Pharmacokinetic and pharmacodynamic aspects of polypeptide delivery

Abstract

The rational design and development of drug delivery systems for polypeptide compounds requires a quantitative understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of the compound in the intended therapeutic indication. In particular it is necessary to define the characteristics of the input function, i.e. the rate and time course of systemic drug input, that will maximize the therapeutic effect, minimize unwanted side effects and prevent tachyphylaxis from occurring. This paper reviews the general concepts of input function, PK and PD, and illustrates these concepts using two examples from the literature: (1) Sandoz compound SMS 201–995 and (2) gonadotropin-releasing hormone (GnRH). For SMS 201–995, a continuous (zero-order) input function is shown to be optimal for suppressing growth hormone secretion in the treatment of acromegaly. For GnRH, a pulsatile input function is optimal for stimulating pituitary gonadotropin secretion, whereas continuous input leads to a paradoxical suppression of gonadotropin secretion. These examples further illustrate the types of novel experimental approaches, using programmable infusion pumps, that are needed for investigating the relationship between PK and PD, and for defining the optimal input function experimentally. In addition, we show how mathematical models may be used to describe the interrelationships between input function, PK and PD. For SMS 201–995, a model based on the “effect compartment” concept offers a self-consistent description of the linkage between PK and PD and provides insight into the superiority of continuous input in the treatment of acromegaly. For GnRH, the complex relationship between input function and gonadotropin secretion is modelled on the basis of heuristic concepts that relate the time-averaged occupancy of the GnRH-receptors (by GnRH) to the expression of GnRH-receptors by the pituitary (i.e. down and up regulation). Together these examples illustrate the diversity of input functions that will be needed in polypeptide delivery and the novel experimental and theoretical approaches required for defining them.