A modified two-portion absorption model to describe double-peak absorption profiles of ranitidine.
BACKGROUND
The pharmacokinetics of oral drugs exhibiting double peaks cannot be adequately described by using conventional compartmental models.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Yin
Ophelia Q P
OQ
School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Tomlinson
Brian
B
Chow
Albert H L
AH
Chow
Moses S S
MS
D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001702:Biopharmaceutics; D003198:Computer Simulation; D006207:Half-Life; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D011899:Ranitidine / Q000493:pharmacokinetics*
D006635:Histamine H2 Antagonists; D011899:Ranitidine