Development of a Semi-mechanistic absorption model for explaining effect of food on itraconazole
Hyun-moon Back (1), Sung-woo Goo(1), Jihyun Jeon(1), Junyoung Kim(1), Nayoung Han(1), Hwi-yeol Yun* (1), Kwang-il Kwon* (1)
(1) College of Pharmacy, Chungnam National University, Korea
Objectives: Oral administration of drugs has several advantages over other administration routes including lack of pain, easy to administer, portability and so on [1]. However, it has certain limitations that can potentially be affected by many factors in gastrointestinal system. Consumption of food is one of the major factors that can affect GI system and consequently absorption of drug [2]. The aim of this study was to develop a mechanistic absorption model for explaining effect of food on itraconazole by food type and volume.
Methods: Itraconazole PK data was pooled from 4 clinical studies and used for model development. The studies included in total 144 healthy Koreans and had three different food conditions (Fasting condition, Korean meal type, Western meal type). Phoenix WinNonlin (ver.7.0, Pharsight) was used for noncompartmental analysis and NONMEM (ver.7.3, ICON) was used for developing mechanistic model. Model diagnostics was assessed by goodness of fit plot and model evaluation was done using visual predictive check.
Results: Multi-compartment model with two physiological & one systemic compartments for itraconazole and four physiological compartments for food consumption (Food calorie, Food volume) was successfully developed. Bioavailability of itraconazole was increased depending on amount of drinking water (150mL, 200mL) when taking drug and also changed by food type. Gastric emptying rate of itraconazole was decreased almost 58% after food consumption. Goodness of fit and visual predictive check plot of final model was adequate and acceptable.
Conclusions: A semi-mechanistic absorption model for explaining effect of food on itraconazole was successfully developed and acceptable parameters were obtained. With this final model, quantification of food effect by food volume and type on itraconazole is possible and can extrapolate to other drug as a basis of mechanistic absorption model.
References:
[1] Sastry S, Nyshadham J, Fix J, Recent technological advances in oral drug delivery – a review. Pharm Sci Technolo Today (2000) 3:138-145.
[2] Fleisher D, Li C, Zhou Y, Pao LH, Karim A. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications. Clin Pharmacokinet (1999) 36:233-254.
