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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 9, pp 1097–1106 | Cite as

A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure

  • Sami UllahEmail author
  • Peter Matzneller
  • Markus Zeitlinger
  • Uwe Fuhr
  • Max Taubert
Original Article

Abstract

Non-compartmental analysis of telavancin microdialysis data indicated a sustained exposure in soft tissues and that unbound plasma concentrations were underestimated in vitro. The objective of the present evaluation was to develop a population pharmacokinetic model of telavancin to describe its plasma protein binding, its distribution into muscle, and subcutaneous tissue and to predict pharmacokinetic/-dynamic target attainment (PTA). Total plasma concentrations and microdialysate concentrations (plasma, subcutaneous, and muscle tissue) were available up to 24 h (plasma microdialysate, up to 8 h) post-dose from eight healthy subjects after a single intravenous infusion of 10 mg/kg telavancin. Population pharmacokinetic modeling and simulations were performed using NONMEM. A two-compartment model with saturable protein binding best described plasma concentrations. Plasma unbound fractions at steady state were 23, 15, and 11% at 100, 50, and 10% of the maximum predicted concentrations respectively. Distribution into muscle and subcutaneous tissue was non-linear and described appropriately by one additional compartment each. Based on total plasma concentrations, predicted median (95% confidence interval) values of AUC/MIC (MIC 0.125 mg/L, clinical breakpoint for MRSA) at steady state were 4009 [3421–4619] with a PTA of 96 [78–100] %. The fAUC/MIC in muscle was 496 [227–1232] with a PTA of 100 [98–100] %. The %fT>MIC was approximately 100% in plasma and interstitial space fluid of muscle and subcutaneous tissues up to an MIC of 0.25 mg/L. The model provided a new hypothesis on telavancin plasma protein binding in vivo. Proposed pharmacodynamic targets in plasma and muscle are achieved with currently approved doses of 10 mg/kg daily.

Keywords

Telavancin Population pharmacokinetics Skin and soft tissue infections Probability of target attainment Saturable protein binding Methicillin-resistant Staphylococcus aureus 

Notes

Author contribution statement

PM and MZ conceived, designed, and conducted the clinical study. SU and MT developed population pharmacokinetic model and performed simulations. MZ and UF supervised the clinical study and population pharmacokinetic analysis respectively. SU wrote initial draft of the manuscript. All authors contributed in and agreed upon the final version of the manuscript.

Funding information

Financial support in the form of PhD scholarship of Sami Ullah from the Higher Education Commission, Pakistan, through the German Academic Exchange Service (DAAD) is highly acknowledged. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

210_2019_1647_MOESM1_ESM.pdf (754 kb)
ESM 1 (PDF 754 kb)

