OBSERVATION OF TIME-DEPENDENT AND VARIABLE SUBJECT KINETICS IN A NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYSTEM BIOEQUIVALENCY STUDY

Significant daily variability occurs in the bioavailability and peak p lasma concentrations of nifedipine given as an immediate-release (IR) oral dosage form, which is attributed to increased absorption or reduc ed presystemic metabolism in the morning. The nifedipine gastrointesti nal therapeutic system (GITS) is an oral osmotic delivery device that exhibits controlled-release properties within the gastrointestinal tra ct, and is designed to provide zero-order nifedipine release for nearl y a full day. Thus, nifedipine's chronopharmacokinetic properties migh t be observed following single-dose administration of a GITS formulati on by comparison of evening plasma concentrations with those of the fo llowing morning (e.g., 12 versus 24 h postdosing, respectively). Time- dependent and variable subject kinetics were assessed in a bioequivale ncy study conducted with 4 commercially available nifedipine GITS form ulations (2 lots of both 30 and 60 mg strengths obtained from the same manufacturer) given in single-dose fashion to 12 healthy subjects. As expected, mean C-max and AUC(0-t) values of the 60 mg doses were appr oximately double those of the 30 mg doses suggesting a linear dose ver sus concentration relationship; however, typical standards of bioequiv alence were not met because of large inter- and intrasubject variabili ty that is only partially explained by the relatively small number of study participants. This latter finding may have important ramificatio ns for others attempting to develop a bioequivalent product. Interesti ngly, mean plasma nifedipine concentrations increased up to 24 h post- dosing with each of the 4 lots tested. In individual kinetic profiles, t(max) was measured as 24 h (corresponding to about 8 AM) more than h alf the time (56%), consistent with previous chronopharmacokinetic fin dings. Alternatively, the results suggest that the location of the GIT S tablet in the gastrointestinal tract influences nifedipine bioavaila bility.