Controlled-release hydrophilic tablets for individualized theophylline therapy

Directly compressible controlled-release (CR) theophylline tablet formulations with a non-zero-order drug release were prepared using various grades of Methocels. These tablet formulations were employed in the individualization of therapy with the aid of a pharmacokinetic simulation model developed with STELLA II computer software. In vitro drug release data were used to simulate plasma concentration-time (C,t) profiles based on a wide range of previously reported patient pharmacokinetic parameters (clearances of 2-5 L/hr and apparent volumes of distribution of 20-50 L). The simulations indicated that formulations containing low-viscosity Methocels (E4, K4, and K4CR) were suitable for individualizing theophylline therapy. Average steady-state concentrations were well within the therapeutic range of 10-20 micrograms/ml. High-viscosity polymers such as E10CR, K15, and K15CR yielded subtherapeutic concentrations and were deemed unsuitable. Thus, a pharmacokinetic simulation program capable of predicting in vivo C,t profiles (even though theophylline release occurred by a non-zero order) may be useful for individualizing theophylline therapy that involves CR formulations.