司帕沙星的药代动力学与药效学研究

Pharmacokinetic /pharmacodynamic study of sparfloxacin

目的研究司帕沙星的药代动力学/药效学结合模型(PK/PD),设计司帕沙星的临床最佳给药方案。方法用琼脂平板二倍稀释法测定司帕沙星对479株分离菌的最低抑菌浓度(MIC)值。在受试者中进行单次口服司帕沙星片0.1,0.2和0.3 g药代动力学研究,计算3种剂量给药后的AUC0-24 h/MIC的值。以AUC0-24 h/MIC≥125为靶值(肺炎链球菌为AUC0-24 h/MIC≥50),用蒙特卡洛模型进行1×104次模拟,每次重复都根据各自的概率分布以不同AUC0-24 h以及MIC值计算,将获得的累计反应分数(CFR)>90%作为最佳临床给药方案。结果0.1 g给药方案仅对沙门菌属的药效学CFR达90%以上;0.2 g给药方案对肺炎链球菌、不动杆菌和甲氧西林敏感的金黄色葡萄球菌(MSSA)的药效学CFR达90%以上,其它菌种均需口服0.3 g才能达到满意的临床疗效并能有效预防细菌耐药性产生,其中耐甲氧西林金黄色葡萄球菌(MRSA)引起的感染应加大用药剂量。结论对于沙门菌属引起的感染,仅需口服0.1 g;对肺炎链球菌、不动杆菌和MSSA引起的感染,口服0.2 g;其他细菌引起的感染用药0.3 g;而对于MRSA引起的感染应考虑,加大用药剂量,如0.4 g qd可能会获得满意的临床疗效。

Objective To optimize clinical dosage regimen of sparfloxa-cin through series of pharmacokinetic/pharmacodynamic （ PK/PD ） val-ues.Methods The minimum inhibitory concentration （ MIC ） of spar-floxacin to 479 isolated bacteria were measured by two -fold agar dilution method.To perform pharmacokinetic test after those healthy volunteers were given a single oral dose of 0.1 , 0.2 , 0.3 g of Sparfloxacin , respec-tively.Based on PK/PD theory, calculation of AUC0-24 h/MIC values af-ter three dosages were done.Estimated value of AUC 0-24 h/MIC≥125 was expected to be the target value （ for streptococcus pneumoniae AUC0-24 h/MIC≥50）.The Monte Carlo simulation was repeated 1 ×104 times, and the cumulative fraction of response （ CFR） value was calculat-ed according to the respective probability distributions and different AUC0-24 h/MIC and MIC values.The dosage achieving a CFR above 90 percent was recognized as the optimal dosage regimen.Results Given dose of 0.1 g, the pharmacodynamics value CFR was above 90%only to salmonella genera.Given dose of 0.2 g, the pharmacodynamics value CFR was above 90%to Nitrate negative bacillus, Streptococcus pneumoni-ae, Acinetobacter and Methicillin -sensitive Staphylococcus aureus （MSSA）.For other strains, oral dose of 0.3 g was needed to not only achieve satisfactory clinical curative effect but also effectively prevent the drug resistance.And for infections caused by Methicillin -resistant Staphylococcus aureus （MRSA）, enhanced drug dose should be considered to achieve satisfactory clinical efficacy.Conclusion For infection caused by salmonella genera, oral dose of 0.1 g was a appropriate dosage regimen.For infection caused by Nitrate negative bacillus, Strepto-coccus pneumoniae, Acinetobacter and MSSA, oral dose of 0.2 g was a proper dosage regimen.For infection caused by others, oral dosage regimen of 0.3 g could achieve the expected satisfactory clinical efficacy.And for infections caused by MRSA, an increasing dosage , such as 0.4 mg, could achieve satisfactory clinical curative effect.