Controlling drug effects through improved oral formulations: The pharmacokinetics of the prazosin gastrointestinal therapeutic system

Abstract

Influences that determine a drug's effects include pharmacokinetic factors (the serum concentrations of drug as determined by the drug dose, absorption, distribution, and excretion) and pharmacodynamic factors (the intensity of drug effect). Most assessments of drug effect focus on the therapeutic range, i.e., the serum concentrations below which therapeutic effects are unlikely and above which toxic effects may be seen. A goal for many treatment regimens is to maintain serum drug concentrations within the therapeutic range. Maintenance of drug concentrations within the therapeutic range can be difficult with many traditional oral dosage formulations. Soon after administration of standard tablets, capsules, or liquids, a pronounced peak level is observed in serum. At the end of a dosage interval, serum concentrations are frequently below those needed to exert therapeutic effect. One reason for the wide range in serum concentrations with standard oral formulations is that these products usually exhibit first-order drug absorption, in which the rate of absorption from the gastrointestinal tract continually varies following a dose (from high to low) and is directly determined by the amount of drug remaining in the gastrointestinal tract. First-order absorption, therefore, results in changing absorption rates, wide swings in serum drug concentrations, a relatively short duration of action, and often, inconsistent drug effects over a dosage interval. One way to address the problems with standard oral products that have first-order absorption is to produce products that control drug release and absorption. A large number of controlled-release oral products are now on the market and use a variety of technologies. The ideal controlled-release formulation would result in zero-order drug absorption, in which the rate of drug absorption from the gastrointestinal tract would be constant and not determined by the amount of drug in the gastrointestinal tract. Zero-order absorption, therefore, results in an unchanging absorption rate, consistent serum levels, a longer duration of action, and more steady drug effect. Zero-order absorption is particularly preferable in situations that require a consistent, long-term therapeutic effect, e.g., in patients with hypertension, asthma, or arrhythmias. Of all the controlled-release preparations on the market, however, very few exhibit zero-order absorption; most can be categorized somewhere between first- and zero-order kinetics. An advanced-technology tablet has been invented to produce zero-order drug absorption for prazosin and nifedipine.(ABSTRACT TRUNCATED AT 400 WORDS)