Observation of time-dependent and variable subject kinetics in a nifedipine gastrointestinal therapeutic system bioequivalency study

Abstract

Significant daily variability occurs in the bioavailability and peak plasma concentrations of nifedipine given as an immediate-release (IR) oral dosage form, which is attributed to increased absorption or reduced presystemic metabolism in the morning. The nifedipine gastrointestinal therapeutic system (GITS) is an oral osmotic delivery device that exhibits controlled-release properties within the gastrointestinal tract, and is designed to provide zero-order nifedipine release for nearly a full day. Thus, nifedipine's chronopharmacokinetic properties might be observed following single-dose administration of a GITS formulation by comparison of evening plasma concentrations with those of the following morning (e.g., 12 versus 24 h postdosing, respectively). Time-dependent and variable subject kinetics were assessed in a bioequivalency study conducted with 4 commercially available nifedipine GITS formulations (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 approximately double those of the 30 mg doses suggesting a linear dose versus concentration relationship; however, typical standards of bioequivalence were not met because of large inter- and intrasubject variability that is only partially explained by the relatively small number of study participants. This latter finding may have important ramifications for others attempting to develop a bioequivalent product. Interestingly, 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 half the time (56%), consistent with previous chronopharmacokinetic findings. Alternatively, the results suggest that the location of the GITS tablet in the gastrointestinal tract influences nifedipine bioavailability.