Yin Ophelia Q P, Tomlinson Brian, Chow Albert H L, Chow Moses S S
School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Clin Pharmacokinet. 2003;42(2):179-92. doi: 10.2165/00003088-200342020-00005.
The pharmacokinetics of oral drugs exhibiting double peaks cannot be adequately described by using conventional compartmental models.
To propose and evaluate a modified two-portion absorption model based on physiological and biopharmaceutical considerations to describe the double-peak concentration-time curve of ranitidine. MODEL DESIGN: The proposed model assumes that oral ranitidine is absorbed sequentially in two portions due to delayed gastric emptying, and thus includes a gut compartment in addition to the central and peripheral compartments.
Validation of the model was performed with respect to structural identifiability, parameter estimability and model applicability. Using initial estimates of parameters obtained from previous intravenous data, the model was used to fit oral ranitidine data from six subjects who manifested clear double-peak concentration-time profiles as well as from six subjects who showed irregular but apparent single-peak concentration-time curves.
Based on goodness-of-fit criteria, the model fitted well for both double-peak and single-peak concentration-time curves of ranitidine (for the two groups: weighted residual sum of squares, 0.044 +/- 0.027 and 0.054 +/- 0.036; correlation between observed and model predicted concentrations, 0.995 +/- 0.003 and 0.995 +/- 0.005). Simulation studies with concentrations generated with 10% normally distributed random error showed that all model fitted parameters had good accuracy and reasonable precision. The mean percentage bias ranged from -7.0 to 28.6%, and the coefficient of variance was within 30% for the majority of parameters compared with the theoretical values.
The modified two-portion absorption model may afford a useful approach to characterise the absorption phase and estimate pharmacokinetic parameters for drugs with two absorption peaks.
传统房室模型无法充分描述呈现双峰的口服药物的药代动力学。
基于生理学和生物药剂学考虑，提出并评估一种改良的两部分吸收模型，以描述雷尼替丁的双峰浓度-时间曲线。
所提出的模型假定，由于胃排空延迟，口服雷尼替丁分两部分依次吸收，因此除中央室和周边室外，还包括一个肠道室。
对该模型进行结构可识别性、参数可估计性和模型适用性方面的验证。利用先前静脉给药数据获得的参数初始估计值，该模型用于拟合6名呈现清晰双峰浓度-时间曲线的受试者以及6名呈现不规则但明显单峰浓度-时间曲线的受试者的口服雷尼替丁数据。
基于拟合优度标准，该模型对雷尼替丁的双峰和单峰浓度-时间曲线拟合良好（两组：加权残差平方和分别为0.044±0.027和0.054±0.036；观测浓度与模型预测浓度之间的相关性分别为0.995±0.003和0.995±0.005）。对具有10%正态分布随机误差的生成浓度进行的模拟研究表明，所有模型拟合参数具有良好的准确性和合理的精密度。与理论值相比，大多数参数的平均偏差百分比范围为-7.0%至28.6%，变异系数在30%以内。
改良的两部分吸收模型可能为表征吸收阶段和估计具有两个吸收峰的药物的药代动力学参数提供一种有用的方法。
