Conte John E, Golden Jeffrey A, Kelley Mary Grace, Zurlinden Elisabeth
Department of Epidemiology & Biostatistics, Infectious Diseases Research Group, University of California at San Francisco, San Francisco, CA 94143-0919, USA.
Int J Antimicrob Agents. 2005 Dec;26(6):449-56. doi: 10.1016/j.ijantimicag.2005.08.015. Epub 2005 Nov 8.
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.
本研究的目的是测定健康志愿者静脉注射美罗培南后的血浆和肺内药代动力学参数。分别向20名、20名和8名健康成年受试者静脉注射0.5 g、1.0 g或2.0 g的美罗培南，各为四剂。在最后一剂给药后进行标准化支气管镜检查和定时支气管肺泡灌洗（BAL）。在给药前和BAL时采集血液进行药物测定。采用高压液相色谱 - 质谱联用技术测定血浆、BAL液和肺泡细胞（ACs）中的美罗培南。采用非房室模型方法推导血浆、上皮衬液（ELF）和AC的药代动力学。对于MIC90值为0.12 - 4μg/mL的常见呼吸道病原体，计算Cmax/MIC90（其中Cmax是血浆最大浓度，MIC90是抑制90%病原体所需的最低抑菌浓度）、AUC/MIC90（其中AUC是平均浓度 - 时间数据的曲线下面积）、肺内药物暴露比和给药间隔期间高于MIC90的时间百分比（%T > MIC90）。在0.5 g剂量组中，血浆的Cmax（均值±标准差）、AUC(0 - 8 h)和半衰期分别为25.8±5.8μg/mL、28.57μg·h/mL和0.77 h；ELF的相应值为5.3±2.5μg/mL、12.27μg·h/mL和1.51 h；ACs的相应值为1.0±0.5μg/mL、4.30μg·h/mL和2.61 h。在1.0 g剂量组中，血浆的Cmax、AUC(0 - 8 h)和半衰期分别为53.5±19.7μg/mL、55.49μg·h/mL和1.31 h；ELF的相应值为7.7±3.1μg/mL、15.34μg·h/mL和0.95 h；ACs的相应值为5.0±3.4μg/mL。
