J Clin Pharmacol
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PHARMACOKINETICS

The Pharmacokinetics of Taurolidine Metabolites in Healthy Volunteers

Li Gong, MD, PhD, Howard E. Greenberg, MD, MSE, MBA, FCP, James L. Perhach, PhD, FCP, Scott A. Waldman, MD, PhD, FCP and Walter K. Kraft, MD, MS

From the Department of Pharmacology and Experimental Therapeutics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Gong, Dr Greenberg, Dr Waldman, Dr Kraft), and Forest Research Institute, Jersey City, New Jersey (Dr Perhach).

Address for reprints: Walter K. Kraft, MD, MS, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South 10th Street, 1170 Main Building, Philadelphia, PA 19107; e-mail: walter.kraft{at}jefferson.edu.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. tmax generally occurred at the end of infusion for taurinamide, whereas that of taurultam was reached before completion of infusion. The taurolidine metabolite taurultam demonstrated a shorter half-life and lower systemic exposure than taurinamide. Shortening of infusion duration increased the Cmax and AUC of taurultam. Changes in infusion rate did not substantially change the pharmacokinetic parameters of taurinamide.

Key Words: Taurolidine • taurinamide • taurultam • pharmacokinetics • healthy volunteers

Taurolidine (TRD) is a small dimeric molecule with bactericidal properties against a broad spectrum of bacteria ranging from anaerobic to aerobic species.1-3 Tauroldine's mechanism of action as an antibiotic agent is associated with a chemical reaction between the active TRD metabolites, taurultam (TRT) and taurinamide (TRM), with the structures of bacterial wall.3-6 In addition, TRD exhibits the ability to neutralize bacterial endotoxins, exotoxins, and lipopolysaccharides.7-9 The most widespread clinical application of TRD at present is as a catheter lock solution to reduce the incidence of vascular access-associated bloodstream infections. Other clinical applications have included peritoneal lavage for prophylaxis against postoperational bacterial infections in patients with established peritonitis following elective colorectal surgeries and as an antiendotoxic agent in patients with systemic inflammatory response syndrome.2,3,10

Taurolidine has also been investigated extensively as an experimental antineoplastic agent in a few in vitro and in vivo studies.11-14 It appears to have a direct effect on various tumor cell lines with a consecutive inhibition in cell growth.12,15 Preclinical investigations have suggested activity against colon, ovarian, and prostate cancer, as well as melanoma and mesothelioma. Of significance, intraperitoneal and systemic application of TRD resulted in a reduction of intraperitoneal and extraperitoneal metastases in rodent models, suggesting utility as a chemopreventive agent against metastases.11,16 Indeed, prophylactic, intraoperative peritoneal lavage with TRD for the prevention of metastatic diseases has been successfully applied, whereas intravenous administration of the agent as the primary treatment of poorly managed malignancies has been currently investigated in clinical trials.17,18


Figure 1
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  		Figure 1. Disposition of taurolidine.

 
Despite administration to more than 13 000 patients, the pharmacokinetics of TRD metabolites have not been comprehensively characterized in humans. Taurolidine in aqueous solution undergoes rapid conversion to TRT, with smaller amounts of hydroxymethyltaurultam. Taurultam is subsequently converted to TRM (Figure 1).19,20 Because of these metabolic characteristics, the TRD metabolites are more important pharmacokinetic markers than the parent compound in studying its pharmacodynamic properties, including the antibacterial and antineoplastic repertoire. In this study, the pharmacokinetics of TRD metabolites were investigated in healthy volunteers following intravenous administration of TRD solution.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Healthy male or female subjects between the ages of 18 and 45 years, between 45 and 100 kg, and within 20% of ideal body weight range for body frame were eligible to participate in the present study. The use of prescription medications and tobacco were exclusion criteria. The study was approved by the Institutional Review Board of Thomas Jefferson University. All subjects gave written informed consent to participate prior to undergoing any study-related procedures.

Study Design
This was an open-labeled, 3-arm, single-dose, parallel study that compared the pharmacokinetics and safety of (1) 5.0 g taurolidine intravenous infusion over 2 hours, (2) 5.0 g taurolidine intravenous infusion over 1 hour, and (3) 5.0 g taurolidine intravenous infusion over 0.5 hours. Taurolidine was prepared as a 2% solution in 250 mL of water and 5% polyvinylpyrrolidone (Kollidon 17, BASF). Healthy volunteers underwent a screening visit within 3 weeks of drug administration. Each subject was admitted to the Clinical Pharmacology Research Unit of Thomas Jefferson University Hospital the day before each treatment. Following an overnight fast, they received 1 of 3 treatments. Clinical laboratory tests, electrocardiograms, and vital signs were performed at baseline and at specified intervals postdose. Twenty-four hours after each treatment, subjects were discharged from the unit.

