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Pharmaceutical Research

, 36:45 | Cite as

Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome

  • Tong Lu
  • Xu Zhu
  • Shansen Xu
  • Mingming Zhao
  • Xueshi Huang
  • Zhanyou Wang
  • Limei ZhaoEmail author
Research Paper
  • 33 Downloads

Abstract

Purpose

The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients.

Methods

Nephrotic syndrome patients (>16 years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus.

Results

The mean apparent clearance (CL/F) of tacrolimus was 13.4 L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndrome patients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2 rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2 rs227707 CC/CT genotype carriers.

Conclusions

A new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndrome patients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration.

KEY WORDS

dosage optimization genetic polymorphisms nephrotic syndrome population pharmacokinetics tacrolimus 

Abbreviations

95% CIs

95% confidence intervals

ALB

Albumin

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

C0

Whole blood trough concentrations

CL

Clearance

CWRES

Conditional weighted residuals

CYP3A4

Cytochrome P450 3A4

CYP3A5

Cytochrome P450 3A5

DV

Observed concentration

F

Bioavailability

HCT

Hematocrit

HGB

Hemoglobin

IPRED

Individual predicted concentration

MDR1

Multiple drug resistance 1

MRP2

Multidrug resistance -associated protein 2

NPDE

Normalized prediction distribution errors

OFV

Objective function value

PRED

Predicted concentration

PsN

Perl-Speaks-NONMEM

PXR

Pregnane X receptor

RBC

Red blood cells

SNPs

Single nucleotide polymorphisms

SUMO4

Small ubiquitin-related modifier 4

Vd

Volume of distribution

VPC

Visual predictive check

Notes

Supplementary material

11095_2019_2579_Fig5_ESM.png (191 kb)
Figure S1

Correlations between covariates. WT weight, ALB albumin, ALT alanine aminotransferase, AST aspartate aminotransferase, RBC red blood cells, HGB hemoglobin, HCT hematocrit. (PNG 190 kb)

11095_2019_2579_MOESM1_ESM.tif (425 kb)
High Resolution Image (TIF 425 kb)
11095_2019_2579_Fig6_ESM.png (348 kb)
Figure S2

Effects of covariates on tacrolimus oral clearance (L/h). AST aspartate aminotransferase, ALT alanine aminotransferase, ALB albumin, HGB hemoglobin, HCT hematocrit, RBC red blood cells, CYP3A4 Cytochrome P450 3A4, CYP3A5 Cytochrome P450 3A5, MDR1 Multiple drug resistance 1, MRP2 Multidrug resistance -associated protein 2, SUMO4 Small ubiquitin-related modifier 4, NR1I2 (PXR) Pregnane X receptor. (PNG 348 kb)

11095_2019_2579_MOESM2_ESM.tif (378 kb)
High Resolution Image (TIF 378 kb)

