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Clinical Pharmacokinetics

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01-01-2021 | Antibiotic | Systematic Review

Can Population Pharmacokinetics of Antibiotics be Extrapolated? Implications of External Evaluations

Authors: Yu Cheng, Chen-yu Wang, Zi-ran Li, Yan Pan, Mao-bai Liu, Zheng Jiao

Published in: Clinical Pharmacokinetics | Issue 1/2021

Abstract

Background and objective

External evaluation is an important issue in the population pharmacokinetic analysis of antibiotics. The purpose of this review was to summarize the current approaches and status of external evaluations and discuss the implications of external evaluation results for the future individualization of dosing regimens.

Methods

We systematically searched the PubMed and EMBASE databases for external evaluation studies of population analysis and extracted the relevant information from these articles. A total of 32 studies were included in this review.

Results

Vancomycin was investigated in 17 (53.1%) articles and was the most studied drug. Other studied drugs included gentamicin, tobramycin, amikacin, amoxicillin, ceftaroline, meropenem, fluconazole, voriconazole, and rifampicin. Nine (28.1%) studies were prospective, and the sample size varied widely between studies. Thirteen (40.6%) studies evaluated the population pharmacokinetic models by systematically searching for previous studies. Seven (21.9%) studies were multicenter studies, and 27 (84.4%) adopted the sparse sampling strategy. Almost all external evaluation studies of antibiotics (93.8%) used metrics for prediction-based diagnostics, while relatively fewer studies were based on simulations (46.9%) and Bayesian forecasting (25.0%).

Conclusion

The results of external evaluations in previous studies revealed the poor extrapolation performance of existing models of prediction- and simulation-based diagnostics, whereas the posterior Bayesian method could improve predictive performance. There is an urgent need for the development of standards and guidelines for external evaluation studies.

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Vincent J-L, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–9. https://doi.org/10.1001/jama.2009.1754.CrossRefPubMed

Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498–509. https://doi.org/10.1016/s1473-3099(14)70036-2.CrossRefPubMedPubMedCentral

Mouton JW, Ambrose PG, Canton R, et al. Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resist Updates. 2011;14(2):107–17. https://doi.org/10.1016/j.drup.2011.02.005.CrossRef

Darwich AS, Ogungbenro K, Vinks AA, et al. Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future. Clin Pharmacol Ther. 2017;101(5):646–56. https://doi.org/10.1002/cpt.659.CrossRefPubMed

Hartmanshenn C, Scherholz M, Androulakis IP. Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine. J Pharmacokinet Pharmacodyn. 2016;43(5):481–504. https://doi.org/10.1007/s10928-016-9492-y.CrossRefPubMedPubMedCentral

Calvo E, Walko C, Dees EC, et al. Pharmacogenomics, pharmacokinetics, and pharmacodynamics in the era of targeted therapies. Am Soc Clin Oncol Educ Book. 2016;35:e175–84. https://doi.org/10.1200/edbk_159061.CrossRefPubMed

Neely M, Philippe M, Rushing T, et al. Accurately achieving target busulfan exposure in children and adolescents with very limited sampling and the BestDose software. Ther Drug Monit. 2016;38(3):332–42. https://doi.org/10.1097/ftd.0000000000000276.CrossRefPubMedPubMedCentral

Kantasiripitak W, Van Daele R, Gijsen M, et al. Software tools for model-informed precision dosing: how well do they satisfy the needs? Front Pharmacol. 2020;11:620. https://doi.org/10.3389/fphar.2020.00620.CrossRefPubMedPubMedCentral

Wicha SG, Kees MG, Solms A, et al. TDMx: a novel web-based open-access support tool for optimising antimicrobial dosing regimens in clinical routine. Int J Antimicrob Agents. 2015;45(4):442–4. https://doi.org/10.1016/j.ijantimicag.2014.12.010.CrossRefPubMed

10.

