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Clinical pharmacokinetics

Galenic development and pharmacokinetic profile of indapamide sustained release 1.5 mg.


PMID 10491729

Abstract

In accordance with international guidelines recommending the use of low doses of antihypertensive agents, a new formulation of indapamide--indapamide sustained release (SR)--has been developed. Indapamide has been used worldwide for many years as an immediate release (IR) formulation at a dose of 2.5 mg. The IR formulation leads to plasma peaks of indapamide immediately after administration of the tablet. These peaks are responsible for possible unfavourable electrolyte or metabolic effects relating to indapamide blood concentrations. The SR formulation, by eliminating plasma peaks, allows a smoothing of the pharmacokinetic profile of indapamide. This new galenic formulation is based on a hydrophilic matrix tablet composed of a cellulose derivative, methylhydroxypropylcellulose (MHPC), and a binder, polyvinylpyrrolidone (povidone). The originality of the matrix lies in the percentages of MHPC and povidone, which permit a linear release in vitro of indapamide. After optimisation, the chosen ratio of these 2 constituents allowed the release of more than 70% of the dosage over 16 hours in a very reproducible manner. The 2 tested formulations (SR and IR) have the same bioavailability; however, the main pharmacokinetic parameters of the new SR 1.5 mg formulation, calculated after single and repeated administration, show a profile typical of an SR formulation, i.e. a lower maximum concentration (Cmax), a longer time to Cmax, and the same minimum concentration as the IR formulation. This new SR formulation, which allows a reduction in the daily dose of indapamide from 2.5 to 1.5 mg, leads to an improvement in its efficacy/tolerability ratio, thereby meeting the recommendations of the international guidelines for the treatment of essential hypertension.