References

  1. 1.
    Samuel S, Bitzan M, Zappitelli M, Dart A, Mammen C, Pinsk M, et al. Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic syndrome in children. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2014;63(3):354–62.CrossRefGoogle Scholar
  2. 2.
    Fan L, Liu Q, Liao Y, Li Z, Ji Y, Yang Z, et al. Tacrolimus is an alternative therapy option for the treatment of adult steroid-resistant nephrotic syndrome: a prospective, multicenter clinical trial. Int Urol Nephrol. 2013;45(2):459–68.CrossRefGoogle Scholar
  3. 3.
    Staatz C, Tett S. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623–53.CrossRefGoogle Scholar
  4. 4.
    Shah S, Hafeez F. Comparison of efficacy of tacrolimus versus cyclosporine in childhood steroid-resistant nephrotic syndrome. J Coll Physicians Surg Pak. 2016;26(7):589–93.PubMedGoogle Scholar
  5. 5.
    Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part II. Clin Pharmacokinet. 2010;49(4):207–21.CrossRefGoogle Scholar
  6. 6.
    de Wildt SN, van Schaik RH, Soldin OP, Soldin SJ, Brojeni PY, van der Heiden IP, et al. The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation. Eur J Clin Pharmacol. 2011;67(12):1231–41.CrossRefGoogle Scholar
  7. 7.
    Picard N, Bergan S, Marquet P, van Gelder T, Wallemacq P, Hesselink DA, et al. Pharmacogenetic biomarkers predictive of the pharmacokinetics and pharmacodynamics of immunosuppressive drugs. Ther Drug Monit. 2016;38(Suppl 1):S57–69.CrossRefGoogle Scholar
  8. 8.
    Hesselink DA, Bouamar R, Elens L, van Schaik RH, van Gelder T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014;53(2):123–39.CrossRefGoogle Scholar
  9. 9.
    Andreu F, Colom H, Elens L, van Gelder T, van Schaik RHN, Hesselink DA, et al. A new CYP3A5*3 and CYP3A4*22 cluster influencing tacrolimus target concentrations: a population approach. Clin Pharmacokinet. 2017;56(8):963–75.CrossRefGoogle Scholar
  10. 10.
    Lopez-Montenegro Soria MA, Kanter Berga J, Beltran Catalan S, Milara Paya J, Pallardo Mateu LM, Jimenez Torres NV. Genetic polymorphisms and individualized tacrolimus dosing. Transplant Proc. 2010;42(8):3031–3.CrossRefGoogle Scholar
  11. 11.
    Ogasawara K, Chitnis SD, Gohh RY, Christians U, Akhlaghi F. Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients. Clin Pharmacokinet. 2013;52(9):751–62.CrossRefGoogle Scholar
  12. 12.
    Pulk RA, Schladt DS, Oetting WS, Guan W, Israni AK, Matas AJ, et al. Multigene predictors of tacrolimus exposure in kidney transplant recipients. Pharmacogenomics. 2015;16(8):841–54.CrossRefGoogle Scholar
  13. 13.
    Gu X, Ke S, Liu D, Sheng T, Thomas PE, Rabson AB, et al. Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents. J Biol Chem. 2006;281(26):17882–9.CrossRefGoogle Scholar
  14. 14.
    Liu CL, Lim YP, Hu ML. Fucoxanthin attenuates rifampin-induced cytochrome P450 3A4 (CYP3A4) and multiple drug resistance 1 (MDR1) gene expression through pregnane X receptor (PXR)-mediated pathways in human hepatoma HepG2 and colon adenocarcinoma LS174T cells. Marine drugs. 2012;10(1):242–57.CrossRefGoogle Scholar
  15. 15.
    Zhang T, Liu Y, Zeng R, Ling Q, Wen P, Fan J, et al. Association of donor small ubiquitin-like modifier 4 rs237025 genetic variant with tacrolimus elimination in the early period after. Liver Transpl. 2018;38(4):724–32.Google Scholar
  16. 16.
    Barraclough KA, Isbel NM, Lee KJ, Bergmann TK, Johnson DW, McWhinney BC, et al. NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. Transplantation. 2012;94(10):1025–32.CrossRefGoogle Scholar
  17. 17.
    Velickovic-Radovanovic R, Catic-Djordjevic A, Milovanovic JR, Djordjevic V, Paunovic G, Jankovic SM. Population pharmacokinetics of tacrolimus in kidney transplant patients. Int J Clin Pharmacol Ther. 2010;48(6):375–82.CrossRefGoogle Scholar
  18. 18.
    Lu YX, Su QH, Wu KH, Ren YP, Li L, Zhou TY, et al. A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients. Acta Pharmacol Sin. 2015;36(2):281–8.CrossRefGoogle Scholar
