The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action

Abstract

The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25–30 h, and high micromolar serum concentrations following ingestion of doses of ≥100 mg of the drug. The serum transport protein—α 1-acid glycoprotein (AAG)—regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone—plus its metabolites—seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception—mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the ≥200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2–5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.

Introduction

Recent clinical studies on the use of mifepristone in medical termination of pregnancy and in emergency contraception have focused on optimization of mifepristone regimens. In termination of first-trimester pregnancy, a 200-mg dose of mifepristone, in combination with vaginally administered prostaglandin, is equally effective as a higher dose (600 mg) of mifepristone [1], [2], [3]. In these studies, the percentages of complete abortions have ranged 88–96% [1], [2], [3]. The results of preliminary studies have suggested that even a 100-mg dose of mifepristone might be equally effective [4]. However, in a randomized multicenter study arranged by the World Health Organization (WHO), 50 mg of mifepristone combined with vaginally administered prostaglandin was 1.6 times more likely to fail in termination of first trimester pregnancy when compared with a regimen containing 200 mg of mifepristone [5].

In emergency contraception, considerably lower doses of mifepristone are needed. In a randomized study arranged by the WHO, a 10-mg dose of mifepristone was equally effective as 50 mg or 600 mg doses, each preventing 84–86% of pregnancies [6]. In fact, the lowest effective dose of mifepristone in emergency contraception has not been characterized. The more than 10-fold difference in the doses of mifepristone required for optimal clinical effects in emergency contraception and in pregnancy termination suggests that different biological mechanisms mediate these clinical effects of mifepristone.

The antiglucocorticoid effects of mifepristone are in sharp contrast with its antiprogestagenic effects in pregnancy termination or in emergency contraception. Early studies by Bertagna et al. [7] and Gaillard et al. [8] showed that activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to mifepristone is clearly a dose-dependent phenomenon, and significant increases in the circulating concentrations of adrenocorticotropic hormone and cortisol are seen following administration of ≥200 mg of the drug. Moreover, more pronounced activation of the HPA axis is seen as the dose of mifepristone is increased [7], [8].

The differences in the clinical effects of mifepristone are also related to its pharmacokinetics—the high efficacy of mifepristone in emergency contraception is seen in the dose range that results in linear kinetics of the drug in serum. However, the doses required for termination of pregnancy or activation of the HPA axis result in saturation level, non linear kinetics of mifepristone. In this article we review the pharmacokinetics of mifepristone in humans, with special emphasis on the relationships between its pharmacokinetics and clinical efficacy.