Gao YC, Jiao Z, Huang H, et al. Development of decision system for individualization of vancomycin dosage (in Chinese). Acta Pharm Sin. 2018;53(1):104–10. https://doi.org/10.16438/j.0513-4870.2017-0673.CrossRef

11.

Keizer RJ, Ter Heine R, Frymoyer A, et al. Model-informed precision dosing at the bedside: scientific challenges and opportunities. CPT Pharmacometrics Syst Pharmacol. 2018;7(12):785–7. https://doi.org/10.1002/psp4.12353.CrossRefPubMedPubMedCentral

12.

Sun H, Fadiran EO, Jones CD, et al. Population pharmacokinetics: a regulatory perspective. Clin Pharmacokinet. 1999;37(1):41–58. https://doi.org/10.2165/00003088-199937010-00003.CrossRefPubMed

13.

Ette EI, Williams PJ. Population pharmacokinetics II: estimation methods. Ann Pharmacother. 2004;38(11):1907–15. https://doi.org/10.1345/aph.1E259.CrossRefPubMed

14.

Sheiner LB, Ludden TM. Population pharmacokinetics/dynamics. Annu Rev Pharmacol Toxicol. 1992;32:185–209. https://doi.org/10.1146/annurev.pa.32.040192.001153.CrossRefPubMed

15.

de Velde F, Mouton JW, de Winter BCM, et al. Clinical applications of population pharmacokinetic models of antibiotics: challenges and perspectives. Pharmacol Res. 2018;134:280–8. https://doi.org/10.1016/j.phrs.2018.07.005.CrossRefPubMed

16.

Wang CH, Liu Y, Zhao SX, et al. Systematic research of vancomycin population pharmacokinetic models (in Chinese). Chin J Clin Pharmacol. 2020;36(3):354–6. https://doi.org/10.13699/j.cnki.1001-6821,2020.03.037.CrossRef

17.

US FDA. Population pharmacokinetics: guidance for industry (draft guidance). 2019. https://www.fda.gov/media/128793/download. Accessed Jul 2019.

18.

Brendel K, Dartois C, Comets E, et al. Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004. Clin Pharmacokinet. 2007;46(3):221–34. https://doi.org/10.2165/00003088-200746030-00003.CrossRefPubMedPubMedCentral

19.

Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. https://doi.org/10.1186/2046-4053-4-1.CrossRefPubMedPubMedCentral

20.

Jamsen KM, McLeay SC, Barras MA, et al. Reporting a population pharmacokinetic-pharmacodynamic study: a journal’s perspective. Clin Pharmacokinet. 2014;53(2):111–22. https://doi.org/10.1007/s40262-013-0114-1.CrossRefPubMed

21.

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.CrossRefPubMed

22.

Moons KGM, Kengne AP, Grobbee DE, et al. Risk prediction models: II. External validation, model updating, and impact assessment. Heart. 2012;98(9):691–8. https://doi.org/10.1136/heartjnl-2011-301247.CrossRefPubMed

23.

Zhang R, Chen M, Liu TT, et al. Comparison of the predictive performance between cystatin C and serum creatinine by vancomycin via a population pharmacokinetic models: a prospective study in a Chinese population. Eur J Drug Metab Pharmacokinet. 2020;45(1):135–49. https://doi.org/10.1007/s13318-019-00578-4.CrossRefPubMed

24.

Šíma M, Bakhouche H, Hartinger J, et al. Therapeutic drug monitoring of antibiotic agents: evaluation of predictive performance. Eur J Hosp Pharm. 2019;26(2):85–8. https://doi.org/10.1136/ejhpharm-2017-001396.CrossRefPubMed

25.

Guo T, van Hest RM, Roggeveen LF, et al. External evaluation of population pharmacokinetic models of vancomycin in large cohorts of intensive care unit patients. Antimicrob Agents Chemother. 2019;63(5):e02543-18. https://doi.org/10.1128/AAC.02543-18.CrossRefPubMedPubMedCentral

26.

