LSS法估算COPD患者茶碱缓释片单用及联用加替沙星时稳态药-时曲线下面积

Area under curve of steady-state concentration of theophylline alone and combined with gatifloxacin in COPD patients by limited sampling strategy

目的用有限采样法(limited sampling strategy,LSS)估算慢性阻塞性肺疾病(COPD)患者单用茶碱缓释片及联用加替沙星时稳态药-时曲线下面积(AUCs0s^12)。方法测得16名COPD患者口服茶碱缓释片稳态时(单用及联用加替沙星)的血药浓度,以多元线性回归法建立(AUCs0s^12与不同时间点的血药浓度的关联数学模型,并用Jackknife法进行验证。结果单点预测时可以采用给药后2 h或4 h的血药浓度值预报药-时曲线下面积,单用茶碱回归方程为:AUCs0s^12=-3.01+11.15C2(R2=0.97,P<0.05)或AUCs0s^12=-1.34+10.91C4(R2=0.97,P<0.05)。联用加替沙星的回归方程:AUCs0s^12=3.14+10.27C2(R2=0.90,P<0.05)或AUCs0s^12=-9.68+11.74C4(R2=0.96,P<0.05)。二点预测可用给药后2 h及12 h的血药浓度值,单用茶碱回归方程为:AUCs0s^12=-0.28+8.47C2+3.18C12(R2=0.98,P<0.05)。联用加替沙星回归方程为:AUCs0s^12=5.74+3.64C2+8.54C12(R2=0.99,P<0.05)。结论考虑到给药后2 h为药物的达峰时间,推荐单点预测时用给药后2 h的血药浓度值;用2个浓度点进行预测采用给药后2、12 h的血药浓度值。

Objective To estimate steady-state theophylline area under curve （AUC0-12^ss） between 0 and 12 h which was taken alone or combined with gatifloxaein in COPD patients by limited sampling strategy. Methods Sixteen COPD patients were enrolled. The concentration of theophylline was determined after single use at first and then combined with gatifloxaein during the steady-state. Mathematic models to estimate AUC of theophylline correlated with various concentrations were established by multi-linear regression and validated by Jackknife approach. Results Model to predict AUC0-12^ss based on one sampling time （2 or 4 h） was recommended at one sampling point prediction. The regression equation was AUC0-12^ss = --3.01 ＋ 11.15 C2 （R^2 = 0.97, P〈0.05） or AUC0-12^ss = -- 1.34 ＋ 10.91 C4 （R^2 = 0. 97, P〈0. 05） for theophylline taken singly . The regression equation was AUC0-12^ss=3.14＋10.27 C2 （R^2 =0.90, P〈 0.05） or AUC0-12^ss=--9.68＋11.74 C4 （R^2 =0.96, P〈0.05） for theophylline combined with gatifloxacin. Models based on two sampling time （ 2 and 12 h） predicted accurately when two sampling concentrations were applied. The regression equation was AUC0-12^ss=--0. 28＋8.47 C2 ＋3. 18 C12 （R^2 =0.98, P〈0.05） for theophylline singly taken,and the regression equation was AUC0-12^ss=5.74＋3.64 C2 ＋8.54 C12 （R^2 =0.99, P〈0.05） for theophylline combined with gatifloxacin. Conclusion Considering the peak concentration, C2 is recommended to predict the AUC estimation by one point sampling. C2 and C12 are recommended when applying two point values for prediction.