Abstract
For the past 25 years, cyclosporine A(CyA) has played a pivotal role in transplant immunosuppressant therapy. From the availability of the 2 primary marketed formulations (Sandimmun® and Sandimmun Neoral®, Novartis), confusion has existed with regard to whether these two formulations are bioequivalent. Due to the underlying clinical relevance of this information, we therefore conducted a meta-analysis of all available comparative pharmacokinetic studies to assess whether the two different CyA formulations, Sandimmun® and Sandimmun Neoral®, can be considered bioequivalent. All clinical studies that compared the bioavailability of the 2 formulations in organ transplant recipients were considered for analysis. We searched computerised databases (Embase/Excerpta Medica and Medline/PubMed) from their inception to May 2010. Only studies with AUC values determined at 12 hours were considered for analysis. Relative bioavailability was calculated with 90% confidence intervals (CI) for Sandimmun® (test substance) versus Sandimmun Neoral® (reference substance) according to Schuirmann's Two One-sided Tests Procedure and the Classical Shortest CI. Homogeneity of data was tested using the χ2 test. Fifteen studies were considered for meta-analysis and none of these studies reported AUC values in the 80%–125% range required for the bioequivalence of two formulations. The overall bioavailability for Sandimmun® versus the microemulsion formulation Sandimmun Neoral® was 76%, with upper CI limits lower than 80% in some cases. Mean AUC values for Sandimmun® were significantly lower than those for Sandimmun Neoral® (p<0.01). This study demonstrates that the 2 main cyclosporine formulations, Sandimmun® and Sandimmun Neoral®, cannot be considered bioequivalent.