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Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys

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Abstract

Purpose

The objective of this study was to compare two different nebulizers: Eflow rapid® and Pari LC star® by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons.

Methods

Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization.

Results

Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC® star than with Eflow Rapid® nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC star® than the Eflow rapid® system.

Conclusions

A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC Star® than with the Eflow Rapid® system.

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Abbreviations

99m Tc-DTPA:

99m technetium-diethylene triamino pentaacetic acid

AUCELF :

Area under the ELF concentrations-time curve

BAL:

Broncho-alveolar lavage

C:

Central lung

CBA:

Colistin base activity

CF:

Cystic fibrosis

CMS:

Colistin methansulphonate

ELF:

Epithelial lining fluid

ET:

Extrathoracic

GDS:

Geometric standard deviation

HPLC:

High-performance liquid chromatography

IIV:

Inter-individual variability

IM:

Intramuscular

IOV:

Inter-occasion variability

IV:

Intravenous

LC-MS/MS:

Liquid chromatography coupled with tandem mass spectrometry

LLOQ:

Lower limit of quantification

MMAD:

Mass median aerodynamic diameter

NLME:

Non-linear mixed effects

OFV:

Objective function value

P:

Peripheral lung

PK:

Pharmacokinetics

ROIs:

Regions of interest

SC:

Subcutaneous

T:

Lung

TH:

Thoracic

VAP:

Ventilator-associated pneumonia

VPC:

Visual predictive checks

References

  1. Li J, Coulthard K, Milne R, Nation RL, Conway S, Peckham D, et al. Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis. J Antimicrob Chemother. 2003;52(6):987–92.

    Article  CAS  PubMed  Google Scholar 

  2. Marchetti F, Giglio L, Candusso M, Faraguna D, Assael BM. Early antibiotic treatment of pseudomonas aeruginosa colonisation in cystic fibrosis: a critical review of the literature. Eur J Clin Pharmacol. 2004;60(2):67–74.

    Article  CAS  PubMed  Google Scholar 

  3. Berlana D, Llop JM, Fort E, Badia MB, Jodar R. Use of colistin in the treatment of multiple-drug-resistant gram-negative infections. Am J Health Syst Pharm. 2005;62(1):39–47.

    CAS  PubMed  Google Scholar 

  4. Falagas ME, Kasiakou SK, Tsiodras S, Michalopoulos A. The use of intravenous and aerosolized polymyxins for the treatment of infections in critically ill patients: a review of the recent literature. Clin Med Res. 2006;4(2):138–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis. 2006;6(9):589–601.

    Article  CAS  PubMed  Google Scholar 

  6. Michalopoulos A, Kasiakou SK, Mastora Z, Rellos K, Kapaskelis AM, Falagas ME. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Crit Care. 2005;9(1):R53–59.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas ME. Inhaled colistin as adjunctive to intravenous colistin for the treatment of microbiologically documented VAP: a comparative cohort study. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2009.

  8. Michalopoulos A, Fotakis D, Virtzili S, Vletsas C, Raftopoulou S, Mastora Z, et al. Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant gram-negative bacteria: a prospective study. Respir Med. 2008;102(3):407–12.

    Article  PubMed  Google Scholar 

  9. Bergen PJ, Li J, Rayner CR, Nation RL. Colistin methanesulfonate is an inactive prodrug of colistin against pseudomonas aeruginosa. Antimicrob Agents Chemother. 2006;50(6):1953–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006;10(1):R27.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Geller DE. Aerosol antibiotics in cystic fibrosis. Respir Care. 2009;54(5):658–70.

    Article  PubMed  Google Scholar 

  12. Marchand S, Gobin P, Brillault J, Baptista S, Adier C, Olivier JC, et al. Aerosol therapy with colistin methanesulfonate: a biopharmaceutical issue illustrated in rats. Antimicrob Agents Chemother. 2010;54(9):3702–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Yapa SWS, Li J, Porter CJ, Nation RL, Patel K, McIntosh MP. Population pharmacokinetics of colistin methanesulfonate in rats: achieving sustained lung concentrations of colistin for targeting respiratory infections. Antimicrob Agents Chemother. 2013;57(10):5087–95.

    Article  CAS  Google Scholar 

  14. Michalopoulos AS. Aerosolized antibiotics: the past, present and future, with a special emphasis on inhaled colistin. Expert Opin Drug Deliv. 2012;9(5):493–5.

    Article  CAS  PubMed  Google Scholar 

  15. Dudley MN, Loutit J, Griffith DC. Aerosol antibiotics: considerations in pharmacological and clinical evaluation. Curr Opin Biotechnol. 2008;19(6):637–43.

