In vivo verification of the in vitro release specification of a sustained release theophylline preparation

Especially in drugs with a narrow therapeutic range, "within product bioequivalence" i.e. "batch-to-batch bioequivalence" should be scrutinized. Therefore, pharmacokinetics and bioavailability of two batches at the upper and lower in vitro specification range as well as a batch representing the middle of the specification range was evaluated in an in vivo bioequivalence study. An open, randomized, 3-way crossover, multiple dose study in 18 healthy, male volunteers was selected for this purpose. Bioequivalence regarding rate (C-max ss; t75%C-max) and extent (AUC(ss)) of absorption could be established for both extreme batches at the lower and upper in vitro specification range. Additionally both batches proved to be bioequivalent compared to the batch in the middle of the in vitro specification range. As a result, reproducible concentration-time profiles can be guaranteed for all batches of this sustained release theophylline (CAS 58-55-9) preparation. Furthermore, pharmacokinetic characteristics of all three batches meet the quality criteria defined for sustained release theophylline preparations, guaranteeing optimal concentration/time profiles for the therapy of asthma.