Predictors of sirolimus pharmacokinetic variability identified using a nonlinear mixed effects approach: a systematic review
Main Article Content
Keywords
anticancer, mmunosuppressant, nonlinear mixed-effects, population pharmacokinetics, sirolimus
Abstract
Several sirolimus (SRL) population pharmacokinetics (PopPK) were conducted to explain its pharmaco-kinetic variability, and the results varied across studies. Thus, we conducted a systematic review to sum-marize significant predictors influencing SRL pharmacokinetic variability. Moreover, discrepancies in model methodologies across studies were also reviewed and discussed. Four databases (PubMed, CINAHL Complete, Science Direct, and Scopus) were systematically searched. The PICO framework was used to identify eligible studies conducted in humans and employ a nonlinear-mixed effects strategy. Based on the inclusion and exclusion criteria, 20 studies were included. SRL pharmacokinetics were explained using 1- or 2-compartment models. Only one study assessed the model using an external approach, while the rest employed basic or advanced internal approaches. Significant covariates influencing SRL pharmacokinetics were bodyweight, age, CYP3A5 polymorphism, gender, BSA, height, cyclosporine dose or trough concen-tration, triglyceride, total cholesterol, hematocrit, albumin, aspartate aminotransferase, alanine amino-transferase, and total bilirubin. Of these, bodyweight, age, and CYP3A5 polymorphism were the three most identified significant predictors for SRL clearance. This review summarizes significant predictors to pre-dict SRL clearance, which can subsequently be used to individualize SRL maintenance dose. However, the PopPK model selected for such prediction should be based on the resemblance of population characteristics between the target population and those used to conduct the model. Moreover, the predictability of the models in the target population should be assessed before implementation in clinical practice.
References
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26. Golubović B, Vučićević K, Radivojević D, et al. Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients - population pharmaco-kinetic approach. J Med Biochem. 2019;38(3):323–31. https://doi.org/10.2478/jomb-2018-0030
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29. Cheng X, Zhao Y, Gu H, et al. The first study in pediatric: population pharmacokinetics of siro-limus and its application in Chinese children with immune cytopenia. Int J Immunopathol Pharmacol. 2020;34:2058738420934936. https://doi.org/10.1177/2058738420934936
30. Brendel K, Dartois C, Comets E, et al. Are pop-ulation pharmacokinetic and/or pharmaco-dynamic models adequately evaluated? Clin Pharmacokinet. 2007;46(3):221–34. https://doi.org/10.2165/00003088-200746030-00003
31. Kanji S, Hayes M, Ling A, et al. Reporting guidelines for clinical pharmacokinetic studies: the ClinPK statement. Clin Pharmacokinet. 2015;54(7):783–95. https://doi.org/10.1007/s40262-015-0236-8
32. Dartois C, Brendel K, Comets E, et al. Overview of model-building strategies in population PK/PD analyses: 2002–2004 literature survey. Br J Clin Pharmacol. 2007;64(5):603–12. https://doi.org/10.1111/j.1365-2125.2007.02975.x
33. Boni JP, Leister C, Bender G, et al. Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther. 2005;77(1):76–89.
34. Mizuno T, Fukuda T, Christians U, et al. Population pharmacokinetics of temsirolimus and sirolimus in children with recurrent solid tumours: a report from the Children’s oncology group. Br J Clin Pharmacol. 2017;83(5):1097–107. https://doi.org/10.1111/bcp.13181
35. Sabo AN, Jannier S, Becker G, et al. Sirolimus pharmacokinetics variability points to the rele-vance of therapeutic drug monitoring in pediatric oncology. Pharmaceutics. 2021;13(4):470. https://doi.org/10.3390/pharmaceutics13040470
36. Wang DD, Chen X, Xu H, et al. Initial dosage recom-mendation for sirolimus in children with tuberous sclerosis complex. Front Pharmacol. 2020;11:890. https://doi.org/10.3389/fphar.2020.00890
37. Wang M, Bao-ling D, Yin-jin Y, et al. Population pharmacokinetic characteristics of sirolimus in healthy Chinese subjects and renal transplant patients. Int J Clin Pharmacol Ther. 2016;54(6):433. https://doi.org/10.5414/cp202499
38. Boni JP, Zhou S, Burns J, et al. 552 POSTER inte-grated population pharmacokinetic analysis of tem-sirolimus in cancer patients following weekly IV treatments. Eur J Cancer Suppl. 2006;4(12):167–8. https://doi.org/10.1053/j.seminoncol.2009.10.009
39. Johnson EM, Zimmerman J, Duderstadt K, et al. A randomized, double-blind, placebo-controlled study of the safety, tolerance, and preliminary pharmacokinetics of ascending single doses of orally administered sirolimus (rapamycin) in sta-ble renal transplant recipients. Transplant Proc. 1996;28(2):987.
