# Presentation: 045153

##  Issues and Challenges in the Evaluation and Labeling of Drug Interaction Potentials of NME 

**Shiew-Mei Huang, Ph.D.**
**Deputy Office Director for Science**
**Office of Clinical Pharmacology & Biopharmaceutics, OPS**
**  ****CDER, FDA**

**Advisory Committee for Pharmaceutical Sciences**
**Clinical Pharmacology Subcommittee meeting**
**April 23, 2003**

## Recent US Market Withdrawal/NA -Examples

- QT
**TdP**

**Others**

**Hepato-**
**tox**

*** reintroduced in 2002 **

## 2,000,000
number of serious ADRs yearly

**number of serious ADRs yearly**

***< JAMA 1998;279:1200–1205; Arch Intern Med *****1995;155(18):1949–1956>**

**136,000,000,000**
**annual cost in dollars associated with ADRs**

**100,000**
**annual number of ADR-related deaths**

**4-6**
**ranking of serious ADRs as causes of death**

**Adverse Drug Reactions- **
**Marketed Drugs **

**Notes:**
Adverse reactions to drugs are among the leading causes of hospitalization and death in this country.  Aside from the human suffering, there is a tremendous pharmacoeconomic impact on health care costs.

## Why are there so many ADRs? 

***< JAMA 2002;287:337-344 >***

**Why are there so many ADRs? **

**Notes:**
Simple,  people take drugs and lots of them.  In any given week, most US adults take at least 1 medication, and many take multiple medications.  There is substantial overlap between use of Rx drugs, OTC drugs and herbal drugs that raise concerns about unintended drug interactions.  81% of consumers had taken at least 1 medication during the preceding week and rates of use increased with age and were greater in women than men in every age group.  Note 57% of older women take 5 or more drugs.

## “...drug interactions represent 3-5% of preventable ADRs and are an important contributor to ER visits and hospital admissions.”

***< JAMA 2003;289 (13):1652>***

**“...****elderly patients with digoxin toxicity were 12 times more likely to have been treated with clarithromycin”**

***< JAMA 1995;274(1):35–43>  ***

**Notes:**
DDI are a significant contributor to ADRs

Ontario, Canada. Ontario, Canada, from January 1, 1994, to December 31, 2000. PATIENTS: All Ontario residents aged 66 years or older treated with glyburide, digoxin, or an angiotensin-converting enzyme (ACE) inhibitor. controls (matched on age, sex, use of the same medication, and presence or absence of renal disease) for receipt of interacting medications (co-trimoxazole with glyburide, clarithromycin with digoxin, and potassium-sparing diuretics with ACE inhibitors).. During the 7-year study period, 909 elderly patients receiving glyburide were admitted with a diagnosis of hypoglycemia. In the primary analysis, those patients admitted for hypoglycemia were more than 6 times as likely to have been treated with co-trimoxazole in the previous week (adjusted odds ratio, 6.6; 95% confidence interval, 4.5-9.7). Patients admitted with digoxin toxicity (n = 1051) were about 12 times more likely to have been treated with clarithromycin (adjusted odds ratio, 11.7; 95% confidence interval, 7.5-18.2) in the previous week, and patients treated with ACE inhibitors admitted with a diagnosis of hyperkalemia (n = 523) were about 20 times more likely to have been treated with a potassium-sparing diuretic (adjusted odds ratio, 20.3; 95% confidence interval, 13.4-30.7) in the previous week. 

## OCPB GRP Quality Review (Steps)

**1. Evaluate drug interactions well**

**2. Evaluate the safety/efficacy database**
**       ****& explore exposure/response relationship**** **

**3. Use prominent warning early in   **
**    ****labeling (project a level of risk in**
**    ****drug interactions)**

***< Lesko LJ, et al, OCPB QA/QC report, 1999 >; ***
***< Huang S-M, et al, Clin Pharmacol Ther ******2000; 67(2): 148 ****** >***

## Recommendations:

**4. Develop better means of **
**    ****communicating dosing information to**
**    ****practitioners and patients **

**What is optimal drug interaction information from NDA submissions? **

** ****Elucidation of metabolic pathways; **
**  ****contribution of CYP; fraction metabolized**

**  ****Enzyme modulating potential (**_**inhibition**_**/**_**induction**_** by NME/metabolites)**

**- Effect **_***of***_** other drugs**

**- Effect **_***on***_** other drugs**

## Relevant guidance/MaPP documents: 

***4-6: intranet***

***1. Preclinical: in vitro studies: 1997 guidance***

**Relevant guidance/MaPP documents:**** **

***5. OCPB Good Review Practice draft MAPP; 2001***

***2. Early phase: in vivo studies: 1999 guidance***

***4. Cross-labeling draft MAPP : 1999***

***6. In vitro metabolism draft MAPP; 2002***

***7. Exposure-response: draft guidance; 2002***

***3. Late phase: population PK studies : 1999 guidance***

## In Vitro Metabolism Data

_***In Vitro***_** Metabolism Data**
**<Studies in Human Tissues>**
**for each key CYP enzyme**

**Substrate?**

**Inhibitor/inducer?**

**No**

-          **Stop-**
**General Labeling***

-        **Stop-**
**General Labeling***

**Pathway**
**Major?**

-         **Stop-**
**General Labeling***

**Yes/**
**unknown**

**No**

**No**

**   **_***In vivo***_**-**
**Most Sensitive**
**Substrates**

-      _***In vivo***_**-**
**Most Potent**
**Inhibitor/inducer**

** ****Obviate certain in **
**  ****vivo metabolic  **
**  ****interaction studies**
** ****Focus on in vivo**
**  ****investigations **

