Single Dose and Steady-State Pharmacokinetic Profiles of Nifedipine GITS Tablets in Healthy Elderly and Young Volunteers

Abstract

The pharmacokinetics of a once-daily extended-release nifedipine formulation [Gastro-Intestinal Therapeutic System (GITS)] was studied in 23 young males and 24 elderly male and female volunteers, after single and multiple dosing of 60mg nifedipine GITS tablets once daily for 7 days, in an open nonrandomised study. Serial blood samples for plasma nifedipine levels were drawn on days I and 7, and the pharmacokinetic profiles of the elderly and young volunteers were compared after both single and multiple dosing.After a single dose the plasma nifedipine concentrations in the young and elderly were similar, but at steady-state after multiple dosing the plasma concentrations were slightly higher in the elderly than in the young volunteers. Nifedipine GITS displayed distinct extended-release properties, and it appears that dose reduction will not be required for otherwise healthy elderly subjects.Nifedipine GITS (Gastro-Intestinal Therapeutic System) is a new extended-release formulation currently undergoing clinical trials. The tablet consists of a coat, which has a laser-drilled delivery orifice in it, and two compartments within the coat, one containing an osmotic drug core, the other a polymer. The release mechanism involves an osmotically driven 'push-pull' process. As water is absorbed across the semipermeable, cellulosic membrane that surrounds the bilayer tablet, nifedipine particles become suspended in solution and are then 'pushed' into the intestinal tract as the osmotically active polymers expand (Murdoch & Brogden 1991). The nifedipine G ITS tablet is de-signed to provide a linear drug release at the beginning, followed by sustained release.Preliminary pharmacokinetic results of the GITS tablet in healthy volunteers show controlled release of nifedipine over a 24-hour period. The formulation has an oral bioavailability of 55 to 65% after a single dose and 75 to 85% at steady-state (Bittar 1989;Chung et al. 1987). After ingestion there is a 2-hour delay before nifedipine appears in the plasma, while hydration of the tablet occurs. Plasma nifedipine concentrations then plateau at approximately 6 hours after administration (Bittar 1989). Because of the design of the tablet, 'dose-dumping' does not occur, but food intake can increase the rate of absorption, without affecting bioavailabil-

Nifedipine concentration in maternal and umbilical cord blood after nifedipine gastrointestinal therapeutic system for tocolysis

“…Interval between last nifedipine GITS and delivery (hours) log U (micrograms/l) Previous studies with nifedipine GITS in nonpregnant healthy volunteers have shown wide interindividual variability of plasma drug concentrations. [6][7][8] Our own preliminary data under nonstandardised conditions confirmed this finding in pregnant women (n = 44, doses ranging from 30 through 170 mg/day, giving concentrations ranging from 2.1 through 208 micrograms/l). 10 The nonstandardised handling of the blood samples possibly accounting in this recent pilot study for such variability included coadministration with food, timing not from nifedipine steady state (ideally between 12 and 24 hours after the last dose), exposure of the samples to light before or after centrifugation, and no immediate centrifugation of the samples).…”

“…[6][7][8] In cardiovascular patients, therapeutic blood levels are 10-100 micrograms/l. 9 We observed wide variability in nifedipine concentrations above this range in women undergoing tocolysis with nifedipine GITS tablets £150 mg/day.…”

“…In healthy male volunteers receiving the nifedipine GITS tablet formulation, steady-state nifedipine concentrations are reached 5 days after dosing with 60 mg/day; the elimination half-life is 4.3 hours. [6][7][8] In cardiovascular patients, therapeutic blood levels are 10-100 micrograms/l. 9 We observed wide variability in nifedipine concentrations above this range in women undergoing tocolysis with nifedipine GITS tablets £150 mg/day.…”

Picture of the Month

“…Even in therapeutic doses, the time to peak plasma concentration is known to be highly variable, as late as 24 hours, and may be affected by other stomach contents. 5,6 In supratherapeutic ingestions, high levels of the drug may persist for several days.…”

The Nifedipine Gastrointestinal Therapeutic System (GITS)

“…Apparent nifedipine C max values (normalised to a 60mg daily dose) after With respect to age, no or only slight differences were found in nifedipine GITS pharmacokinetic parameters after single or multiple doses in young and elderly volunteers, and thus no dosage adjustment is apparently necessary. [26,43] Similarly, impaired renal function in patients does not appear to significantly affect the plasma concentrations of nifedipine even following multiple doses of the nifedipine GITS, and thus dosage adjustment seems unnecessary. [27] Food does not alter the bioavailability of this device ; however, an increase in the drug absorption rate with food has been reported.F'l Some fluctuations in plasma nifedipine concentrations are apparent during multiple dosage with the GITS, due perhaps, in part, to carry-over from the dose of the previous day.…”