Clinical pharmacokinetics of nifedipine gastrointestinal therapeutic system. A controlled-release formulation of nifedipine.

The pharmacokinetics of nifedipine following intravenous administration can be represented by an open two-compartment model with a terminal elimination half-life of about two hours. Nifedipine is extensively biotransformed to inactive metabolites, and the total body clearance (450 to 700 ml/minute) is primarily due to hepatic metabolism. Nifedipine undergoes significant tissue distribution in that the steady-state volume of distribution (0.62 to 0.77 liter/kg) is more than twice the volume of distribution of the central compartment (0.25 to 0.29 liter/kg). Although nifedipine is almost completely absorbed from the gastrointestinal tract, oral bioavailability ranges from 45 to 68 percent because of first-pass metabolism. Nifedipine given three times daily shows no accumulation in plasma and no changes in pharmacokinetic behavior during a one-week study period. Pharmacokinetic studies on the gastrointestinal therapeutic system (GITS) show that the bioavailability of the GITS dosage form (relative to the capsule) is about 65 percent after a single dose, but increases to about 86 percent at steady-state because of residual absorption more than 24 hours after dosing. Linear pharmacokinetics are seen following administration of single oral doses of nifedipine GITS as indicated by dose-proportional increases in the area under the plasma drug concentration-time curve over the range of 30 to 180 mg. Administration of the GITS dosage form in the presence of food slightly increases the rate of drug absorption, but does not influence the extent of drug bioavailability. Dose-dumping has not been observed, even with dosing after a meal containing a high level of fat. The GITS tablets provide zero-order delivery of nifedipine, and drug absorption persists beyond the dosing interval of 24 hours. Thus, the GITS dosage form will permit once-a-day dosing and maintain the desired, constant plasma drug concentration with minimal fluctuation.