Pharmacodynamic and pharmacokinetic rationales for the development of an oral controlled-release amoxicillin dosage form.

The goal of this investigation was to develop an oral sustained-release formulation for amoxicillin that would maximize the duration of active drug concentration in the extracellular fluid, thus increasing the dosing interval while assuring antimicrobial activity. This rationale is based on the pharmacodynamic properties of the drug which is non- concentration dependent on the one hand, while requiring long exposure of the pathogen to the drug with minimal post-antibiotic effect on the other. Due to pharmacokinetic constraints, including short biological half-life and limited 'absorption window' (confined to the small intestine) with poor colonic absorption, the new matrix tablet formulation, composed of hydrophilic (hydroxypropyl methyl-cellulose) polymer, was designed to release 50% of its contents within the first 3 h and to complete the drug release process over 8 h (under in vitro conditions). The pharmacokinetics of the new formulation was evaluated in 12 healthy volunteers and compared to a conventional gelatin capsule with both formulations containing 500 mg amoxicillin. The plasma concentrations of active amoxicillin and penicilloic acid were determined by an HPLC method with a fluorometric detector. It was found that the area under the concentration-time curve and maximal serum amoxicillin concentrations following the sustained release preparation were lower than the immediate release formulation. However, the time over the required threshold concentrations, i.e. the minimal inhibitory concentration (MIC) as well as the more clinically relevant parameter--four times MIC of the drug against susceptible pathogens, was found to be maintained for significantly longer periods. The results suggest that in order to achieve a twice daily dosing regimen that will provide therapeutic concentrations for the whole 12 h dosing intervals, a larger dose of the new formulation should be given (e.g. 750 mg or even 1 g twice daily). This recommendation is based on the large interindividual differences of the extent of amoxicillin absorption found in this investigation, and is intended to assure that the 'poor' absorbers will also benefit from full antibiotic efficacy. This dosing regimen will lead to increased patient compliance and improved therapeutic outcome.