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Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients

Zuur, M. A., Ghimire, S., Bolhuis, M. S., Wessels, A. M. A., van Altena, R., de Lange, W. C. M., Kosterink, J. G. W., Touw, D. J., van der Werf, T. S., Akkerman, O. W. & Alffenaar, J. W. C., May-2018, In : Antimicrobial Agents and Chemotherapy. 62, 5, 7 p., 02250.

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Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis. Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC(0-infinity)) was 2,032 (1,751 to 2,346) mg center dot h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than doseproportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T > MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T > MIC for most of the patients, and exploration in a phase 2 study can be advocated.

Original languageEnglish
Article number02250
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number5
Early online date12-Feb-2018
Publication statusPublished - May-2018

    Keywords

  • ertapenem, tuberculosis, pharmacokinetics, MIC, MYCOBACTERIUM-TUBERCULOSIS, RESISTANT TUBERCULOSIS, ANTIBACTERIAL, TOLERABILITY, CARBAPENEMS, VOLUNTEERS, MEROPENEM, SAFETY

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