Atsushi Kambayashi1, Takehiko Yasuji2, Jennifer B Dressman3. 1. Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan; Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, D-60438 Frankfurt am Main, Germany. Electronic address: atsushi.kanbayashi@astellas.com. 2. Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan. 3. Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, D-60438 Frankfurt am Main, Germany.
Abstract
BACKGROUND: Precipitation of poorly soluble, weakly basic drugs upon entering the small intestine may lead to poor bioavailability. It would be useful to be able to predict the extent of in vivo precipitation so that formulation measures to counteract this problem can be taken. AIM: The aim of this research was to characterize the precipitation kinetics of two representative weak base drugs, dipyridamole and ketoconazole in vitro using a simplified transfer model approach, and to establish a predictive model for the total and dissolved concentrations in the small intestine after oral administration using in silico modeling and simulation. METHODS: A simplified transfer ("dumping") method based on the USP paddle apparatus was used to obtain the precipitation profiles of the two weak base drugs by adding a solution of the drug in 0.02N hydrochloric acid to FaSSIF-V2. The observed precipitation curves obtained with various initial concentrations were fitted to first order kinetics. An in silico pharmacokinetic model for weak base drugs with precipitation in the small intestine was designed using STELLA® software and coupled with the precipitation profiles in order to simulate the total and dissolved drug concentrations in the small intestinal lumen in the fasted state in humans. RESULTS: The predicted total and dissolved concentration curves in small intestine for the two weak base drugs were similar to the concentration profiles observed in vivo. The fraction precipitated of the drugs in the small intestine was also well predicted, although the precipitation of ketoconazole at higher initial concentrations was somewhat overestimated. A sensitivity analysis conducted on the simulation of the precipitation of the drugs indicated that a higher fraction precipitated when gastric emptying was faster and/or the concentration of the drug in the added solution was higher. CONCLUSION: The dumping method provides a useful screen for precipitation in the small intestine, especially in the context of early development.
BACKGROUND: Precipitation of poorly soluble, weakly basic drugs upon entering the small intestine may lead to poor bioavailability. It would be useful to be able to predict the extent of in vivo precipitation so that formulation measures to counteract this problem can be taken. AIM: The aim of this research was to characterize the precipitation kinetics of two representative weak base drugs, dipyridamole and ketoconazole in vitro using a simplified transfer model approach, and to establish a predictive model for the total and dissolved concentrations in the small intestine after oral administration using in silico modeling and simulation. METHODS: A simplified transfer ("dumping") method based on the USP paddle apparatus was used to obtain the precipitation profiles of the two weak base drugs by adding a solution of the drug in 0.02N hydrochloric acid to FaSSIF-V2. The observed precipitation curves obtained with various initial concentrations were fitted to first order kinetics. An in silico pharmacokinetic model for weak base drugs with precipitation in the small intestine was designed using STELLA® software and coupled with the precipitation profiles in order to simulate the total and dissolved drug concentrations in the small intestinal lumen in the fasted state in humans. RESULTS: The predicted total and dissolved concentration curves in small intestine for the two weak base drugs were similar to the concentration profiles observed in vivo. The fraction precipitated of the drugs in the small intestine was also well predicted, although the precipitation of ketoconazole at higher initial concentrations was somewhat overestimated. A sensitivity analysis conducted on the simulation of the precipitation of the drugs indicated that a higher fraction precipitated when gastric emptying was faster and/or the concentration of the drug in the added solution was higher. CONCLUSION: The dumping method provides a useful screen for precipitation in the small intestine, especially in the context of early development.