12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.

12.2 Pharmacodynamics

Because mifepristone acts at the receptor level to block the effects of cortisol, its antagonistic actions affect the hypothalamic-pituitary-adrenal (HPA) axis in such a way as to further increase circulating cortisol levels while, at the same time, blocking their effects.

Mifepristone and the three active metabolites have greater affinity for the glucocorticoid receptor [100% (mifepristone), 61% (metabolite 1), 48% (metabolite 2), and 45% (metabolite 3)] than either dexamethasone (23%) or cortisol (9%).

12.3 Pharmacokinetics

Absorption

Following oral administration, time to peak plasma concentrations of mifepristone occurred between 1 and 2 hours following single dose, and between 1 and 4 hours following multiple doses of 600 mg of KORLYM in healthy volunteers. Mean plasma concentrations of three active metabolites of mifepristone peak between 2 and 8 hours after multiple doses of 600 mg/day, and the combined concentrations of the metabolites exceed that of the parent mifepristone. Exposure to mifepristone is substantially less than dose proportional. Time to steady state is within 2 weeks, and the mean (SD) half-life of the parent mifepristone was 85 (61) hours following multiple doses of 600 mg/day of KORLYM.

Studies evaluating the effects of food on the pharmacokinetics of KORLYM demonstrate a significant increase in plasma levels of mifepristone when dosed with food. To achieve consistent plasma drug concentrations, patients should be instructed to always take their medication with meals.

Distribution

Mifepristone is highly bound to alpha-1-acid glycoprotein (AAG) and approaches saturation at doses of 100 mg (2.5 μM) or more. Mifepristone and its metabolites also bind to albumin and are distributed to other tissues, including the central nervous system (CNS). As determined in vitro by equilibrium dialysis, binding of mifepristone and its three active metabolites to human plasma proteins was concentration-dependent. Binding was approximately 99.2% for mifepristone, and ranged from 96.1 to 98.9% for the three active metabolites at clinically relevant concentrations.

Metabolism

Cytochrome P450 3A4 (CYP3A4) has been shown to be involved in mifepristone metabolism in human liver microsomes. Two of the known active metabolites are the product of demethylation (one monodemethylated and one di-demethylated), while a third active metabolite results from hydroxylation (monohydroxylated).

Elimination and Excretion

Excretion is primarily (approximately 90%) via the fecal route.

Specific Populations

Renal Impairment

The pharmacokinetics of mifepristone in subjects with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min, but not on dialysis) was evaluated following multiple doses of 1200 mg KORLYM for 7 days. Mean exposure to mifepristone increased 31%, with similar or smaller increases in metabolite exposure as compared to subjects with normal renal function (CrCL ≥ 90 mL/min). There was large variability in the exposure of mifepristone and its metabolites in subjects with severe renal impairment as compared to subjects with normal renal function (geometric least square mean ratio [CI] for AUC of mifepristone: 1.21 [0.71-2.06]; metabolite 1: 1.43 [0.84-2.44]; metabolite 2: 1.18 [0.64-2.17] and metabolite 3: 1.19 [0.71-1.99]). No change in the initial dose of KORLYM is needed for renal impairment; the maximum dose should not exceed 600 mg per day.

Hepatic Impairment

The pharmacokinetics of mifepristone in subjects with moderate hepatic impairment (Child-Pugh Class B) was evaluated in a single- and multiple-dose study (600 mg for 7 days). The pharmacokinetics in subjects with moderate hepatic impairment was similar to those with normal hepatic function. There was large variability in the exposure of mifepristone and its metabolites in subjects with moderate hepatic impairment as compared to subjects with normal hepatic function (geometric least square mean ratio [CI] for AUC of mifepristone: 1.02 [0.59-1.76]; metabolite 1: 0.95 [0.52-1.71]; metabolite 2: 1.37 [0.71-2.62] and metabolite 3: 0.62 [0.33-1.16]). Due to limited information on safety in patients with mild-to-moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. The pharmacokinetics of mifepristone in patients with severe hepatic disease has not been studied. KORLYM is not recommended in patients with severe hepatic disease.

Drug-Drug Interactions

In Vitro Assessment of Drug Interactions

In vitro studies indicate a potential for CYP-mediated drug interactions by mifepristone and/or its metabolites with substrates of CYP2A6, CYP2C8/2C9, CYP2C19, CYP3A4, CYP1A2, CYP2B6, CYP2D6, and CYP2E1. In vitro studies also indicated an interaction potential for drug transport mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In vitro studies indicate mifepristone metabolism is mediated by CYP3A, and that mifepristone also inhibits and induces CYP3A.

In Vivo Assessment of Drug Interactions (see Table 3)

Table 3. Summary Table of KORLYM Drug-Drug Interaction Effects
*No effect = 90% CI within range 0.80 – 1.25
†See Section 12.2 for the relative potencies of the three metabolites
1 Simvastatin 40 mg dose used as reference for the comparison. Result could be representative of other oral drugs with CYP3A metabolism and high first pass effect: cyclosporine, midazolam, triazolam, pimozide, sildenafil, sirolimus, and tacrolimus
2 Result could be representative of other oral drugs with CYP3A metabolism and low first pass effect. Clinical significance of any interaction will depend on the therapeutic margin of the drug.
3 Result could be representative of other oral drugs with CYP2C8/C9 metabolism
4 Plasma digoxin concentration should be measured after 1 to 2 weeks of concomitant use and following usual clinical practice at appropriate intervals thereafter.
5Result could be representative of other mild inhibitors of CYP3A
Dosing of Mifepristone	Coadministered Drug	Dosing of Coadministered Drug	Geometric Mean Ratio (analyte ratio with/without drug coadministration)
Dosing of Mifepristone	Coadministered Drug	Dosing of Coadministered Drug	Analyte	AUC	Cmax
Effect of KORLYM on Coadministered Drug
Contraindicated with mifepristone[See Contraindications (4)]
1200 mg once daily for 10 days	simvastatin1	80 mg single dose	simvastatin acid simvastatin	15.70 10.40	18.20 7.02
Use lowest dose of coadministered drug, based on clinical experience and/or use of therapeutic drug monitoring
1200 mg once daily for 10 days	alprazolam2	1 mg single dose	alprazolam 4-hydroxy-alprazolam	1.80 0.76	0.81 0.39
1200 mg once daily for 7 days	fluvastatin3	40 mg single dose	fluvastatin	3.57	1.76
1200 mg once daily for 10 days	digoxin4	0.125 mg once daily	digoxin	1.40	1.64
Effect of Coadministered Drug on KORLYM
Dose adjustment required
600 mg once daily for 17 days	ketoconazole	200 mg bid on days 13-17	mifepristone Metabolite 1† Metabolite 2† Metabolite 3†	1.38 1.02 1.67 0.95	1.28 1.06 1.69 0.96
900 mg once daily for 14 days	itraconazole	200 mg daily for 14 days	mifepristone Metabolite 1† Metabolite 2† Metabolite 3†	1.10 1.04 1.23 0.97	1.20 1.00 1.19 0.94
Effect of Coadministered Drug on KORLYM
No dosing adjustment required
300 mg once daily for 14 days	cimetidine5	800 mg once daily	mifepristone	0.85*	0.75