40. Benedetti MS, Whomsley R, Baltes EL. Differences in absorption, distribution, metab-olism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005;1(3):447–71. https://doi.org/10.1517/17425255.1.3.447
41. Weber DR, Leonard MB, Zemel BS. Body compo-sition analysis in the pediatric population. Pediatr Endocrinol Rev. 2012;10(1):130–9.
42. Zimmerman JJ, Harper D, Getsy J, et al. Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers. J Clin Pharmacol. 2003;43(10):1168–76. https://doi.org/10.1177/0091270003257227
43. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in phar-macokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32. https://doi.org/10.1146/annurev.pharmtox.48.113006.094708
44. Gibaldi M. Drug distribution in renal fail-ure. Am J Med. 1977;62(4):471–4. https://doi.org/10.1016/0002-9343(77)90399-0
45. Ahn JE, Birnbaum AK, Brundage RC. Inherent correlation between dose and clearance in thera-peutic drug monitoring settings: possible misinter-pretation in population pharmacokinetic analyses. J Pharmacokinet Pharmacodyn. 2005;32(5-6):703-18. https://doi.org/10.1007/s10928-005-0083-6
46. Staatz CE, Willis C, Taylor PJ, et al. Population pharmacokinetics of tacrolimus in adult kid-ney transplant recipients. Clin Pharmacol Ther. 2002;72(6):660-9.https://doi.org/10.1067/mcp.2002.129304
2. Rini BI. Temsirolimus, an inhibitor of mam-malian target of rapamycin. Clin Cancer Res. 2008;14(5):1286–90. https://doi.org/10.1158/1078-0432.CCR-07-4719
3. Stenton SB, Partovi N, Ensom MH. Sirolimus. Clin Pharmacokinet. 2005;44(8):769–86. https://doi.org/10.2165/00003088-200544080-00001
4. MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22:B101–B21. https://doi.org/10.1016/s0149-2918(00)89027-x
5. Mahalati K, Kahan BD. Clinical pharmacokinet-ics of sirolimus. Clin Pharmacokinet. 2001;40(8):573–85. https://doi.org/10.2165/00003088-200140080-00002
6. Yatscoff R. Pharmacokinetics of rapamycin. Transplant Proc. 1996;28(2):970–3.
7. Yatscoff R, LeGatt D, Keenan R, Chackowsky P. Blood distribution of rapamycin. Transplantation. 1993;56(5):1202–6. https://doi.org/10.1097/00007890-199311000-00029
8. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol. 1997;37(5):405–15. https://doi.org/10.1002/j.1552-4604.1997.tb04318.x
9. Shi HQ, Yang J, Zhang LQ, et al. The population pharmacokinetics of sirolimus and CYP3A5*3 polymorphism in Chinese renal transplant patients. Int J Clin Exp Med. 2016;9(3):5854–66. https://doi.org/10.1111/j.1365-2125.2009.03392.x
10. Fryer J, Yatscoff RW, Pascoe EA, et al. The rela-tionship of blood concentrations of rapamycin and cyclosporine to suppression of allograft rejection in a rabbit heterotopic heart transplant model. Transplantation. 1993;55(2):340–5. https://doi.org/10.1097/00007890-199302000-00021
11. Granger DK, Cromwell JW, Chen SC, et al. Prolongation of renal allograft survival in a large animal model by oral rapamycin monotherapy. Transplantation. 1995;59(2):183–6.
