Intrapulmonary pharmacokinetics and pharmacodynamics of meropenem.
The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered meropenem in healthy volunteers. Four doses of 0.5 g, 1.0 g or 2.0 g meropenem were administered intravenously to 20, 20 and 8 healthy adult subjects, respectively. Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Meropenem was measured in plasma, BAL fluid and alveolar cells (ACs) using a combined high pressure liquid chromatographic-mass spectrometric technique. Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. Cmax/MIC90 (where Cmax is the maximum plasma concentration and MIC90 is the minimum inhibitory concentration required to inhibit 90% of the pathogen), AUC/MIC90 (where AUC is the area under the curve for the mean concentration-time data), intrapulmonary drug exposure ratios and percent time above MIC90 during the dosing interval (%T > MIC90) were calculated for common respiratory pathogens with MIC90 values of 0.12-4 microg/mL. In the 0.5 g dose group, the Cmax (mean+/-S.D.), AUC(0-8 h) and half-life for plasma were, respectively, 25.8+/-5.8 microg/mL, 28.57 microg h/mL and 0.77 h; for ELF the values were 5.3+/-2.5 microg/mL, 12.27 microg h/mL and 1.51 h; and for ACs the values were 1.0+/-0.5 microg/mL, 4.30 microg h/mL and 2.61 h. In the 1.0 g dose group, the Cmax, AUC(0-8 h) and half-life for plasma were, respectively, 53.5+/-19.7 microg/mL, 55.49 microg h/mL and 1.31 h; for ELF the values were 7.7+/-3.1 microg/mL, 15.34 microg h/mL and 0.95 h; and for ACs the values were 5.0+/-3.4 microg/mL, 14.07 microg h/mL and 2.17 h. In the 2.0 g dose group, the Cmax, AUC(0-8 h) and half-life for plasma were, respectively 131.7+/-18.2 microg/mL, 156.7 microg h/mL and 0.89 h. The time above MIC in plasma ranged between 28% and 78% for the 0.5 g dose and between 45% and 100% for the 1.0 g and 2.0 g doses. In ELF, the time above MIC ranged from 18% to 100% for the 0.5 g dose and from 25% to 88% for the 1.0 g dose. In ACs, the time above MIC ranged from 0% to 100% for the 0.5 g dose and from 24% to 100% for the 1.0 g dose. Time above MIC in ELF and ACs for the 2.0 g dose was not calculated because of sample degradation. The prolonged T > MIC90 and high intrapulmonary drug concentrations following every 8 h administration of 0.5-2.0 g doses of meropenem are favourable for the treatment of common respiratory pathogens.
Conte
John E
JE
Department of Epidemiology & Biostatistics, Infectious Diseases Research Group, University of California at San Francisco, San Francisco, CA 94143-0919, USA. jconte1@itsa.ucsf.edu
Golden
Jeffrey A
JA
Kelley
Mary Grace
MG
Zurlinden
Elisabeth
E
D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008168:Lung / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D000077731:Meropenem; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D013845:Thienamycins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
D013845:Thienamycins; D000077731:Meropenem