THE NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYSTEM (GITS) - EVALUATION OF PHARMACEUTICAL, PHARMACOKINETIC AND PHARMACOLOGICAL PROPERTIES

Nifedipine is a short-acting calcium antagonist formulated into severa l different oral preparations, each of which offers a distinct drug re lease profile, Of these, the nifedipine gastrointestinal therapeutic s ystem (GITS) affords (rate)-controlled-release (CR) and once-daily adm inistration, Although it is recognised that CR drug formulations may e nhance the treatment compliance of patients by reducing the number of daily doses, there are several pharmaceutical, pharmacokinetic and pha rmacological considerations which may influence the ultimate selection of a particular dosage form, The formulation design of the nifedipine GITS involves an osmotic pump process which provides approximately ze ro-order delivery of the drug, This mechanism serves to prevent the po ssibility of dose dumping, but more importantly allows for maintenance of the relatively constant plasma drug concentrations assumed necessa ry to maintain smooth control of blood pressure. The pharmacokinetic c haracteristics of the nifedipine GITS have been evaluated in both sing le- and multiple-dose studies. The GITS formulation provides drug conc entrations which reach a plateau within 6 hours after administration o f a single dose, and continue at that concentration until at least 24 hours after administration. In this way large fluctuations in plasma d rug concentrations are avoided, which may improve the efficacy and tol erability of the drug. Although a trend showing a small increase in th e 24-hour plasma nifedipine concentrations has been observed by our gr oup from some single-dose studies, it does not appear to be clinically relevant. One potentially important disadvantage of the GITS compared with 'naturally' long-acting agents is that the 'intrinsic' pharmacok inetic properties of nifedipine may be exposed in poorly compliant pat ients, leading to extended periods of subtherapeutic drug concentratio ns. Drug delivery by the nifedipine GITS is unaffected by changes in p H and gastrointestinal (GI) motility, but the rate of drug release can increase slightly with food intake (although absolute bioavailability remains unchanged). No stud ies have been conducted to determine the average GI transit time of this particular dosage form, but it is poss ible that inadequate retention may occur in some patients, perhaps lea ding to less optimal clinical outcomes. For example, the median GI tra nsit time for both oxprenolol and metoprolol Ores drug delivery system s has been reported as 27.4 hours, with individual times ranging from 5.1 to 58.3 hours. The possibility of inadequate GI retention of the n ifedipine GITS is perhaps more likely in patients who have pre-existin g GI motility disorders or who are taking other medications that enhan ce GI motility. The interaction between grapefruit juice and nifedipin e is interesting, considering that the exact mechanism involved has ye t to be determined. Nonetheless, inhibition of presystemic metabolic p rocesses (probably involving liver enzymes but possibly also enzymes c ontained within the wall of the small intestine) is likely to be a fac tor in the increased bioavailability of nifedipine observed in individ uals coingesting grapefruit juice. Thus, potential nifedipine formulat ion differences with respect to the degree of interaction with grapefr uit juice may occur if a significant degree of extrahepatic metabolism is involved. The majority of clinical trials with the nifedipine GITS have assessed its efficacy in patients with mild-to-moderate essentia l hypertension, and have found it to be at least equivalent to other d osage forms of the drug. Since there is limited information available directly comparing the efficacy and adverse effects of the different t ypes of nifedipine formulation, little attention has been focused on t his subject. However, modifying the rate and duration of nifedipine re lease may profoundly affect the clinical performance of this drug. A s lower rate of intravenous nifedipine infusion has been shown to reduce the incidence of vasodilator-related adverse effects and to improve b lood pressure control. Therefore, these advantages may also apply to r educed rates of oral nifedipine absorption. Another important advantag e of the nifedipine GITS is that the trough/peak effect ratio followin g once-daily administration is maintained above a value of 0.5 to 0.66 , as is now typically suggested for antihypertensive therapy.