12. Kahan BD, Julian BA, Pescovitz MD, et al. Sirolimus reduces the incidence of acute rejec-tion episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: a phase II trial. Transplantation. 1999;68(10):1526–32. https://doi.org/10.1097/00007890-199911270-00016
13. Kahan BD, Podbielski J, Napoli KL, et al. Immunosuppressive effects and safety of a siroli-mus/cyclosporine combination regimen for renal transplantation. Transplantation. 1998;66(8):1040–6. https://doi.org/10.1097/00007890-199810270-00013
14. Kahan B, Napoli K, Kelly P, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant. 2000;14(2):97–109.https://doi.org/10.1034/j.1399-0012.2000.140201.x
15. Ferron GM, Mishina EV, Zimmerman JJ, et al. Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther. 1997;61(4):416–28. https://doi.org/10.1016/S0009-9236(97)90192-2
16. Ferron GM, Mishina EV, Jusko WJ, et al. Population pharmacokinetics of sirolimus. Clin Pharmacol Ther. 1998;63(4):494. https://doi.org/10.1111/j.1365-2125.2009.03392.x
17. Djebli N, Rousseau A, Hoizey G, et al. Sirolimus population pharmacokinetic/phar-macogenetic analysis and bayesian mod-elling in kidney transplant recipients. Clin Pharmacokinet. 2006;45(11):1135–48. https://doi.org/10.2165/00003088-200645110-00007
18. Sato E, Shimomura M, Masuda S, et al. Temporal decline in sirolimus elimination immediately after pancreatic islet transplantation. Drug Metab Pharmacokinet. 2006;21(6):492–500.
19. Zahir H, Keogh AM, Akhlaghi F. Apparent clear-ance of sirolimus in heart transplant recipients: impact of primary diagnosis and serum lipids. Ther Drug Monit. 2006;28(5):614–22. https://doi.org/10.1097/01.ftd.0000246765.05248.fa
20. Jiao Z, Shi XJ, Li ZD, et al. Population phar-macokinetics of sirolimus in de novo Chinese adult renal transplant patients. Br J Clin Pharmacol. 2009;68(1):47–60. https://doi.org/10.1111/j.1365-2125.2009.03392.x
21. Wu K, Cohen EE, House LK, et al. Nonlinear pop-ulation pharmacokinetics of sirolimus in patients with advanced cancer. CPT: Pharmacomet Syst Pharmacol. 2012;1(12):e17. https://doi.org/10.1038/psp.2012.18
22. Goyal RK, Han K, Wall DA, et al. Sirolimus phar-macokinetics in early postmyeloablative pediat-ric blood and marrow transplantation. Biol Blood Marrow Transplant. 2013;19(4):569–75. https://doi.org/10.1016/j.bbmt.2012.12.015
23. Emoto C, Fukuda T, Mizuno T, et al. Characterizing the developmental trajectory of sirolimus clear-ance in neonates and infants. CPT: Pharmacomet Syst Pharmacol. 2016;5(8):411–7. https://doi.org/10.1002/psp4.12096
24. Mizuno T, Emoto C, Fukuda T, et al. Model-based precision dosing of sirolimus in pediatric patients with vascular anomalies. Eur J Pharm Sci. 2017;109s:s124–s31. https://doi.org/10.1016/j.ejps.2017.05.037
25. Peng M, Zhao G, Li X, et al. Population pharmaco-kinetics of sirolimus in healthy Chinese subjects. Indian J Pharm Sci. 2018;80(2):291–7. https://doi.org/10.4172/pharmaceutical-sciences.1000357
26. Golubović B, Vučićević K, Radivojević D, et al. Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients - population pharmaco-kinetic approach. J Med Biochem. 2019;38(3):323–31. https://doi.org/10.2478/jomb-2018-0030
27. Wang D, Chen X, Li Z. Population pharmacoki-netics of sirolimus in pediatric patients with kapo-siform hemangioendothelioma: a retrospective study. Oncol Lett. 2019;18(3):2412–9. https://doi.org/10.3892/ol.2019.10562
28. Chen X, Wang DD, Xu H, et al. Initial dose recom-mendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on popula-tion pharmacokinetics and pharmacogenomics. J Int Med Res. 2020;48(8):300060520947627. https://doi.org/10.1177/0300060520947627
29. Cheng X, Zhao Y, Gu H, et al. The first study in pediatric: population pharmacokinetics of siro-limus and its application in Chinese children with immune cytopenia. Int J Immunopathol Pharmacol. 2020;34:2058738420934936. https://doi.org/10.1177/2058738420934936
30. Brendel K, Dartois C, Comets E, et al. Are pop-ulation pharmacokinetic and/or pharmaco-dynamic models adequately evaluated? Clin Pharmacokinet. 2007;46(3):221–34. https://doi.org/10.2165/00003088-200746030-00003
31. Kanji S, Hayes M, Ling A, et al. Reporting guidelines for clinical pharmacokinetic studies: the ClinPK statement. Clin Pharmacokinet. 2015;54(7):783–95. https://doi.org/10.1007/s40262-015-0236-8
32. Dartois C, Brendel K, Comets E, et al. Overview of model-building strategies in population PK/PD analyses: 2002–2004 literature survey. Br J Clin Pharmacol. 2007;64(5):603–12. https://doi.org/10.1111/j.1365-2125.2007.02975.x
