CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202107Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- JEE E LEE 01/23/2012 JAYABHARATHI VAIDYANATHAN 01/23/2012 Reference ID: 3075281 interaction. Thus, the quantitative data for effect of ketoconazole on the pharmacokinetics of mifepristone would be beneficial to the target populations. A drug-drug interaction study with ketoconazole is recommended as a Post Marketing Requirement (PMR). The goal of this study is to get a quantitative estimate of the change in exposure of mifepristone following co-administration with ketoconazole. Based on the results of this study, the effect of moderate CYP3A inhibitors on mifepristone pharmacokinetics may need to be addressed. This will help provide more therapeutic options available to Cushing’s patients and appropriate labeling of mifepristone when co-administered with CYP3A inhibitors. 2 Reference ID: 3074721 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- JEE E LEE 01/20/2012 JAYABHARATHI VAIDYANATHAN 01/20/2012 CHANDRAHAS G SAHAJWALLA 01/20/2012 Reference ID: 3074721 2.2.1 What are the design features of the clinical pharmacology and clinical studies used to support dosing? .......................................................................................................................... 9 2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or surrogate endpoints)?................................................................................................................................10 2.2.3 What are characteristics of the exposure-response relationships (dose-response, concentration-response) for efficacy/safety?.......................................................................... 11 2.2.4 What are the pharmacokinetic characteristics?.................................................................... 15 2.3 Intrinsic factors....................................................................................................................................................... 23 2.3.1 What intrinsic factors influence exposure and/or response, and what is the impact of any differences in exposure on efficacy or safety response?........................................................ 23 2.3.2 Should dose of mifepristone be adjusted in patients with severe hepatic impairment?..... 24 2.3.3 Should dose of mifepristone be adjusted in patients with renal impairment?.................... 25 2.3.4 Is there any effect of gender or race on mifepristone PK? ................................................... 25 2.4 Extrinsic factors...................................................................................................................................................... 25 2.4.1 What extrinsic factors influence exposure and/or response, and what is the impact of any differences in exposure on efficacy or safety responses? ...................................................... 26 2.4.2 Should dose of mifepristone be adjusted with concomitant use of strong, moderate, and mild CYP3A4 inhibitors? ........................................................................................................ 31 2.4.3 Are DDI studies with moderate and/or strong CYP3A4 inhibitors needed? ...................... 32 2.4.4 Should CYP2B6 substrates such as bupropion and efavirenz be avoided? ........................ 32 2.4.5 Should dose of CYP2C8/9 substrates be adjusted or use of CYP3A4 substrates be contraindicated with concomitant use of mifepristone? ....................................................... 33 2.5 General Biopharmaceutics..................................................................................................................................... 33 2.5.1 Based on the biopharmaceutics classification system principles, under which category is this drug classified?.................................................................................................................. 33 2.5.2 What are protein-binding properties of the drug?................................................................ 34 2.6 Analytical Section ................................................................................................................................................... 35 2.6.1 What bioanalytical methods are used to assess the drug concentrations? .......................... 35 REFERENCE:.................................................................................................................36 3 LABELING ......................................................................................................36 4 APPENDIX ......................................................................................................36 4.1 Individual Clinical Study Review.......................................................................................................................... 36 4.1.1 C-1073-05: Effect of Hepatic Impairment Study with Subjects with Child-Pugh B .......... 37 4.1.2 C-1073-19: Effect of Renal Impairment Study ...................................................................... 42 4.1.3 C-1073-25: DDI with Simvastatin........................................................................................... 49 4.1.4 C-1073-23: DDI with Digoxin.................................................................................................. 54 4.1.5 C-1073-24: DDI with Alprazolam........................................................................................... 58 4.1.6 C-1073-26: DDI with Cimetidine ............................................................................................ 65 4.1.7 C-1073-16: DDI with Fluvastatin............................................................................................ 71 4.1.8 C-1073-20: Food Effect Study with 1200 mg Dose ................................................................ 74 4.1.9 C-1073-27: Food Effect with 1200 mg/day Multiple Dose .................................................... 81 4.1.10 C-1073-12: Food Effect Study with 600 mg Dose .................................................................. 85 4.1.11 C-1073-22: Bioavailability Comparison for Three Formulations........................................ 87 4.1.12 C-1073-425: Multiple dose study at 600 mg/day to assess effects on high-density lipoproteins ............................................................................................................................... 90 4.1.13 Summary of In Vitro Studies................................................................................................... 93 4.2 Cover Sheet and OCP Filing.................................................................................................................................. 97 2/100 Reference ID: 3072217 AUC0-∞ (hr*ng/mL) 170059 (61717) 369177 (205164) AUC0-last (hr*ng/mL) 164816 (60913) 323797 (146061) Cmax (ng/mL) 2982.3 (1040) 3329.3 (1259) Tmax (hr)* 1.25 [0.5, 6] 1 [0.5, 2] t1/2 (hr) 40.7 (14.6) 84.6 (60.9) *Median with range Figure 1. Pharmacokinetics profiles of mifepristone following single dose of mifepristone 600 mg or multiple doses of mifepristone 600 mg/day for 7 days (source: C-1073-05) Simvastatin: The exposure of simvastatin and simvastatin acid (AUC) was increased greater than 10-fold and 15-fold, respectively following 80 mg of simvastatin co- administered with multiple doses of mifepristone (1200 mg/day) compared to that following 40 mg of simvastatin only. Fluvastatin: Following the first and last dose of mifepristone 1200 mg/day given for 7 days, there was a 2.67-fold and 3.57 fold increase, respectively, in AUC0-24 of fluvastatin. Digoxin: The drug-drug interaction study with digoxin did not find significant effect of mifepristone on digoxin pharmacokinetics. Alprazolam: The exposure of alprazolam is expected to increase approximately 2-fold with concomitant administration of mifepristone. Cimetidine: No evidence for the effect of cimetidine, a mild inhibitor of CYP3A4, on the pharmacokinetics of mifepristone was observed. 5/100 Reference ID: 3072217 Hepatic/renal impairment: No dose adjustment of mifepristone is recommended to subjects with renal impairment, but the sponsor set the maximum dose as 600 mg per day. No dose adjustment of mifepristone is recommended to patients with mild/moderate hepatic impairment, but the maximum dose should be set to 600 mg per day as it is to patients with renal impairment. The administration of mifepristone to patients with severe hepatic impairment is not recommended 2 Question Based Review 2.1 General Attributes 2.1.1 What the chemistry and physicochemical properties of the drug substance? Chemical Structure: 11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one