Tobramycin exposure from active calcium sulfate bone graft substitute

BMC Clinical Pharmacology

Thierry Buclin³  Emanuel Gautier²  Chantal Csajka¹  Peter Wahl²  Françoise Livio³ 

[1] Department of Pharmaceutical Sciences, Clinical Pharmacy Unit, University of Geneva, Rue du Général- Dufour 24, Genève 4 1211, Switzerland;Department of Orthopedic Surgery, Cantonal Hospital, Fribourg, Switzerland;Division of Clinical Pharmacology, Biomedicine, Department of Laboratories, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland

关键词: Renal failure;    Pharmacokinetics;    Bone graft substitute;    Tobramycin;   

Others  :  860378
DOI  :  10.1186/2050-6511-15-12

 received in 2013-08-22, accepted in 2014-02-20,  发布年份 2014

【 摘 要 】

Background

Bone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T).

Methods

Nine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417).

Results

The patients were 52 +/− 20 years old, their mean body weight was 73 +/− 17 kg and their mean CLCr was 119 +/− 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively.

Conclusions

Osteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.

【 授权许可】

   
2014 Livio et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Nelson CL, McLaren SG, Skinner RA, Smeltzer MS, Thomas JR, Olsen KM: The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets. J Orthop Res 2002, 20:643-647.
• [2]Sterling GJ, Crawford S, Potter JH, Koerbin G, Crawford R: The Pharmacokinetics of Simplex-tobramycin bone cement. J Bone Joint Surg 2003, 85-B:646-649.
• [3]Beal SL, Sheiner LB, Boeckmann AJ: NONMEM Users Guides 1989–2006. Ellicott City, Maryland, USA: Eds Icon Development Solutions;
• [4]Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976, 16:31-41.
• [5]Wahl P, Livio F, Jacobi M, Gautier E, Buclin T: Systemic exposure to tobramycin after local antibiotic treatment with calcium sulfate as carrier material. Arch Orthop Trauma Surg 2011, 131:657-662.
• [6]Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH: Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother 1997, 39:677-686.
• [7]Burton ME, Shaw LM, Schentag JJ, Evans WE: Aminoglycosides. In Applied Pharmacokinetics and Pharmacodynamics – Principles of Therapeutic Drug Monitoring. 4th edition. Edited by Troy D, Hauber M, Remsberg C. Philadelphia: Lippincott Williams and Wilkins; 2006:285-327.
• [8]Wu IM, Marin EP, Kashgarian M, Brewster UC: A case of an acute kidney injury secondary to an implanted aminoglycoside. Kidney Int 2009, 75:1109-1112.