Broeker A, Nardecchia M, Klinker KP, et al. Towards precision dosing of vancomycin: a systematic evaluation of pharmacometric models for Bayesian forecasting. Clin Microbiol Infect. 2019;25(10):1286.e1–7. https://doi.org/10.1016/j.cmi.2019.02.029.CrossRef

27.

Kimura H, Shigematsu M, Tanaka A, et al. Predictive performance of vancomycin trough concentrations in patients with diabetes with microalbuminuria. Ther Drug Monit. 2017;39(6):614–6. https://doi.org/10.1097/ftd.0000000000000454.CrossRefPubMed

28.

Medellin-Garibay SE, Ortiz-Martin B, Rueda-Naharro A, et al. Pharmacokinetics of vancomycin and dosing recommendations for trauma patients. J Antimicrob Chemother. 2016;71(2):471–9. https://doi.org/10.1093/jac/dkv372.CrossRefPubMed

29.

Taghizadeh-Ghehi M, Rezaee S, Gholami K, et al. Predictive performance of Vancomycin population pharmacokinetic models in Iranian patients underwent hematopoietic stem cell transplantation. J Res Pharm Pract. 2015;4(3):129–34. https://doi.org/10.4103/2279-042X.162357.CrossRefPubMedPubMedCentral

30.

Stockmann C, Hersh AL, Roberts JK, et al. Predictive performance of a vancomycin population pharmacokinetic model in neonates. Infect Dis Ther. 2015;4(2):187–98. https://doi.org/10.1007/s40121-015-0067-9.CrossRefPubMedPubMedCentral

31.

Hahn A, Frenck RW Jr, Zou Y, et al. Validation of a pediatric population pharmacokinetic model for vancomycin. Ther Drug Monit. 2015;37(3):413–6. https://doi.org/10.1097/ftd.0000000000000153.CrossRefPubMedPubMedCentral

32.

Ng TM, Lye DC, Chan M, et al. Predictive performance of pharmacokinetic models for outpatients receiving vancomycin continuous infusion. Int J Antimicrob Agents. 2014;43(2):197–9. https://doi.org/10.1016/j.ijantimicag.2013.10.007.CrossRefPubMed

33.

Zhao W, Kaguelidou F, Biran V, et al. External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings. Br J Clin Pharmacol. 2013;75(4):1068–80. https://doi.org/10.1111/j.1365-2125.2012.04406.x.CrossRefPubMed

34.

Deng C, Liu T, Wu K, et al. Predictive performance of reported population pharmacokinetic models of vancomycin in Chinese adult patients. J Clin Pharm Ther. 2013;38(6):480–9. https://doi.org/10.1111/jcpt.12092.CrossRefPubMed

35.

Marsot A, Vialet R, Boulamery A, et al. Vancomycin: predictive performance of a population pharmacokinetic model and optimal dose in neonates and young infants. Clin Pharmacol Drug Dev. 2012;1(4):144–51. https://doi.org/10.1177/2160763X12456843.CrossRefPubMed

36.

Sanchez JL, Dominguez AR, Lane JR, et al. Population pharmacokinetics of vancomycin in adult and geriatric patients: comparison of eleven approaches. Int J Clin Pharmacol Ther. 2010;48(8):525–33. https://doi.org/10.5414/cpp48525.CrossRefPubMed

37.

Rushing TA, Ambrose PJ. Clinical application and evaluation of vancomycin dosing in adults. J Pharm Technol. 2001;17(2):33–8. https://doi.org/10.1177/875512250101700201.CrossRef

38.

Beringer PM, Wong-Beringer A, Rho JP. Predictive performance of a vancomycin-aminoglycoside population model. Ann Pharmacother. 1998;32(2):176–81. https://doi.org/10.1345/aph.17129.CrossRefPubMed

39.

Fernandez de Gatta MM, Fruns I, Dominguez-Gil A. Individualizing vancomycin dosing regimens: an evaluation of two pharmacokinetic dosing programs in critically ill patients. Pharmacotherapy. 1994;14(2):196–201.PubMed

40.

