Skip to main content
SpringerLink
Log in

Assessment of micafungin loading dosage regimens against Candida spp. in ICU patients by Monte Carlo simulations

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

To assess the efficacy of loading dose on micafungin by simulating different dosage regimens.

Methods

A published study of micafungin in ICU patients was employed to simulate nine different dosage regimens which were sorted out three groups in terms of three maintenance doses. Using pharmacokinetic parameters and pharmacodynamic data, 5000-subject Monte Carlo simulations were conducted to simulate concentration-time profiles of micafungin, calculate probabilities of target attainment (PTAs), and cumulative fractions of response (CFRs) in terms of AUC/MIC targets. PTAs were calculated using AUC/MIC cut-offs: 285 (Candida parapsilosis), 3000 (all Candida spp.), and 5000 (non-parapsilosis Candida spp.). PTA or CFR > 90% was considered optimal for a dosage regimen.

Results

The concentration-time profiles of micafungin-simulated dosage regimens were obtained. PTA values were over 90% while applying the loading dose in each group of regimens: for Candida albicans and Candida glabrata (AUC/MIC = 5000), all regimens with loading dose provided PTAs of ≥ 90% for MIC ≤ 0.008 mg/L. The PTAs (AUC/MIC = 3000) were over 90% for MIC ≤ 0.008 mg/L in any regimen. However, for MIC inferior to 0.016 mg/L, only loading dosage regimens provided PTAs exceeding 90%. For C. parapsilosis (AUC/MIC = 285), the maximum MIC of achieving a PTA ≥ 90% was 0.25 mg/L both in the regimens of B (150 mg maintenance dose) and C (200 mg maintenance dose) with loading dose. In addition, CFR of any regimen with loading dose was ≥ 90% against C. albicans and C. glabrata. None of the dosage regimens achieved an expected CFR against C. parapsilosis.

Conclusions

The dosage regimen of micafungin which had a loading dose of 1.5 times was more suitable for ICU patients infected by Candida spp.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Sobel JD (2015) Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of america. Clin Infect Dis 62(4):409

    Article  Google Scholar 

  2. Vincent J-L (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302(21):2323–2329

    Article  CAS  Google Scholar 

  3. Maesaki S, Hossain MA, Miyazaki Y, Tomono K, Tashiro T, Kohno S (2000) Efficacy of fk463, a (1,3)-beta -d-glucan synthase inhibitor, in disseminated azole-resistant Candida albicans infection in mice. Antimicrob Agents Chemother 44(6):1728–1730

    Article  CAS  Google Scholar 

  4. Katragkou A, Roilides E (2011) Best practice in treating infants and children with proven, probable or suspected invasive fungal infections. Curr Opin Infect Dis 24(3):225–229

    Article  CAS  Google Scholar 

  5. Maseda E, Grau S, Villagran MJ, Hernandez-Gancedo C, Lopez-Tofino A, Roberts JA et al (2014) Micafungin pharmacokinetic/pharmacodynamic adequacy for the treatment of invasive candidiasis in critically ill patients on continuous venovenous haemofiltration. J Antimicrob Chemother 69(6):1624–1632

    Article  CAS  Google Scholar 

  6. Pfaller MA, Diekema DJ, Ostrosky-Zeichner L, Rex JH, Alexander BD, Andes D et al (2008) Correlation of mic with outcome for candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive mic breakpoints. J Clin Microbiol 46(8):2620–2629

    Article  CAS  Google Scholar 

  7. Micafungin in drugbank. https://www.drugbank.ca/drugs/DB01141. Accessed 9 Nov 2019

  8. Tabata K, Katashima M, Kawamura A, Tanigawara Y, Sunagawa K (2006) Linear pharmacokinetics of micafungin and its active metabolites in Japanese pediatric patients with fungal infections. Biol Pharm Bull 29(8):1706–1711

