The Unique Adalat Story – Nifedipine Gastrointestinal Therapeutic System

Abstract

At a time of resource constraints in the healthcare system worldwide, cost issues increasingly influence medication-prescribing habits. For this reason, healthcare providers encourage physicians and pharmacists to use generic drugs, which offer the single advantage of being cheaper than the original proprietary product. Whether this approach is eventually justified with regard to the efficient and safe treatment of the medical conditions of the patients is often a matter of debate, and definitive clinical studies are usually lacking. Increased awareness of potential adverse clinical consequences of generic therapeutic substitution is warranted. Physicians and pharmacists alike should be alerted to the critical issues of pharmacokinetic bioequivalence, pharmacokinetic/pharmacodynamic correlations and international guideline recommendations concerning differences between different formulations and, in particular, the various formulations of MR nifedipine. Nifedipine GITS Formulation The nifedipine GITS formulation provides a once-daily dosing regimen with a continuous and slow release of the drug into the intestinal tract, resulting in a smooth plasma concentration/time profile. This formulation consists of a two-layer core of nifedipine and osmotic polymer surrounded by a semi-permeable membrane, which contains a precisely laser-drilled hole. When the tablet is ingested, water is absorbed from the gastrointestinal tract through the semi-permeable membrane and the nifedipine-containing core forms a suspension that is released through the laser-drilled hole at a constant rate owing to expansion of the polymer core layer. 1 The GITS formulation delivers nifedipine at a constant rate for approximately 18–22 hours. Pharmacokinetic studies comparing the GITS formulation with immediate-release (capsule) and less sophisticated MR formulation (retard tablet for twice-daily administration) have confirmed the controlled release of nifedipine from the GITS tablet into the intestinal tract, resulting in a smooth, predictable plasma concentration. 2,3 Pharmacokinetics and Pharmacodynamics of Different Nifedipine Formulations in Patients with Hypertension The response to many antihypertensive drugs in an individual patient is determined by the drug disposition (pharmacokinetics) and the relationship between concentration and effect. This is certainly true for the dihydropyridine calcium channel blockers (CCBs) and nifedipine in particular, with the pharmacokinetic characteristics of the specific formulation being the major determinant of the pharmacological response elicited. This is because the rate of delivery of nifedipine into the systemic circulation is an additional factor influencing the antihypertensive response. This has been demonstrated when comparing two regimens of intravenous nifedipine infusions (slow infusion versus bolus/exponential infusion) 4 or comparing intravenous infusion with immediate-release and an MR tablet. 3,5 These studies showed that slowly increasing plasma concentrations of nifedipine resulted in heart rate being essentially unchanged while decreasing diastolic and systolic blood pressure (BP) in healthy subjects, as well as in patients with hypertension. In contrast, a rapid increase of nifedipine concentrations resulted in a corresponding increase in heart rate and had no relevant influence on diastolic BP. It was therefore recognised that a predictable and controlled release of nifedipine into the intestinal tract results in a smooth plasma concentration/time profile. This not only has the desired blood pressure-lowering effect, but also avoids an increase in heart rate. When compared with other formulations of nifedipine, the unique dissolution characteristics of nifedipine GITS translate into distinctly different pharmacokinetic (see Figure 1) and haemodynamic profiles in hypertensive patients (see Figure 2 and Figure 3). 3 Figure 1 shows that oral dosing with the capsule formulation of nifedipine results in large peak concentrations of the drug being rapidly achieved with subsequent rapid elimination of the drug. The retard formulation (slow-release for twice-daily administration) reduces the peak concentration and delays drug elimination, but only to a limited extent. In contrast, the GITS formulation produces a gradual increase in plasma concentrations of nifedipine, which are then sustained at an almost constant level for at least 24 hours. These distinct pharmacokinetic differences are translated into clinically relevant pharmacodynamic differences (see Figure 2 and Figure 3). Nifedipine capsules produce modest and short-term reductions in BP accompanied by marked increases in heart rate. In contrast, the nifedipine GITS formulation had little or no effect on heart rate, but had a slow and sustained effect on BP. These highly desirable characteristics were also apparent during maintenance therapy with nifedipine GITS. Pharmacokinetics of Modified-release Nifedipine Formulations – Are They All The Same? Underlying physiological processes that determine the effect of the dosage form on drug absorption include 1 transit through the gastrointestinal tract; 2 disintegration of the dosage form; 3 dissolution of the active compound; 4 and absorption from the gastrointestinal lumen into the blood. The profile of absorption, and thus bioavailability, is controlled by 97 © T O U C H B R I E F I N G S 2 0 0 7