Ge S, Beechinor RJ, Hornik CP, et al. External evaluation of a gentamicin infant population pharmacokinetic model using data from a mational electronic health record database. Antimicrob Agents Chemother. 2018;62(9):e00669-18. https://doi.org/10.1128/aac.00669-18.CrossRefPubMedPubMedCentral

41.

Bukkems LH, Roger C, Hodiamont CJ, et al. Predictive performance of a gentamicin population pharmacokinetic model in two western populations of critically ill patients. Int J Antimicrob Agents. 2018;52(2):218–25. https://doi.org/10.1016/j.ijantimicag.2018.04.016.CrossRefPubMed

42.

Llanos-Paez CC, Staatz CE, Lawson R, et al. A population pharmacokinetic model of gentamicin in pediatric oncology patients to facilitate personalized dosing. Antimicrob Agents Chemother. 2017;61(8):e00205–17. https://doi.org/10.1128/aac.00205-17.CrossRefPubMedPubMedCentral

43.

Sampson MR, Frymoyer A, Rattray B, et al. Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia. Ther Drug Monit. 2014;36(5):584–9. https://doi.org/10.1097/ftd.0000000000000056.CrossRefPubMedPubMedCentral

44.

Alghanem S, Paterson I, Touw DJ, et al. Influence of multiple courses of therapy on aminoglycoside clearance in adult patients with cystic fibrosis. J Antimicrob Chemother. 2013;68(6):1338–47. https://doi.org/10.1093/jac/dkt035.CrossRefPubMed

45.

Wolowich WR, Steinberg JG. External validation of aminoglycoside models used in web calculators and clinical decision support systems after laboratory conversion to serum creatinine isotope dilution mass spectrometry assay. Clin Ther. 2012;34(4):803–10. https://doi.org/10.1016/j.clinthera.2012.02.005.CrossRefPubMed

46.

Burgard M, Sandaradura I, van Hal SJ, et al. Evaluation of tobramycin exposure predictions in three Bayesian forecasting programmes compared with current clinical practice in children and adults with cystic fibrosis. Clin Pharmacokinet. 2018;57(8):1017–27. https://doi.org/10.1007/s40262-017-0610-9.CrossRefPubMed

47.

Bloomfield C, Staatz CE, Unwin S, et al. Assessing predictive performance of published population pharmacokinetic models of intravenous tobramycin in pediatric patients. Antimicrob Agents Chemother. 2016;60(6):3407–14. https://doi.org/10.1128/aac.02654-15.CrossRefPubMedPubMedCentral

48.

Gauthier T, Lacarelle B, Marre F, et al. Predictive performance of two software packages (USC*PACK PC and Abbott PKS system) for the individualization of amikacin dosage in intensive care unit patients. Int J Biomed Comput. 1994;36(1–2):131–4. https://doi.org/10.1016/0020-7101(94)90104-x.CrossRefPubMed

49.

Tang BH, Wu YE, Kou C, et al. Population pharmacokinetics and dosing optimization of amoxicillin in neonates and young infants. Antimicrob Agents Chemother. 2019;63(2):e02336-18. https://doi.org/10.1128/AAC.02336-18.CrossRefPubMedPubMedCentral

50.

Van Wart SA, Forrest A, Khariton T, et al. Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community-acquired bacterial pneumonia. J Clin Pharmacol. 2013;53(11):1155–67. https://doi.org/10.1002/jcph.153.CrossRefPubMed

51.

Dhaese SAM, Farkas A, Colin P, et al. Population pharmacokinetics and evaluation of the predictive performance of pharmacokinetic models in critically ill patients receiving continuous infusion meropenem: a comparison of eight pharmacokinetic models. J Antimicrob Chemother. 2019;74(2):432–41. https://doi.org/10.1093/jac/dky434.CrossRefPubMed

52.