    Article  CAS  Google Scholar 

  9. Glöckner A (2011) Treatment and prophylaxis of invasive candidiasis with anidulafungin, caspofungin and micafungin: review of the literature. Eur J Med Res 16(4):167–179

    Article  Google Scholar 

  10. Martial LC, Ter Heine R et al (2017) Population pharmacokinetic model and pharmacokinetic target attainment of micafungin in intensive care unit patients. Clin Pharmacokinet 56(10):1197–1206

    Article  CAS  Google Scholar 

  11. Hiemenz J, Cagnoni P, Simpson D, Devine S, Chao N, Keirns J, Lau W, Facklam D, Buell D (2005) Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant. Antimicrob Agents Chemother 49(4):1331–1336

    Article  CAS  Google Scholar 

  12. Sugawara T, Murakami N, Uetake N, Matsumoto S, Miyamori S, Okamoto R, Hiraki K (2014) Relationship between the effectiveness and dose of micafungin in the treatment of candidemia. Yakugaku Zasshi 134(3):433–438

    Article  CAS  Google Scholar 

  13. Gumbo T (2007) Impact of pharmacodynamics and pharmacokinetics on echinocandin dosing strategies. Curr Opin Infect Dis 20(6):587–591

    Article  CAS  Google Scholar 

  14. EUCAST (2013) Micafungin and Candida spp. Rational for the EUCAST Clinical Breakpoints, Version 1.0. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Rationale_documents/Micafungin_rationale_document_1_0_final.pdf. Accessed 17 Apr 2019

  15. Yamaguchi M, Kurokawa T, Ishiyama K, Aoki G, Ueda M, Matano S, Takami A, Yamazaki H, Sawazaki A, Yamauchi H, Yoshida T, Nakao S (2011) Efficacy and safety of micafungin as an empirical therapy for invasive fungal infections in patients with hematologic disorders: a multicenter, prospective study. Ann Hematol 90(10):1209–1217

    Article  CAS  Google Scholar 

  16. Ota Y, Tatsuno K, Okugawa S, Yanagimoto S, Kitazawa T, Fukushima A, Tsukada K, Koike K (2007) Relationship between the initial dose of micafungin and its efficacy in patients with candidemia. J Infect Chemother 13(4):208–212

    Article  CAS  Google Scholar 

  17. Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A (2010) In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother 54(6):2497–2506

    Article  CAS  Google Scholar 

  18. Andes D, Ambrose PG, Hammel JP, Van Wart SA, Iyer V, Reynolds DK et al (2011) Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. Antimicrob Agents Chemother 55(5):2113–2121

    Article  CAS  Google Scholar 

  19. Xu G, Zhu L, Ge T, Liao S, Li N, Qi F (2016) Pharmacokinetic/pharmacodynamic analysis of voriconazole against Candida spp. and aspergillus spp. in children, adolescents and adults by Monte Carlo simulation. Int J Antimicrob Agents 47(6):439–445

    Article  CAS  Google Scholar 

  20. Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL (2002) Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs. 19(4):355–358

  21. Zvada SP, Denti P, Sirgel FA, Chigutsa E, Hatherill M, Charalambous S, Mungofa S, Wiesner L, Simonsson US, Jindani A, Harrison T, McIlleron H (2014) Moxifloxacin population pharmacokinetics and model-based comparison of efficacy between moxifloxacin and ofloxacin in african patients. Antimicrob Agents Chemother 58(1):503–510

    Article  Google Scholar 

  22. Andes DR, Diekema DJ, Pfaller MA, Marchillo K, Bohrmueller J (2008) In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother 52(10):3497–3503

    Article  CAS  Google Scholar 

  23. Maseda E, Grau S, Luque S, Castillo-Mafla MP, Suárez-de-la-Rica A, Montero-Feijoo A, Salgado P, Gimenez MJ, García-Bernedo CA, Gilsanz F, Roberts JA (2018) Population pharmacokinetics/pharmacodynamics of micafungin against Candida species in obese, critically ill, and morbidly obese critically ill patients. Crit Care 22(1):94