    Article  CAS  PubMed  Google Scholar 

  16. Westerman EM, de Boer AH, Le Brun PP, Touw DJ, Frijlink HW, Heijerman HG. Dry powder inhalation of colistin sulphomethate in healthy volunteers: a pilot study. Int J Pharm. 2007;335(1–2):41–5.

    Article  CAS  PubMed  Google Scholar 

  17. Le Brun PP, de Boer AH, Mannes GP, de Fraiture DM, Brimicombe RW, Touw DJ, et al. Dry powder inhalation of antibiotics in cystic fibrosis therapy: part 2. Inhalation of a novel colistin dry powder formulation: a feasibility study in healthy volunteers and patients. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Pharm Chem Eng. 2002;54(1):25–32.

    Article  Google Scholar 

  18. Byrne NM, Keavey PM, Perry JD, Gould FK, Spencer DA. Comparison of lung deposition of colomycin using the HaloLite and the Pari LC Plus nebulisers in patients with cystic fibrosis. Arch Dis Child. 2003;88(8):715–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Ratjen F, Rietschel E, Kasel D, Schwiertz R, Starke K, Beier H, et al. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother. 2006;57(2):306–11.

    Article  CAS  PubMed  Google Scholar 

  20. Yapa SW, Li J, Patel K, Wilson JW, Dooley MJ, George J, Clark D, Poole S, Williams E, Porter CJ, Nation RL, McIntosh MP. Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: targeting advantage of inhalational administration. Antimicrob Agents Chemother. 2014.

  21. Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K. Evaluation of colistin as an agent against multi-resistant gram-negative bacteria. Int J Antimicrob Agents. 2005;25(1):11–25.

    Article  PubMed  Google Scholar 

  22. Li J, Nation RL. Comment on: pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother. 2006;58(1):222–3. author reply 223.

    Article  CAS  PubMed  Google Scholar 

  23. Chua HL, Collis GG, Newbury AM, Chan K, Bower GD, Sly PD, et al. The influence of age on aerosol deposition in children with cystic fibrosis. Eur Respir J. 1994;7(12):2185–91.

    Article  CAS  PubMed  Google Scholar 

  24. Kelly JT, Asgharian B, Wong BA. Inertial particle deposition in a monkey nasal mold compared with that in human nasal replicas. Inhal Toxicol. 2005;17(14):823–30.

    Article  CAS  PubMed  Google Scholar 

  25. Martonen TB, Katz IM, Musante CJ. A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies. Inhal Toxicol. 2001;13(4):307–24.

    Article  CAS  PubMed  Google Scholar 

  26. Patra AL. Comparative anatomy of mammalian respiratory tracts: the nasopharyngeal region and the tracheobronchial region. J Toxicol Environ Health. 1986;17(2–3):163–74.

    Article  CAS  PubMed  Google Scholar 

  27. Patra AL, Gooya A, Menache MG. A morphometric comparison of the nasopharyngeal airway of laboratory animals and humans. Anat Rec. 1986;215(1):42–50.

    Article  CAS  PubMed  Google Scholar 

  28. Albuquerque-Silva I, Vecellio L, Durand M, Avet J, Le Pennec D, de Monte M, et al. Particle deposition in a child respiratory tract model: in vivo regional deposition of fine and ultrafine aerosols in baboons. PLoS One. 2014;9(4):e95456.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Pitance L, Reychler G, Leal T, Reychler H, Liistro G, Montharu J, et al. Aerosol delivery to the lung is more efficient using an extension with a standard jet nebulizer than an open-vent jet nebulizer. J Aerosol Med Pulm Drug Deliv. 2013;26(4):208–14.

    Article  CAS  PubMed  Google Scholar 

  30. European Pharmacopoeia 8th Edition (8.5). Chapter 2.09.44: preparation for nebulization-characterization. Available from: http://online6edqmeu/ep805/[Website]. 2015.

  31. Dubus JC, Vecellio L, De Monte M, Fink JB, Grimbert D, Montharu J, et al. Aerosol deposition in neonatal ventilation. Pediatr Res. 2005;58(1):10–4.

    Article  PubMed  Google Scholar 

  32. Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, et al. Consistent global approach on reporting of colistin doses to promote safe and effective use. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014;58(1):139–41.