Hwang MF, Beechinor RJ, Wade KC, et al. External evaluation of two fluconazole infant population pharmacokinetic models. Antimicrob Agents Chemother. 2017;61(12):e01352-17. https://doi.org/10.1128/aac.01352-17.CrossRefPubMedPubMedCentral

53.

Farkas A, Daroczi G, Villasurda P, et al. Comparative evaluation of the predictive performances of three different structural population pharmacokinetic models to predict future voriconazole concentrations. Antimicrob Agents Chemother. 2016;60(11):6806–12. https://doi.org/10.1128/aac.00970-16.CrossRefPubMedPubMedCentral

54.

van Beek SW, ter Heine R, Keizer RJ, et al. Personalized tuberculosis treatment through model-informed dosing of rifampicin. Clin Pharmacokinet. 2019;58(6):815–26. https://doi.org/10.1007/s40262-018-00732-2.CrossRefPubMed

55.

Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82(1):17–20. https://doi.org/10.1038/sj.clpt.6100241.CrossRefPubMed

56.

Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm. 1981;9(4):503–12. https://doi.org/10.1007/bf01060893.CrossRefPubMed

57.

Zhao CY, Jiao Z, Mao JJ, et al. External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients. Br J Clin Pharmacol. 2016;81(5):891–907. https://doi.org/10.1111/bcp.12830.CrossRefPubMedPubMedCentral

58.

Hennig S, Holthouse F, Staatz CE. Comparing dosage adjustment methods for once-daily tobramycin in paediatric and adolescent patients with cystic fibrosis. Clin Pharmacokinet. 2015;54(4):409–21. https://doi.org/10.1007/s40262-014-0211-9.CrossRefPubMed

59.

Mould DR, D’Haens G, Upton RN. Clinical decision support tools: the evolution of a revolution. Clin Pharmacol Ther. 2016;99(4):405–18. https://doi.org/10.1002/cpt.334.CrossRefPubMed

60.

Purwonugroho TA, Chulavatnatol S, Preechagoon Y, et al. Population pharmacokinetics of vancomycin in Thai patients. ScientificWorldJournal. 2012;2012:762649. https://doi.org/10.1100/2012/762649.CrossRefPubMedPubMedCentral

61.

Bleeker SE, Moll HA, Steyerberg EW, et al. External validation is necessary in prediction research: a clinical example. J Clin Epidemiol. 2003;56(9):826–32. https://doi.org/10.1016/s0895-4356(03)00207-5.CrossRefPubMed

62.

Aljutayli A, Marsot A, Nekka F. An update on population pharmacokinetic analyses of vancomycin, part I: in adults. Clin Pharmacokinet. 2020;59(6):671–98. https://doi.org/10.1007/s40262-020-00866-2.CrossRefPubMed

63.

Standing JF. Understanding and applying pharmacometric modelling and simulation in clinical practice and research. Br J Clin Pharmacol. 2017;83(2):247–54. https://doi.org/10.1111/bcp.13119.CrossRefPubMed

64.

Duffull SB, Wright DF. What do we learn from repeated population analyses? Br J Clin Pharmacol. 2015;79(1):40–7. https://doi.org/10.1111/bcp.12233.CrossRefPubMed

65.

Aarons L, Ogungbenro K. Optimal design of pharmacokinetic studies. Basic Clin Pharmacol Toxicol. 2010;106(3):250–5. https://doi.org/10.1111/j.1742-7843.2009.00533.x.CrossRefPubMed

66.

Vergouwe Y, Steyerberg EW, Eijkemans MJC, et al. Substantial effective sample sizes were required for external validation studies of predictive logistic regression models. J Clin Epidemiol. 2005;58(5):475–83. https://doi.org/10.1016/j.jclinepi.2004.06.017.CrossRefPubMed

67.

Steyerberg EW, Borsboom GJJM, van Houwelingen HC, et al. Validation and updating of predictive logistic regression models: a study on sample size and shrinkage. Stat Med. 2004;23(16):2567–86. https://doi.org/10.1002/sim.1844.CrossRefPubMed

68.

