Ambrose Paul G, Meagher Alison K, Passarell Julie A, Van Wart Scott A, Cirincione Brenda B, Rubino Chris M, Korth-Bradley Joan M, Babinchak Timothy, Ellis-Grosse Evelyn
Institute for Clinical Pharmacodynamics, Ordway Research, Latham, NY, USA.
Diagn Microbiol Infect Dis. 2009 Jan;63(1):38-42. doi: 10.1016/j.diagmicrobio.2008.09.014.
Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value. Using a previously derived tigecycline population pharmacokinetic model and Monte Carlo simulation, a probability density function of steady-state area under the concentration-time curve for 24 h (AUC(SS(0-24))) values for 9999 patients was generated. AUC(SS(0-24)) values were divided by clinically relevant fixed MIC values to derive AUC(SS(0-24))/MIC ratios, which were used to calculate the clinical response expectation by MIC value based upon a logistic regression model for efficacy (1st approach). For the 2nd approach, the probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment was calculated as the proportion of patients with AUC(SS(0-24))/MIC ratios greater than the threshold value of 6.96, the PK-PD target associated with optimal clinical response. Probabilities of clinical response and PK-PD target attainment were poorly correlated at MIC values >0.25 mg/L. For instance, the median probability of clinical success was 0.76, whereas the probability of PK-PD target attainment was 0.27 at an MIC value of 1 mg/L, suggesting that the probability of PK-PD target attainment metrics underestimates the clinical performance of tigecycline at higher MIC values.
采用两种方法评估替加环素对肠杆菌科细菌的潜在敏感性断点，这两种方法在根据MIC值评估的概率性质上有所不同。利用先前推导的替加环素群体药代动力学模型和蒙特卡罗模拟，生成了9999例患者24小时稳态浓度-时间曲线下面积（AUC(SS(0 - 24))）值的概率密度函数。将AUC(SS(0 - 24))值除以临床相关的固定MIC值，得出AUC(SS(0 - 24))/MIC比值，这些比值用于基于疗效的逻辑回归模型，按MIC值计算临床反应期望值（第一种方法）。对于第二种方法，药代动力学-药效学（PK-PD）目标达成概率的计算方法为，AUC(SS(0 - 24))/MIC比值大于6.96阈值（与最佳临床反应相关的PK-PD目标）的患者比例。在MIC值>0.25 mg/L时，临床反应概率与PK-PD目标达成概率的相关性较差。例如，在MIC值为1 mg/L时，临床成功的中位概率为0.76，而PK-PD目标达成概率为0.27，这表明在较高MIC值时，PK-PD目标达成指标低估了替加环素的临床疗效。