References

  1. Akaike H (1974) A new look at the statistical model identification. IEEE Trans Automat Contr 19:716–723.  https://doi.org/10.1109/TAC.1974.1100705 CrossRefGoogle Scholar
  2. Ambrose PG, Drusano GL, Craig WA (2012) In vivo activity of oritavancin in animal infection models and rationale for a new dosing regimen in humans. Clin Infect Dis 54:S220–S228.  https://doi.org/10.1093/cid/cis001 CrossRefGoogle Scholar
  3. Beer J, Wagner CC, Zeitlinger M (2009) Protein binding of antimicrobials: methods for quantification and for investigation of its impact on bacterial killing. AAPS J 11:1–12.  https://doi.org/10.1208/s12248-008-9072-1 CrossRefGoogle Scholar
  4. Brill MJE, Houwink API, Schmidt S, van Dongen EPA, Hazebroek EJ, van Ramshorst B, Deneer VH, Mouton JW, Knibbe CAJ (2014) Reduced subcutaneous tissue distribution of cefazolin in morbidly obese versus non-obese patients determined using clinical microdialysis. J Antimicrob Chemother 69:715–723.  https://doi.org/10.1093/jac/dkt444 CrossRefGoogle Scholar
  5. EUCAST (2014) Consultation on proposed EUCAST telavancin breakpoint changes. http://www.eucast.org/eucast_news/news_singleview/?tx_ttnews[tt_news]=114&cHash=edb6bd58f7a3d341fdc937a3f1679359Google Scholar
  6. Hegde SS, Reyes N, Wiens T, Vanasse N, Skinner R, McCullough J, Kaniga K, Pace J, Thomas R, Shaw JP, Obedencio G, Judice JK (2004) Pharmacodynamics of telavancin (TD-6424), a novel bactericidal agent, against gram-positive bacteria. Antimicrob Agents Chemother 48:3043–3050.  https://doi.org/10.1128/AAC.48.8.3043-3050.2004 CrossRefGoogle Scholar
  7. Higgins DL, Chang R, Debabov DV, Leung J, Wu T, Krause KM, Sandvik E, Hubbard JM, Kaniga K, Schmidt DE, Gao Q, Cass RT, Karr DE, Benton BM, Humphrey PP (2005) Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 49:1127–1134.  https://doi.org/10.1128/AAC.49.3.1127-1134.2005 CrossRefGoogle Scholar
  8. Kim A, Suecof LA, Sutherland CA, Gao L, Kuti JL, Nicolau DP (2008) In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers. Antimicrob Agents Chemother 52:3941–3946.  https://doi.org/10.1128/AAC.00589-08 CrossRefGoogle Scholar
  9. Krekels EHJ, van Hasselt JGC, Tibboel D, Danhof M, Knibbe CAJ (2011) Systematic evaluation of the descriptive and predictive performance of paediatric morphine population models. Pharm Res 28:797–811.  https://doi.org/10.1007/s11095-010-0333-1 CrossRefGoogle Scholar
  10. Lepak AJ, Zhao M, Andes DR (2017) Comparative pharmacodynamics of telavancin and vancomycin in the neutropenic murine thigh and lung infection models against Staphylococcus aureus. Antimicrob Agents Chemother 61:e00281–e00217.  https://doi.org/10.1128/AAC.00281-17 Google Scholar
  11. Lodise T, Patel N, Hedge S, et al (2010) Mouse thigh MRSA infection model data and mathematical modelling to determine telavancin dosing for complicated skin and skin structure infection trials. In: Eur Congr Clin Microbiol Infect Dis. Blackwell Publishing, ViennaGoogle Scholar
  12. Lodise TP, Butterfield JM, Hegde SS, Samara E, Barriere SL (2012) Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function. Antimicrob Agents Chemother 56:2062–2066.  https://doi.org/10.1128/AAC.00383-11 CrossRefGoogle Scholar
  13. Lodise TP, Gotfried M, Barriere S, Drusano GL (2008) Telavancin penetration into human epithelial lining fluid determined by population pharmacokinetic modeling and Monte Carlo simulation. Antimicrob Agents Chemother 52:2300–2304.  https://doi.org/10.1128/AAC.01110-07 CrossRefGoogle Scholar
  14. Matzneller P, Österreicher Z, Reiter B, Lackner E, Stimpfl T, Zeitlinger M (2016) Tissue pharmacokinetics of telavancin in healthy volunteers: a microdialysis study. J Antimicrob Chemother 71:3179–3184.  https://doi.org/10.1093/jac/dkw269 CrossRefGoogle Scholar
