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-

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tolerance Granisetron (BRL 43694) is a potent 5-HT~ receptor antagonist which, at doses of 40 ggkg 1, is effective for the treatment of emesis induced by cytotoxic chemotherapeutic agents [1][2][3][4]. Preliminary examination of its pharmacokinetics in healthy young volunteers over the intravenous dose range 30-300 gg-kghas shown that granisetron is extensively distributed (Vz-~ 3 1. kg 1) and rapidly eliminated in most subjects, with a mean total plasma clearance (predominantly non-renal) of 30-50 1. h-1 and terminal phase half-life of about 5 h [5,6]. The present study was conducted to evaluate any difference in the pharmacokinetics of granisetron between young and elderly volunteers. Patients and methodsTwenty young adults [mean (range) age 29.5 (18 to 45) years, mean (range) weight 63.5 (49 to 82) kg] and twenty elderly adults aged above 65 years [where 50% were older than 70 years; mean age 71.1 years, mean (range) weight 63.8 (43 to 82) kg at two centres, balanced between the centres for both gender and age were included in the study. Granisetron (40 ug/kg as a solution in 0.9% saline) was administered to all subjects by intravenous infusion into a forearm vein, after an overnight fast. Plasma samples were obtained by centrifugation from blood samples taken predose, at the end of infusion (3 min), 10, 20, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30 and 48 h after the start of the infusion for plasma drug assay. Urine samples were taken predose, and at 0 2, 2-4, 4-8, 8 12, 1~24 and 24-48 h after the start of the infusion. All samples were stored at approximately -20 °C until analysed.All plasma and urine samples were analysed for granisetron using a specific reversed phase HPLC method with fluorimetric detection [7]; sensitivity 0.1 ng-ml -~ (plasma) and 0.5ng.ml -~ (urine), and coefficient of variation and accuracy generally within 10%. Pharmacokinetic parameters (C .... AUG, CL, Vz, t~j2, MRT, Ae48 and CLR) for granisetron were calculated by model-independent methods [8] and compared between young and elderly subjects by analysis of variance, before and after logarithmic transformation. Results and conclusionsIn the elderly, volume of distribution (4.0 (1.4) l'kg -1) was significantly higher than in the young (3.0 (1,1) 1 kg 1; Table 1), In addition, there was, in the elderly, an approximately 45% reduction in mean (S.D.) systemic clearance compared to values in younger subjects, though this difference was only statistically significant when data were not log-transformed. Consequently values of terminal phase half-life and mean residence time (MRT) were overall about 57% and 46%, respectively, longer in the elderly than in the young subjects. The lower clearance in the elderly was associated with a somewhat higher mean area under the plasma concentration-time curve, AUC, (115 (52.2) ng h m1-1) than in the young (89.7 (58.8) ng h ml 1), though this difference was not statistically significant. C .... extent of urinary excretion and renal clearance were unaffected by age. Despite the observed diff...

Healthy elderly people aged 70 or more should receive a starting dosage of the anxiolytic drug suriclone half that recommended for younger people; frail or ill elderly people may require further dosage reduction. These conclusions were based on a study of the pharmacokinetics and tolerability of orally administered suriclone after a single dose of 0.2mg and after multiple doses of 0.2mg 3-times daily in 8 male and 8 female healthy elderly volunteers. Informal comparisons of the pharmacokinetic data from this study with studies in younger volunteers showed a 53% decrease in clearance and an 84% increase in elimination half-life. Area under the plasma concentration-time curve (AUC) for suriclone and total antigenic products in the elderly were twice the values in younger volunteers when adjusted for different dosage. There were no significant changes in pulse rate or blood pressure during the study. One person showed a change from sinus rhythm to atrial fibrillation. Six people had transient adverse events including unsteadiness, vomiting, difficulty in reaching for objects, urinary incontinence and sedation.