Pharmacokinetic determinants in the design and evaluation of sustained-release dosage forms.

A new method employing the principle of superimposition was developed to aid in the formulation of sustained-release dosage forms. Independently absorbed components of a product, e.g., waxed pellets for an oral capsule, are administered separately and their plasma level-time profiles determined. Using a trial and error procedure, the ratios of pellets are varied to obtain a desired plasma level-time profile. The use of (1) time averaged plasma concentration-time data, (2) amount remaining to be absorbed (excreted) plots, and (3) cumulative amount absorbed (excreted) plots were all shown to be inappropriate for pharmacokinetic analyses in general, and evaluation of sustained-release products in particular. It was recommended that raw plasma concentration-time data be made available for sustained-released products, and that individual rate of absorption plots be used to assess absorption kinetics. It was concluded that much of the sustained-release pharmacokinetic data presently in the literature have been presented in such a manner, e.g. averaged data, as to be of limited value.