  19. 19.
    Benkali K, Premaud A, Picard N, Rerolle JP, Toupance O, Hoizey G, et al. Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients. Clin Pharmacokinet. 2009;48(12):805–16.CrossRefGoogle Scholar
  20. 20.
    Storset E, Holford N, Midtvedt K, Bremer S, Bergan S, Asberg A. Importance of hematocrit for a tacrolimus target concentration strategy. Eur J Clin Pharmacol. 2014;70(1):65–77.CrossRefGoogle Scholar
  21. 21.
    Staatz CE, Willis C, Taylor PJ, Tett SE. Population pharmacokinetics of tacrolimus in adult kidney transplant recipients. Clin Pharmacol Ther. 2002;72(6):660–9.CrossRefGoogle Scholar
  22. 22.
    Zhang XQ, Wang ZW, Fan JW, Li YP, Jiao Z, Gao JW, et al. The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in Chinese adult liver-transplant patients. Ther Drug Monit. 2012;34(2):126–33.CrossRefGoogle Scholar
  23. 23.
    Zhang H, Bu F, Li L, Jiao Z, Ma G, Cai W, et al. Prediction of drug-drug interaction between tacrolimus and principal ingredients of Wuzhi capsule in Chinese healthy volunteers using physiologically-based pharmacokinetic modelling. Basic Clin Pharmacol Toxicol. 2017.Google Scholar
  24. 24.
    Qin XL, Bi HC, Wang XD, Li JL, Wang Y, Xue XP, et al. Mechanistic understanding of the different effects of Wuzhi tablet (Schisandra sphenanthera extract) on the absorption and first-pass intestinal and hepatic metabolism of tacrolimus (FK506). Int J Pharm. 2010;389(1–2):114–21.CrossRefGoogle Scholar
  25. 25.
    Xin HW, Wu XC, Li Q, Yu AR, Zhu M, Shen Y, et al. Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. Br J Clin Pharmacol. 2007;64(4):469–75.CrossRefGoogle Scholar
  26. 26.
    Wei H, Tao X, Di P, Yang Y, Li J, Qian X, et al. Effects of traditional chinese medicine Wuzhi capsule on pharmacokinetics of tacrolimus in rats. Drug Metab Dispos. 2013;41(7):1398–403.CrossRefGoogle Scholar
  27. 27.
    Zuo XC, Ng CM, Barrett JS, Luo AJ, Zhang BK, Deng CH, et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis. Pharmacogenet Genomics. 2013;23(5):251–61.CrossRefGoogle Scholar
  28. 28.
    Jacobo-Cabral CO, Garcia-Roca P, Romero-Tejeda EM, Reyes H, Medeiros M, Castaneda-Hernandez G, et al. Population pharmacokinetic analysis of tacrolimus in Mexican paediatric renal transplant patients: role of CYP3A5 genotype and formulation. Br J Clin Pharmacol. 2015;80(4):630–41.CrossRefGoogle Scholar
  29. 29.
    Grover A, Frassetto LA, Benet LZ, Chakkera HA. Pharmacokinetic differences corroborate observed low tacrolimus dosage in native American renal transplant patients. Drug metabolism and disposition: the biological fate of chemicals. 2011;39(11):2017–9.CrossRefGoogle Scholar
  30. 30.
    Sam WJ, Tham LS, Holmes MJ, Aw M, Quak SH, Lee KH, et al. Population pharmacokinetics of tacrolimus in whole blood and plasma in asian liver transplant patients. Clin Pharmacokinet. 2006;45(1):59–75.CrossRefGoogle Scholar
  31. 31.
    Zhang HJ, Li DY, Zhu HJ, Fang Y, Liu TS. Tacrolimus population pharmacokinetics according to CYP3A5 genotype and clinical factors in Chinese adult kidney transplant recipients. J Clin Pharm Ther. 2017;42(4):425–32.CrossRefGoogle Scholar
  32. 32.
    Sam WJ, Aw M, Quak SH, Lim SM, Charles BG, Chan SY, et al. Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients. Br J Clin Pharmacol. 2000;50(6):531–41.CrossRefGoogle Scholar
  33. 33.
    Lindbom L, Pihlgren P, Jonsson EN. PsN-toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Prog Biomed. 2005;79(3):241–57.CrossRefGoogle Scholar
  34. 34.
    Comets E, Brendel K, Mentre F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Prog Biomed. 2008;90(2):154–66.CrossRefGoogle Scholar
  35. 35.
    Scholten EM, Cremers SC, Schoemaker RC, Rowshani AT, van Kan EJ, den Hartigh J, et al. AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. Kidney Int. 2005;67(6):2440–7.CrossRefGoogle Scholar
  36. 36.