Collection and Determination of Analyte Concentrations
Blood was drawn for TRT and TRM pharmacokinetics predose and at 5, 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, and 24 hours postdose. Time zero was the beginning of intravenous infusion. Blood samples were collected in sodium heparin-containing tubes and immediately (within 40 seconds) mixed with the derivatizing agent 9-fluorenylmethylchlorformate (FMOC-CI) in an acetonitrile and pseudoephedrine processing solution. Samples were incubated at room temperature between 30 and 45 minutes, followed by freezing at –20°C. Analysis was performed by Kansas City Analytical Services (Shawnee, Kan) using a validated high-performance liquid chromatography (HPLC) method. In addition to the precolumn derivatization, the method consisted of liquid-liquid extraction, gradient HPLC separation, and fluorescence detection using a 260-nm excitation/340-nm emission cutoff filter. The analytic range for TRT was 20 to 1000 µM and 20 to 900 µM for TRM. At the time of analysis, samples were thawed, combined with additional derivatizing reagent FMOC-CL, and respective TRT and TRM internal standards. The samples were allowed to react for 10 minutes, quenched with the addition of taurine, and extracted into an organic solvent. The extracts were reconstituted in mobile phase and subjected to reverse-phase HPLC using a 5-µm ODS column. The analytes were detected using fluorescence detection, and system calibration was accomplished by weighted linear least squares regression of the weight-normalized peak height ratio (analyte/internal standard) versus the nominal concentration of analyte. During validation, the correlation coefficient (r) was ≥0.995 for TRT and ≥0.997 for TRM, respectively. The precision for this assay was 1.3% to 15.95% coefficient of variation (CV) for TRT and 2.3% to 8.5% for TRM, respectively, whereas accuracy (percentage of recovery) was 94.9% to 116.3% for TRT and 102.1% to 114.6% for TRM.

Pharmacokinetic Analysis
The apparent clearance (CL) and volume of distribution (Vd) of TRD metabolites, TRT and TRM, following intravenous infusion of TRD, along with the terminal elimination rate constant ({lambda}z) and corresponding half-life (t1/2), maximum concentration (Cmax), time to maximum concentration (tmax), observed area under the curve (AUC0-24), and area under the curve extrapolated to infinity (AUC0-{infty}), were estimated based on whole-blood concentration (µg/mL) versus time (h) data using noncompartmental methods (WinNonlin 5.01 software; Pharsight, Mountain View, Calif).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Demographics
Eighteen healthy volunteers (16 men and 2 women) with a mean age of 30.7 years (range, 21-42) participated in the study. Ten subjects were black, 6 were white, 1 was Hispanic, and 1 subject was self-described as mixed race. Detailed demographic data are summarized in Table I. All subjects completed the study.


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  		Table I Demographic Characteristics of Research Subjects

 

Pharmacokinetics
The present study compared the pharmacokinetics of TRD metabolites over 3 different durations of intravenous infusion with parent compound TRD (Tables II, III; Figure 2). Data from a subject in the 1-hour infusion group who had his infusion rate decreased on account of infusional burning were not included in pharmacokinetic (PK) analysis. Estimated clearance and volume of distribution were calculated using the assumption of a 5-g dose of parent compound. The mean clearance (L/h) was 124.6 (SD, 35.7) for TRT and 16.5 (SD, 3.2) for TRM. The mean volume of distribution (L) was 252.9 (SD, 132.9) for TRT and 155.1 (SD, 32.5) for TRM. Each metabolite is proportional to parent on a molar basis but involves the liberation of water, so the clearance and volume of distribution presented are likely overestimates of actual values. The AUC and Cmax of TRT increased, and CL decreased with decreasing infusion time, suggesting a saturable elimination process. Taurinamide lacked such changes, and with the exception of tmax, pharmacokinetic parameters were comparable across different durations of infusion. Due to the limited number of time points during the first hour after the initiation of intravenous infusion, tmax values should be considered estimates. Maximum concentrations were reached sooner for TRT in the order of 0.5-hour infusion < 1-hour infusion < 2-hour infusion (P = .0017). The tmax for TRM occurred essentially at the end of infusion, whereas that of TRT appeared generally to be achieved before completing the infusion (P < .05).


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  		Table II Mean Pharmacokinetic Parameters of Taurultam

 

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  		Table III Mean Pharmacokinetic Parameters of Taurinamide

 

Figure 2
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  		Figure 2. Concentration time curves for taurultam (TRT) and taurinamide (TRM) following intravenous infusion of taurolidine. Time-concentration relationship of the taurolidine metabolites, taurultam and taurinamide, in 3 intravenous infusion groups. (A) 2-, 1-, and 0.5-hour infusion groups for taurultam and (B) 2-, 1-, and 0.5-hour infusion groups for taurinamide. All data are presented as mean ± SD.

