Introduction: Theophylline is used to prevent and treat wheezing, shortness of breath, and difficulty breathing caused by asthma, chronic bronchitis, emphesema, and other lung diseases. Immediate release oral theophylline preparations have a higher incidence of side effects due to its rapid absorption, short elimination half-life, and narrow therapeutic index. For these reasons, sustained-release formulations of theophylline are desirable.
It has been reported that theophylline ‘s rate of absorption (as measured by the absorption half-life) decreases along the GI tract, particularly when it is dosed into the colon.
Convolution methods that assume the same absorption rate along the GI tract over predict the theophylline absorption rate in the lower GI tract making it difficult to develop an in vitro-in vivo correlation (IVIVC). The objective of this study is to utilize the mechanistic ACAT™ model within GastroPlus to develop an IVIVC for theophylline.
Methods: A theophylline pharmacokinetic (PK) model that takes into account the absorption profile along the entire GI tract was developed using GastroPlus™ v7.0 (Simulations Plus, Inc.). Simulated theophylline plasma concentration-time profiles for different doses ranging from 125-500 mg with both intravenous (i.v.) dosing and immediate release (IR) tablets were compared with published plasma concentration-time profiles. Plasma concentration-time data after theophylline solution was released into the stomach, terminal ileum and ascending colon of the GI tract by a remote-controlled drug release system was also obtained from the literature4 and compared to simulated plasma concentration-time profiles for theophylline solution directly dosed to the different regions. In vitro release and plasma concentration-time profiles for a theophylline sustained-release dosage form were obtained from the literature5. Deconvolution of the in vivo release profile for the theophylline sustained-release dosage form, construction of a Levy Plot, formation of an IVIVC, and convolution were all performed within the IVIVCPlus™ Module of GastroPlus.
American Association of Pharmaceutical Scientists (AAPS), November 14-18, 2010, New Orleans, LA
By John I. Chung, Viera Lukacova, Michael B. Bolger, & Walter S. Woltosz