  15. Post TM, Freijer JI, Ploeger BA, Danhof M (2008) Extensions to the visual predictive check to facilitate model performance evaluation. J Pharmacokinet Pharmacodyn 35:185–202.  https://doi.org/10.1007/s10928-007-9081-1 CrossRefGoogle Scholar
  16. Samara E, Shaw J-P, Barriere SL, Wong SL, Worboys P (2012) Population pharmacokinetics of telavancin in healthy subjects and patients with infections. Antimicrob Agents Chemother 56:2067–2073.  https://doi.org/10.1128/AAC.05915-11 CrossRefGoogle Scholar
  17. Savic RM, Karlsson MO (2009) Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J 11:558–569.  https://doi.org/10.1208/s12248-009-9133-0 CrossRefGoogle Scholar
  18. Schaeftlein A, Minichmayr IK, Kloft C (2014) Population pharmacokinetics meets microdialysis: benefits, pitfalls and necessities of new analysis approaches for human microdialysis data. Eur J Pharm Sci 57:68–73.  https://doi.org/10.1016/j.ejps.2013.11.004 CrossRefGoogle Scholar
  19. Shaw JP, Seroogy J, Kaniga K, Higgins DL, Kitt M, Barriere S (2005) Pharmacokinetics, serum inhibitory and bactericidal activity, and safety of telavancin in healthy subjects. Antimicrob Agents Chemother 49:195–201.  https://doi.org/10.1128/AAC.49.1.195-201.2005 CrossRefGoogle Scholar
  20. Sun HK, Duchin K, Nightingale CH, Shaw JP, Seroogy J, Nicolau DP (2006) Tissue penetration of telavancin after intravenous administration in healthy subjects. Antimicrob Agents Chemother 50:788–790.  https://doi.org/10.1128/AAC.50.2.788-790.2006 CrossRefGoogle Scholar
  21. Theravance (2016) VIBATIV (telavancin) prescribing information. https://www.vibativ.com/pdf/PrescribingInformation.pdf
  22. Theravance (2008) Telavancin for the treatment of complicated skin and skin structure infections FDA briefing document for anti-infective drugs advisory committee meeting. https://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4394b2-01-FDA.pdf
  23. Tsuji BT, Leonard SN, Rhomberg PR, Jones RN, Rybak MJ (2008) Evaluation of daptomycin, telavancin, teicoplanin, and vancomycin activity in the presence of albumin or serum. Diagn Microbiol Infect Dis 60:441–444.  https://doi.org/10.1016/J.DIAGMICROBIO.2007.11.011 CrossRefGoogle Scholar
  24. Tunblad K, Hammarlund-Udenaes M, Jonsson EN (2004) An integrated model for the analysis of pharmacokinetic data from microdialysis experiments. Pharm Res 21:1698–1707.  https://doi.org/10.1023/B:PHAM.0000041468.00587.c6 CrossRefGoogle Scholar
  25. Wise R (1983) Protein binding of beta-lactams: the effects on activity and pharmacology particularly tissue penetration. II. Studies in man. J Antimicrob Chemother 12:105–118CrossRefGoogle Scholar
  26. Wong SL, Barriere SL, Kitt MM, Goldberg MR (2008) Multiple-dose pharmacokinetics of intravenous telavancin in healthy male and female subjects. J Antimicrob Chemother 62:780–783.  https://doi.org/10.1093/jac/dkn273 CrossRefGoogle Scholar
  27. Worboys PD, Wong SL, Barriere SL (2015) Pharmacokinetics of intravenous telavancin in healthy subjects with varying degrees of renal impairment. Eur J Clin Pharmacol 71:707–714.  https://doi.org/10.1007/s00228-015-1847-6 CrossRefGoogle Scholar
  28. Wright DFB, Duffull SB (2017) A general empirical model for renal drug handling in pharmacokinetic analyses. Br J Clin Pharmacol 83:1869–1872.  https://doi.org/10.1111/bcp.13306 CrossRefGoogle Scholar
  29. Zandvliet A, Copalu W, Schellens JHM et al (2006) Saturable binding of indisulam to plasma proteins and distribution to human erythrocytes. Drug Metab Dispos 34:1041–1046.  https://doi.org/10.1124/dmd.105.008326 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for PharmacologyUniversity of CologneCologneGermany
  2. 2.Department of Clinical PharmacologyMedical University of ViennaViennaAustria

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