The Pharmacokinetics of 2000 mg Ertapenem in Tuberculosis Patients [PublishAheadOfPrint]

Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis. Dose simulations in a hollow fiber infection model showed that 2000 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 is to confirm the pharmacokinetics of 2000 mg once daily in TB patients. Twelve TB patients received a single intravenous dose of 2000 mg ertapenem as 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post administration. Drug concentrations were measured using a validated LC-MS/MS assay. A large inter-individual variation in the pharmacokinetics of ertapenem was observed. The median (IQR) area under the plasma concentration-time curve to infinity (AUC (t=) (h*mg/l)) was 2032 (1751 – 2346) mg*h/L, the inter-compartmental clearance (CL₁₂) 1.941 (0.979 – 2.817) L/h and the volume of distribution in the central compartment (V₁) 1.514 (1.064 – 2.210) L. A more than dose-proportional increase in AUC was observed comparing the results to reported 1000 mg ertapenem in MDR-TB patients. Based on a minimal inhibitory concentration (MIC) of 1.0 mg/L, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of time (f40% T>MIC). In conclusion, this study shows that 2000 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.

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