    Article  Google Scholar 

  33. Gagnadoux F, Diot P, Marchand S, Thompson R, Dieckman K, Lemarie E, et al. Pulmonary deposition of colistin aerosols in cystic fibrosis. Comparison of an ultrasonic nebulizer and a pneumatic nebulizer. Rev Mal Respir. 1996;13(1):55–60.

    CAS  PubMed  Google Scholar 

  34. Diot P, Gagnadoux F, Martin C, Ellataoui H, Furet Y, Breteau M, et al. Nebulization and anti-pseudomonas aeruginosa activity of colistin. Eur Respir J. 1997;10(9):1995–8.

    Article  CAS  PubMed  Google Scholar 

  35. Vecellio None L, Grimbert D, Becquemin MH, Boissinot E, Le Pape A, Lemarie E, et al. Validation of laser diffraction method as a substitute for cascade impaction in the European project for a nebulizer standard. J Aerosol Med Off J Int Soc Aerosol Med. 2001;14(1):107–14.

    Article  CAS  Google Scholar 

  36. Vecellio None L, Grimbert D, Bordenave J, Benoit G, Furet Y, Fauroux B, et al. Residual gravimetric method to measure nebulizer output. J Aerosol Med Off J Int Soc Aerosol Med. 2004;17(1):63–71.

    Article  Google Scholar 

  37. Pitcairn GR, Newman SP. Tissue attenuation corrections in gamma scintigraphy. J Aerosol Med Off J Int Soc Aerosol Med. 1997;10(3):187–98.

    Article  Google Scholar 

  38. Snell NJ, Ganderton D. Assessing lung deposition of inhaled medications. Consensus statement from a workshop of the British Association for Lung Research, held at the Institute of Biology, London, U.K. on 17 April 1998. Respir Med. 1999;93(2):123–33.

    Article  CAS  PubMed  Google Scholar 

  39. Ilowite JS, Gorvoy JD, Smaldone GC. Quantitative deposition of aerosolized gentamicin in cystic fibrosis. Am Rev Respir Dis. 1987;136(6):1445–9.

    Article  CAS  PubMed  Google Scholar 

  40. Gobin P, Lemaitre F, Marchand S, Couet W, Olivier JC. Assay of colistin and colistin methanesulfonate in plasma and urine by liquid chromatography tandem mass spectrometry (LC-MS/MS). Antimicrob Agents Chemother. 2010;54:1941–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34(5):711–26.

    Article  CAS  PubMed  Google Scholar 

  42. Boisson M, Jacobs M, Gregoire N, Gobin P, Marchand S, Couet W, et al. Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients. Antimicrob Agents Chemother. 2014;58(12):7331–9.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504.

    Article  CAS  PubMed  Google Scholar 

  44. Bulitta JB, Bingolbali A, Shin BS, Landersdorfer CB. Development of a new pre- and post-processing tool (SADAPT-TRAN) for nonlinear mixed-effects modeling in S-ADAPT. AAPS J. 2011;13(2):201–11.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.

    Book  Google Scholar 

  46. Karjagin J, Lefeuvre S, Oselin K, Kipper K, Marchand S, Tikkerberi A, et al. Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock. Clin Pharmacol Ther. 2008;83(3):452–9.

    Article  CAS  PubMed  Google Scholar 

  47. Dahyot-Fizelier C, Lefeuvre S, Laksiri L, Marchand S, Sawchuk RJ, Couet W, et al. Kinetics of imipenem distribution into the peritoneal fluid of patients with severe peritonitis studied by microdialysis. Clin Pharmacokinet. 2010;49(5):323–34.

    Article  CAS  PubMed  Google Scholar 

  48. Dahyot C, Marchand S, Bodin M, Debeane B, Mimoz O, Couet W. Application of basic pharmacokinetic concepts to analysis of microdialysis data: illustration with imipenem muscle distribution. Clin Pharmacokinet. 2008;47(3):181–9.

    Article  CAS  PubMed  Google Scholar 

  49. Marchand S, Dahyot C, Lamarche I, Mimoz O, Couet W. Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of noninfected rats. Antimicrob Agents Chemother. 2005;49(6):2356–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Marchand S, Forsell A, Chenel M, Comets E, Lamarche I, Couet W. Norfloxacin blood–brain barrier transport in rats is not affected by probenecid coadministration. Antimicrob Agents Chemother. 2006;50(1):371–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Lefeuvre S, Marchand S, Pariat C, Lamarche I, Couet W. Microdialysis study of imipenem distribution in the peritoneal fluid of rats with experimental acute pancreatitis. Antimicrob Agents Chemother. 2008;52(4):1516–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Dahyot-Fizelier C, Timofeev I, Marchand S, Hutchinson P, Debaene B, Menon D, et al. Brain microdialysis study of meropenem in two patients with acute brain injury. Antimicrob Agents Chemother. 2010;54(8):3502–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Dahyot-Fizelier C, Frasca D, Gregoire N, Adier C, Mimoz O, Debaene B, et al. Microdialysis study of cefotaxime cerebral distribution in patients with acute brain injury. Antimicrob Agents Chemother. 2013;57(6):2738–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Gontijo AV, Gregoire N, Lamarche I, Gobin P, Couet W, Marchand S. Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats. 2. Colistin. Antimicrob Agents Chemother. 2014.