    Article  Google Scholar 

  24. Heresi GP, Gerstmann DR, Reed MD, van den Anker JN, Blumer JL, Kovanda L, Keirns JJ, Buell DN, Kearns GL (2006) The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants. Pediatr Infect Dis J 25(12):1110–1115

    Article  Google Scholar 

  25. Keirns J, Sawamoto T, Holum M, Buell D, Wisemandle W, Alak A (2007) Steady-state pharmacokinetics of micafungin and voriconazole after separate and concomitant dosing in healthy adults. Antimicrob Agents Chemother 51(2):787–790

    Article  CAS  Google Scholar 

  26. Kauffman CA, Bustamante B, Chapman SW, Pappas PG (2007) Clinical practice guidelines for the management of sporotrichosis: 2007 update by the infectious diseases society of america. Clin Infect Dis 45(10):1255–1265

    Article  CAS  Google Scholar 

  27. Pfaller MA, Messer SA, Woosley LN, Jones RN, Castanheira M (2013) Echinocandin and triazole antifungal susceptibility profiles for clinical opportunistic yeast and mold isolates collected from 2010 to 2011: application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic and temporal trends of antifungal resistance. J Clin Microbiol 51(8):2571–2581

    Article  CAS  Google Scholar 

  28. Forrest GN, Weekes E, Johnson JK (2008) Increasing incidence of Candida parapsilosis candidemia with caspofungin usage. J Inf Secur 56(2):126–129

    Google Scholar 

  29. Honore PM, Bels DD, Gutierrez LB, Redant S, Attou R, Gallerani A et al (2018) Optimizing micafungin dosing in critically ill patients: what about extracorporeal therapies? Crit Care 22(1):289

    Article  Google Scholar 

  30. Wasmann RE, Muilwijk EW, Burger DM, Verweij PE, Knibbe CA, Brüggemann RJ (2018) Clinical pharmacokinetics and pharmacodynamics of micafungin. Clin Pharmacokinet 57(3):267–286

    Article  CAS  Google Scholar 

  31. Abdelkefi A, Ben Romdhane N, Kriaa A et al (2006) A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation. Bone Marrow Transplant 38(1):47–51

    Article  Google Scholar 

  32. European Medicines Agency (2012) Summary of product characteristics: mycamine. https://www.ema.europa.eu/en/documents/product-information/mycamine-epar-product-information_en.pdf. Accessed 22 May 2017

  33. Package Insert of Mycamine™ (micafungin sodium) For Injection. https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB01141.pdf?1265922795. Accessed 9 Nov 2019

Download references

Author information

Author notes

  1. Xiaoqing Lu, Gaoqi Xu and Lu Chen contributed equally to this work.

Authors and Affiliations

  1. Pharmaceutical College Tianjin Medical University, Tianjin, China

    Xiaoqing Lu, Lu Chen, Mengxue Li & Liqin Zhu

  2. Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Zhejiang, China

    Gaoqi Xu

  3. Department of Pharmacy, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang, China

    Gaoqi Xu

  4. Department of Pharmacy, Zhejiang Cancer Hospital, Zhejiang, China

    Gaoqi Xu

  5. Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Jingjing Fan

  6. Department of Pharmacy, Tianjin First Central Hospital, #24 Fukang Road, Nankai District, Tianjin, 300192, China

    Liqin Zhu

Authors
  1. Xiaoqing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gaoqi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingjing Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mengxue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liqin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Liqin Zhu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Statement on the human participants or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.”

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 1656 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, X., Xu, G., Chen, L. et al. Assessment of micafungin loading dosage regimens against Candida spp. in ICU patients by Monte Carlo simulations. Eur J Clin Pharmacol 76, 695–702 (2020). https://doi.org/10.1007/s00228-020-02840-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-020-02840-0

Keywords

Search

Navigation