of a volumetric absorptive microsampling assay for analysis of voriconazole and voriconazole N-oxide in human whole blood. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1105: 67-75.
37. Wilcox CS, Pearlman A. Chemistry and antihypertensive effects of tempol and other nitroxides. Pharmacol Rev 2008; 60: 418-69.
38. Rivera R, Antognini JF. Perioperative drug therapy in elderly patients. Anesthesiology 2009; 110: 1176-81.
39. Nixon E, Mays TP, Routh PA, Yeatts JL, Fajt VR, Hairgrove T, Baynes RE. Plasma, urine and tissue concentrations of Flunixin and Meloxicam in Pigs. BMC Vet Res 2020; 16: 340.
40. Gutiérrez L, Velasco ZH, Vázquez C, Vargas D, Sumano H. Pharmacokinetics of an injectable long-acting formulation of doxycycline hyclate in dogs. Acta Vet Scand 2012; 54: 35.
41. Blaschke TF, Skinner MH. The clinical pharmacokinetics of rifabutin. Clin Infect Dis 1996; 22 Suppl 1: S15-21; discussion S21-2.
42. Li X, Frechen S, Moj D, Lehr T, Taubert M, Hsin CH, Mikus G, Neuvonen PJ, Olkkola KT, Saari TI, Fuhr U. A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions. Clin Pharmacokinet 2020; 59: 781-808.
43. Iwamoto T, Monma F, Fujieda A, Nakatani K, Gayle AA, Nobori T, Katayama N, Okuda M. Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation. Ther Drug Monit 2015; 37: 581-8.
Authorship: Liqin Zhu provided ideas for the manuscript and reviewed the manuscript; Meiling Zuo wrote the manuscript and analyzed the data; Yuxuan Sun collected the data and analyzed data. Ailin Zhang and Jingtao Chen contributed to validate the PBPK model; Liqin Zhu provided a venue for research; All authors have approved the final version of this manuscript.
Funding: All authors declare that no external funding has been received.
Disclosure statement: The authors declare no conflicts of interest.
Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
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