    Benkali K, Rostaing L, Premaud A, Woillard JB, Saint-Marcoux F, Urien S, et al. Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in renal transplant recipients on a new once-daily formulation. Clin Pharmacokinet. 2010;49(10):683–92.CrossRefGoogle Scholar
  37. 37.
    Larriba J, Imperiali N, Groppa R, Giordani C, Algranatti S, Redal MA. Pharmacogenetics of immunosuppressant polymorphism of CYP3A5 in renal transplant recipients. Transplant Proc. 2010;42(1):257–9.CrossRefGoogle Scholar
  38. 38.
    Han N, Yun HY, Hong JY, Kim IW, Ji E, Hong SH, et al. Prediction of the tacrolimus population pharmacokinetic parameters according to CYP3A5 genotype and clinical factors using NONMEM in adult kidney transplant recipients. Eur J Clin Pharmacol. 2013;69(1):53–63.CrossRefGoogle Scholar
  39. 39.
    Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev. 2002;23(5):687–702.CrossRefGoogle Scholar
  40. 40.
    Andreu F, Colom H, Grinyo JM, Torras J, Cruzado JM, Lloberas N. Development of a population PK model of tacrolimus for adaptive dosage control in stable kidney transplant patients. Ther Drug Monit. 2015;37(2):246–55.CrossRefGoogle Scholar
  41. 41.
    Chen P, Li J, Li J, Deng R, Fu Q, Chen J, et al. Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients. J Clin Pharm Ther. 2017;42(1):93–7.CrossRefGoogle Scholar
  42. 42.
    Hendijani F, Azarpira N, Kaviani M. Effect of CYP3A5*1 expression on tacrolimus required dose for transplant pediatrics: a systematic review and meta-analysis. Pediatr Transplant. 2018;22:e13248.CrossRefGoogle Scholar
  43. 43.
    Qin XL, Chen X, Zhong GP, Fan XM, Wang Y, Xue XP, et al. Effect of tacrolimus on the pharmacokinetics of bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) and the potential roles of CYP3A and P-gp. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2014;21(5):766–72.CrossRefGoogle Scholar
  44. 44.
    Qin XL, Chen X, Wang Y, Xue XP, Wang Y, Li JL, et al. In vivo to in vitro effects of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on the CYP3A/P-glycoprotein-mediated absorption and metabolism of tacrolimus. Drug metabolism and disposition: the biological fate of chemicals. 2014;42(1):193–9.CrossRefGoogle Scholar
  45. 45.
    Jiang W, Wang X, Xu X, Kong L. Effect of Schisandra sphenanthera extract on the concentration of tacrolimus in the blood of liver transplant patients. Int J Clin Pharmacol Ther. 2010;48(3):224–9.CrossRefGoogle Scholar
  46. 46.
    Xin HW, Li Q, Wu XC, He Y, Yu AR, Xiong L, et al. Effects of Schisandra sphenanthera extract on the blood concentration of tacrolimus in renal transplant recipients. Eur J Clin Pharmacol. 2011;67(12):1309–11.CrossRefGoogle Scholar
  47. 47.
    Mu Y, Zhang J, Zhang S, Zhou HH, Toma D, Ren S, et al. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J Pharmacol Exp Ther. 2006;316(3):1369–77.CrossRefGoogle Scholar
  48. 48.
    Hao GX, Huang X, Zhang DF, Zheng Y, Shi HY. Li Y, et al. Population pharmacokinetics of tacrolimus in children with nephrotic syndrome. 2018;84(8):1748–56.Google Scholar
  49. 49.
    Malyszko J, Oberbauer R, Watschinger B. Anemia and erythrocytosis in patients after kidney transplantation. Transplant international : official journal of the European Society for Organ Transplantation. 2012;25(10):1013–23.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Tong Lu
    • 1
    • 2
  • Xu Zhu
    • 1
  • Shansen Xu
    • 1
  • Mingming Zhao
    • 1
  • Xueshi Huang
    • 3
  • Zhanyou Wang
    • 4
  • Limei Zhao
    • 1
    • 2
    Email author
  1. 1.Department of PharmacyShengjing Hospital of China Medical UniversityShenyangChina
  2. 2.School of Life Science and BiopharmaceuticsShenyang Pharmaceutical UniversityShenyangChina
  3. 3.College of Life and Health SciencesNortheastern UniversityShenyangChina
  4. 4.Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of educationChina Medical UniversityShenyangChina

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