Development of A Mechanistic in vitro – in vivo Correlation for Theophylline

Conference: AAPS
Software: GastroPlus®
Division: Simulations Plus


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