33. Boni JP, Leister C, Bender G, et al. Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther. 2005;77(1):76–89.
34. Mizuno T, Fukuda T, Christians U, et al. Population pharmacokinetics of temsirolimus and sirolimus in children with recurrent solid tumours: a report from the Children’s oncology group. Br J Clin Pharmacol. 2017;83(5):1097–107. https://doi.org/10.1111/bcp.13181
35. Sabo AN, Jannier S, Becker G, et al. Sirolimus pharmacokinetics variability points to the rele-vance of therapeutic drug monitoring in pediatric oncology. Pharmaceutics. 2021;13(4):470. https://doi.org/10.3390/pharmaceutics13040470
36. Wang DD, Chen X, Xu H, et al. Initial dosage recom-mendation for sirolimus in children with tuberous sclerosis complex. Front Pharmacol. 2020;11:890. https://doi.org/10.3389/fphar.2020.00890
37. Wang M, Bao-ling D, Yin-jin Y, et al. Population pharmacokinetic characteristics of sirolimus in healthy Chinese subjects and renal transplant patients. Int J Clin Pharmacol Ther. 2016;54(6):433. https://doi.org/10.5414/cp202499
38. Boni JP, Zhou S, Burns J, et al. 552 POSTER inte-grated population pharmacokinetic analysis of tem-sirolimus in cancer patients following weekly IV treatments. Eur J Cancer Suppl. 2006;4(12):167–8. https://doi.org/10.1053/j.seminoncol.2009.10.009
39. Johnson EM, Zimmerman J, Duderstadt K, et al. A randomized, double-blind, placebo-controlled study of the safety, tolerance, and preliminary pharmacokinetics of ascending single doses of orally administered sirolimus (rapamycin) in sta-ble renal transplant recipients. Transplant Proc. 1996;28(2):987.
40. Benedetti MS, Whomsley R, Baltes EL. Differences in absorption, distribution, metab-olism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005;1(3):447–71. https://doi.org/10.1517/17425255.1.3.447
41. Weber DR, Leonard MB, Zemel BS. Body compo-sition analysis in the pediatric population. Pediatr Endocrinol Rev. 2012;10(1):130–9.
42. Zimmerman JJ, Harper D, Getsy J, et al. Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers. J Clin Pharmacol. 2003;43(10):1168–76. https://doi.org/10.1177/0091270003257227
43. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in phar-macokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32. https://doi.org/10.1146/annurev.pharmtox.48.113006.094708
44. Gibaldi M. Drug distribution in renal fail-ure. Am J Med. 1977;62(4):471–4. https://doi.org/10.1016/0002-9343(77)90399-0
45. Ahn JE, Birnbaum AK, Brundage RC. Inherent correlation between dose and clearance in thera-peutic drug monitoring settings: possible misinter-pretation in population pharmacokinetic analyses. J Pharmacokinet Pharmacodyn. 2005;32(5-6):703-18. https://doi.org/10.1007/s10928-005-0083-6
46. Staatz CE, Willis C, Taylor PJ, et al. Population pharmacokinetics of tacrolimus in adult kid-ney transplant recipients. Clin Pharmacol Ther. 2002;72(6):660-9.https://doi.org/10.1067/mcp.2002.129304
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Dec 09, 2022
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Methaneethorn, J., Art-arsa, P., Kosiyaporn, R., & Leelakanok, N. (2022). Predictors of sirolimus pharmacokinetic variability identified using a nonlinear mixed effects approach: a systematic review. Journal of Population Therapeutics and Clinical Pharmacology, 29(04), 11-29. https://doi.org/10.47750/jptcp.2022.940
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How to Cite
Methaneethorn, J., Art-arsa, P., Kosiyaporn, R., & Leelakanok, N. (2022). Predictors of sirolimus pharmacokinetic variability identified using a nonlinear mixed effects approach: a systematic review. Journal of Population Therapeutics and Clinical Pharmacology, 29(04), 11-29. https://doi.org/10.47750/jptcp.2022.940