  55. Gontijo AV, Brillault J, Gregoire N, Lamarche I, Gobin P, Couet W, et al. Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 1. Ciprofloxacin, Moxifloxacin, and Grepafloxacin. Antimicrob Agents Chemother. 2014;58(7):3942–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Hubert D, Leroy S, Nove-Josserand R, Murris-Espin M, Mely L, Dominique S, et al. Pharmacokinetics and safety of tobramycin administered by the PARI eFlow rapid nebulizer in cystic fibrosis. J Cyst Fibros. 2009;8(5):332–7.

    Article  CAS  PubMed  Google Scholar 

  57. Lu Q, Girardi C, Zhang M, Bouhemad B, Louchahi K, Petitjean O, et al. Nebulized and intravenous colistin in experimental pneumonia caused by pseudomonas aeruginosa. Intensive Care Med. 2010;36(7):1147–55.

    Article  CAS  PubMed  Google Scholar 

  58. Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O. Tissue concentrations: do we ever learn? J Antimicrob Chemother. 2008;61(2):235–7.

    Article  CAS  PubMed  Google Scholar 

  59. Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother. 2008;52(1):24–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K. Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate. J Antimicrob Chemother. 2004;53(5):837–40.

    Article  CAS  PubMed  Google Scholar 

  61. Marchand S, Lamarche I, Gobin P, Couet W. Dose-ranging pharmacokinetics of colistin methanesulphonate (CMS) and colistin in rats following single intravenous CMS doses. J Antimicrob Chemother. 2010;65(8):1753–8.

    Article  CAS  PubMed  Google Scholar 

  62. Couet W, Gregoire N, Gobin P, Saulnier PJ, Frasca D, Marchand S, et al. Pharmacokinetics of colistin and colistimethate sodium after a single 80-mg intravenous dose of CMS in young healthy volunteers. Clin Pharmacol Ther. 2011;89(6):875–9.

    Article  CAS  PubMed  Google Scholar 

  63. Dudhani RV, Turnidge JD, Coulthard K, Milne RW, Rayner CR, Li J, et al. Elucidation of pharmacokinetic/pharmacodynamic determinant of colistin activity against pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother. 2010;54(3):1117–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Georges Roseau for its technical assistance in this study.

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Authors and Affiliations

  1. INSERM U-1070, Pôle Biologie Santé, 1 Rue Georges Bonnet, TSA 51106, 86073, Poitiers Cedex 9, France

    Sandrine Marchand, Nicolas Grégoire, Patrice Gobin & William Couet

  2. Faculté de Médecine et de Pharmacie, Université de Poitiers, 6 rue de la Milétrie, 86073, Poitiers Cedex 9, France

    Sandrine Marchand, Nicolas Grégoire & William Couet

  3. Laboratoire de Toxicologie et de Pharmacocinétique, CHU de Poitiers, 2 rue de la Milétrie, 86000, Poitiers, France

    Sandrine Marchand, Patrice Gobin & William Couet

  4. Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden

    Salim Bouchene

  5. Centre d’Etude des Pathologies Respiratoires, INSERM UMR 1100/EA6305, Université de Tours, Faculté de Médecine, 10 Boulevard Tonnellé, 37032, Tours, France

    Michèle de Monte, Laurent Guilleminault, Jérôme Montharu, Maria Cabrera, Patrice Diot & Laurent Vecellio

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  1. Sandrine Marchand
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  2. Salim Bouchene
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  3. Michèle de Monte
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  5. Jérôme Montharu
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  6. Maria Cabrera
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  7. Nicolas Grégoire
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  8. Patrice Gobin
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  9. Patrice Diot
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  10. William Couet
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  11. Laurent Vecellio
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Correspondence to Sandrine Marchand.

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Marchand, S., Bouchene, S., de Monte, M. et al. Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys. Pharm Res 32, 3403–3414 (2015). https://doi.org/10.1007/s11095-015-1716-0

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