Sheiner LB. NONMEM users guides: parts I–VII. NONMEM Project Group. San Francisco (CA): University of California, San Francisco; 1992.

69.

Prémaud A, Weber LT, Tönshoff B, et al. Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches. Pharmacol Res. 2011;63(3):216–24. https://doi.org/10.1016/j.phrs.2010.10.017.CrossRefPubMed

70.

Altman DG, Royston P. What do we mean by validating a prognostic model? Stat Med. 2000;19(4):453–73. https://doi.org/10.1002/(sici)1097-0258(20000229)19:4%3c453:aid-sim350%3e3.0.co;2-5.CrossRefPubMed

71.

Lamarre P, Lebel D, Ducharme MP. A population pharmacokinetic model for vancomycin in pediatric patients and its predictive value in a naive population. Antimicrob Agents Chemother. 2000;44(2):278–82. https://doi.org/10.1128/aac.44.2.278-282.2000.CrossRefPubMedPubMedCentral

72.

Piana C, Danhof M, Della Pasqua O. Influence of covariate distribution on the predictive performance of pharmacokinetic models in paediatric research. Br J Clin Pharmacol. 2014;78(1):145–57. https://doi.org/10.1111/bcp.12322.CrossRefPubMedPubMedCentral

73.

Donagher J, Barras MA. Therapeutic drug monitoring: using Bayesian methods to evaluate hospital practice. J Pharm Pract Res. 2018;48(6):522–9. https://doi.org/10.1002/jppr.1432.CrossRef

74.

Mao JJ, Jiao Z, Yun HY, et al. External evaluation of population pharmacokinetic models for ciclosporin in adult renal transplant recipients. Br J Clin Pharmacol. 2018;84(1):153–71. https://doi.org/10.1111/bcp.13431.CrossRefPubMed

75.

Cai X, Li R, Sheng C, et al. Systematic external evaluation of published population pharmacokinetic models for tacrolimus in adult liver transplant recipients. Eur J Pharm Sci. 2020;145:105237. https://doi.org/10.1016/j.ejps.2020.105237.CrossRefPubMed

76.

Donagher J, Martin JH, Barras MA. Individualised medicine: why we need Bayesian dosing. Intern Med J. 2017;47(5):593–600. https://doi.org/10.1111/imj.13412.CrossRefPubMed

77.

Tsamandouras N, Rostami-Hodjegan A, Aarons L. Combining the ‘bottom up’ and ‘top down’ approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data. Br J Clin Pharmacol. 2015;79(1):48–55. https://doi.org/10.1111/bcp.12234.CrossRefPubMed

78.

Upreti VV, Venkatakrishnan K. Model-based meta-analysis: optimizing research, development, and utilization of therapeutics using the totality of evidence. Clin Pharmacol Ther. 2019;106(5):981–92. https://doi.org/10.1002/cpt.1462.CrossRefPubMed

79.

Espié P, Tytgat D, Sargentini-Maier M-L, et al. Physiologically based pharmacokinetics (PBPK). Drug Metab Rev. 2009;41(3):391–407. https://doi.org/10.1080/10837450902891360.CrossRefPubMed

Title: Can Population Pharmacokinetics of Antibiotics be Extrapolated? Implications of External Evaluations
Authors: Yu Cheng
Chen-yu Wang
Zi-ran Li
Yan Pan
Mao-bai Liu
Zheng Jiao
Publication date: 01-01-2021
Publisher: Springer International Publishing
Keywords: Antibiotic
Vancomycin
Published in: Clinical Pharmacokinetics / Issue 1/2021
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-020-00937-4

At a glance: The STEP trials

Springer Medicine

Can Population Pharmacokinetics of Antibiotics be Extrapolated? Implications of External Evaluations

Abstract

Background and objective

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background and objective

Methods

Results

Conclusion

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