 

Safety
Safety data on all subjects in the trial are reported. There were no serious adverse effects associated with the administration of taurolidine infusions. No hypotension was noted during drug infusion. All subjects noted burning at the infusion site. Five were graded as mild, 12 as moderate, and 1 subject in the 1-hour infusion rate group had severe burning that required a decrease in the rate of infusion. Seven subjects also described a numbness or soreness in the infusion arm or shoulder. Four episodes were ranked as mild and 3 as moderate. Infusion-related symptoms began within 1 minute of onset and generally ceased at the end of infusion. Four subjects had mild erythematous streaking at the site of the IV, which also resolved quickly after the end of infusion. Five subjects had facial flushing, of which 4 were mild and 1 was moderate. Four of the flushing episodes took place in the 0.5-hour infusion group and 1 in the 1-hour group. Other adverse events included single occurrences of headache, epistaxis, and nausea. There were no clinically significant abnormalities in vital signs, electrocardiograms, and clinical laboratory tests except 1 subject with a single elevated prothrombin time value felt to be possibly related to study drug.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Taurolidine was synthesized in the 1970s and was originally used as an antibiotic in the prophylactic treatment of intraperitoneal bacterial infections in patients with established peritonitis.1-3 The utility of taurolidine as an antitumor agent has been investigated extensively recently.17 Although intraoperative peritoneal lavage of TRD for prophylactic therapies either as an antibiotic or as an antitumor agent against metastatic diseases has been administered clinically, the pharmacokinetics of TRD metabolites after intravenous administration were not well established. Pharmacokinetic characterization of taurolidine metabolites had been hampered by the rapid in vivo conversion of TRT to TRM. Key to the present investigation was the development of a sensitive assay and careful attention to derivatizing samples immediately after collection.

Previous analytical studies on animal specimens revealed that TRD exists in equilibrium with TRT, which further reversibly converts to TRM and other degradation products (Figure 1).19,20 In a clinical investigation, Erb et al19 reported a biphasic elimination of TRT in a model-based analysis after intravenous (IV) administration of 1 g over 1 hour in 6 subjects using a different analytic method. Beta t1/2 was reported as 2.2 hours, and Vd was 162 ± 93 L, which is comparable to the findings reported here (Table II). In the present study, IV infusion of 5.0 g taurolidine resulted in a smaller AUC for TRT than for TRM and, conversely, a larger CL for the former than for the latter (Tables II, III). These findings demonstrate that TRT is an unstable and short-lived metabolite. Prior investigations revealed that the antibiotic action of TRD appeared to be related to the action of active metabolites methylol TRT and methylol TRM (Figure 1) on bacterial cell walls,2,21 whereas the antitumor activities were likely due to its proapoptotic and antiangiogenic effects on tumor cells.17,18 The present study did not include pharmacodynamic measures to define mechanisms of action of each metabolite.

Taurolidine not only acts as an antibacterial agent to suppress infection but also prevents the growth and spread of tumor cells. In oncology patients, IV infusions were reported of up to 20 g/d (1000 mL of 2% TRD), which were ~4 times more than that examined in the present study, and few clinically relevant drug adverse effects were observed.15,17,22 Antitumor activity has been noted preclinically at micromolar concentrations in many tumor cell lines.18 These concentrations were demonstrated for both metabolites in the present study. The PK parameters generated in this study will assist in the rational dose and infusion interval selection in future human clinical trials.

Finally, safety data reported here in healthy adults indicate that local reactions, including burning at the infusion site, numbness or soreness of the infusion arm, and erythematous streaking at the IV site, were the most common adverse effects associated with IV TRD administration. Systemic clinically relevant drug toxicities were minimal in this study, in accordance with the other prior clinical investigations related to the low toxicity of this agent.17

In summary, no serious adverse events occurred in IV administrations of 5 g TRD 2% solution in healthy subjects. Local irritation at infusion sites was observed, although all subjects completed the infusion. The TRD metabolite TRT demonstrated a shorter half-life and systemic exposure than TRM. Shortening of infusion duration increased the Cmax and AUC of TRT relative to that of TRM. Characterization of metabolite pharmacokinetics will assist in the further clinical development of TRD.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors thank Lisa A. Turner and Gene F. Ray of Kansas City Analytical Services Inc for the development of the analytic method.

Financial disclosure: This study was supported by Wallace Laboratories (Cranbury, NJ). Data analysis was supported by Geistlich Pharma (Wolhusen, Switzerland). Dr Gong is supported by National Institutes of Health training grant 5 T32 GM008562-11. Dr Waldman is the Samuel M. V. Hamilton Endowed Professor. Dr Perhach was an employee of Wallace Laboratories during the conduct of this study.

DOI: 10.1177/0091270007299929


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Browne MK, Leslie GB, Pfirrmann RW, Brodhuge H. The in vitro and in vivo activity of Taurolin against anaerobic pathogenic organisms. Surg Gynecol Obstet. 1977;145: 842-846.[Web of Science][Medline] [Order article via Infotrieve]

2. Knight BI, Skellern GG, Smail GA, et al. NMR studies and GC analysis of the antibacterial agent, taurolidine. J Pharm Sci. 1983;72: 705-707.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Browne MK. Pharmacological and clinical studies on Taurolin. In: Bruckner WL, Pfirrmann RW, eds. A New Concept in Antimicrobial Chemotherapy for Surgical Infection. Baltimore: Urban & Schwarzenberg; 1985: 51-63.

4. Browne MK. The treatment of peritonitis by an antiseptic—Taurolin. Pharmatherapeutica. 1981;2: 517-522.[Web of Science][Medline] [Order article via Infotrieve]

5. Blenkharn JJ. Sustained anti-adherence activity of taurolidine (Taurolin) and noxythiolin (Noxyflex S). J Pharmacol. 1988;40: 509-511.[Web of Science]

6. Gorman SP, McCafferty DF, Woolfson AD, Junes DS. Electron microscope observations of bacterial cell surface effects due to taurolidine treatment. Lett Appl Microbiol. 1987;4: 103-109.[Web of Science]

7. Monson JR, Ramsey PS, Donohue JH. Taurolidine inhibits tumor necrosis factor (TNF) toxicity: new evidence of TNF and endotoxin synergy. Eur J Surg Oncol. 1993;3: 226-231.

8. Watson RW, Redmond HP, McCarthy J, Bouchier-Hayes D. Taurolidine, an antilipopolysaccharide agent, has immunoregulatory properties that are mediated by amino acid taurine. J Leukoc Biol. 1995;58: 299-306.[Abstract]

9. Leithauser ML, Rob PM, Sack K. Pentoxifylline, cyclosporine A and taurolidine inhibit endotoxin-stimulated tumor necrosis factor-alpha production in rat mesangial cell cultures. Exp Nephrol. 1997;1: 100-104.

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11. Jacobi CA, Peter FJ, Wenger FA, et al. New therapeutic strategies to avoid intra- and extraperitoneal metastases during laparoscopy: results of a tumor model in the rat. Dig Surg. 1999;16: 393-399.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. McCourt M, Wang JH, Sookhai S, Redmond HP. Taurolidine inhibits tumor cell growth in vitro and in vivo. Ann Surg Oncol. 2000;7: 685-691.[Abstract]

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15. Da Costa ML, Redmond HP, Bouchier-Hayes DJ. Taurolidine improves survival by abrogating the accelerated development and proliferation of solid tumors and development of organ metastases from circulating tumor cells released following surgery. J Surg Res. 2001;101: 111-119.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

16. Braumann C, Ordemann J, Kilian M, et al. Local and systemic chemotherapy with taurolidine and taurolidine/heparin in colon cancer-bearing rats undergoing laparotomy. Clin Exp Metastasis. 2003;20: 387-394.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

17. Jacobi CA, Menenakosa C, Braumann C. Taurolidine: a new drug with anti-tumor and anti-angiogenic effects. Anti-Cancer Drugs. 2005;16: 917-921.[CrossRef][Medline] [Order article via Infotrieve]

18. Nici L, Monfils B, Calabresi P. The effects of taurolidine, a novel antineoplastic agent, on human malignant mesothelioma. Clin Cancer Res. 2004;10: 7655-7661.[Abstract/Free Full Text]

19. Erb F, Imbenotte M, Huvenne JP, et al. Structural investigation of a new organic antiseptic: taurolidine. Analytical study and application to identification and quantitation in biological fluids. Eur J Drug Metab Pharmacokinet. 1983;8: 163-173.[Web of Science]

20. Woolfson AD, Gorman SP, McCafferty DF, Jones DS. Assay procedures for Taurolin solutions using pre-column derivatisation and high-performance liquid chromatography with fluorescence detection. Int J Pharmaceutics. 1989;49: 135-140.[CrossRef]

21. Gorman SP, McCafferty DF, Woolfson AD, Junes DS. Electron microscope observations of bacterial cell surface effects due to taurolidine treatment. Lett Appl Microbiol. 1987;4: 103-109.[Web of Science]

22. Braumann C, Winkler G, Rogalla P, et al. Prevention of disease progression in a patient with a gastric cancer-recurrence: outcome after intravenous treatment with the novel antineoplastic agent taurolidine. World J Surg Oncol. 2006;4: 34-39.[CrossRef][Medline] [Order article via Infotrieve]
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