- *Population PK studies

**Yes/**
**unknown**

**Yes/**
**unknown**

**OCPB**
**GRP**

## In Vitro Metabolism Data

_***In Vitro***_** Metabolism Data**
**<Studies in Human Tissues>**
**for each key CYP enzyme**

**Substrate?**

**Inhibitor/inducer?**

**No**

-          **Stop-**
**General Labeling***

-        **Stop-**
**General Labeling***

**Pathway**
**Major?**

-         **Stop-**
**General Labeling***

**Yes/**
**unknown**

**No**

**No**

**   **_***In vivo***_**-**
**Most Sensitive**
**Substrates**

-      _***In vivo***_**-**
**Most Potent**
**Inhibitor/inducer**

- *Population PK studies

**Yes/**
**unknown**

**Yes/**
**unknown**

- Classification system
- for CYP3A**

**OCPB**
**GRP**

- ** PhRMA White paper JCP 2003; 43 (2)

## 
Ketoconazole
Itraconazole
Clarithromycin
Saquinavir
Erythromycin
Diltiazem
Fluconazole
Verapamil
Grapefruit juice
Cimetidine
Ranitidine
Azithromycin

**Ketoconazole**
**Itraconazole**
**Clarithromycin**
**Saquinavir**
**Erythromycin**
**Diltiazem**
**Fluconazole**
**Verapamil**
**Grapefruit juice**
**Cimetidine**
**Ranitidine**
**Azithromycin**

**% AUC vs. baseline**

_**Mild**_

_**Moderate**_

_**Potent**_

***Oral Midazolam****** as probe substrate***

**500**
**200**

**Notes:**
Literature data 

 In vitro inhibition 
 (hyperforin, 13, II8, biapigenin, hypercirin, quercetin)
 In vivo induction
 Amitryptyline, cyclosporine, digoxin, 6-b-OH-cortisol, theophylline, EE/desogestrel/warfarin/pheprocoumain

**Classification system-potential use **

** ****Used to guide *****in vivo***** studies**

** ****Used in labeling inhibitors/substrates**

** ****Concerns**

** ****Potent inhibitors may affect other enzymes/transporters**
**  ****(UGT, P-gp)**

**  ****Substrates are also substrates of other enzymes/transporters**

** ****Multiple drugs are prescribed**

** ****Varied data from various study designs**

** ****others**

**Discussion of drug interaction issues **

**  ****CDER Scientific rounds, ****February 26,  2003**

**  ****Professional meetings**

**- AAPS open forum, ****November 2002, Toronto**** **

**- ASCPT annual  meeting, April, 2003, Washington DC **

** ****ACPS subcommittee meetings, 2003**

##  Case 1-

**NME as a Substrate**

**Drug interactions evaluated?**

**Clinical significance (exposure-response)?**

**Labeling language?**

## In Vitro Metabolism Data

_***In Vitro***_** Metabolism Data**
**<Studies in Human Tissues>**
**for each CYP enzyme**

**Substrate?**

**Inhibitor/inducer?**

**No**

-          **Stop-**
**General Labeling***

-        **Stop-**
**General Labeling***

**Pathway**
**Major?**

-         **Stop-**
**General Labeling***

**Yes/**
**unknown**

**No**

**No**

**   **_***In vivo***_**-**
**Most Sensitive**
**Substrates**

-      _***In vivo***_**-**
**Most Potent**
**Inhibitor/inducer**

- *Population PK studies

**Yes/**
**unknown**

**Yes/**
**unknown**

- Step 1

## Drug A with     	    AUC	    Cmax

**Ketoconazole   ****	****	****6x****	****	****4x**

**NME -  CYP3A substrate **

**Erythromycin ****	****	****4x****	****	****3x**
**Verapamil ****	****	****	****4x****	****	****3x**

- Step 1

**Drug A **

## Exposure-response data

**Proposed clinical dose 15, 30, 60**

**Approved 15, 30**

**How to label drug interactions?**

- Step 2

## Do not take with potent CYP3A inhibitors.....

***Do not take***** with **_**potent**_** CYP3A inhibitors.....**

**	****	****	****      ****Ketoconazole, itraconazole, TAO, ritonavir, nelfinavir, nefazodone, clarithromycin**

***Use lower doses***** with **_**moderate **_**CYP3A inhibitors.....**

**	****	****	****                   ****erythromycin, verapamil, diltiazem...**

- Step 3

##  Case 2-

**NME as an inhibitor**

**Drug interactions evaluated?**

**Clinical significance (exposure-response of the substrates)?**

**Labeling language?**

## In Vitro Metabolism Data

_***In Vitro***_** Metabolism Data**
**<Studies in Human Tissues>**
**for each CYP enzyme**

**Substrate?**

**Inhibitor/inducer?**

**No**

-          **Stop-**
**General Labeling***

-        **Stop-**
**General Labeling***

**Pathway**
**Major?**

-         **Stop-**
**General Labeling***

**Yes/**
**unknown**

**No**

**No**

**   **_***In vivo***_**-**
**Most Sensitive**
**Substrates**

-      _***In vivo***_**-**
**Most Potent**
**Inhibitor/inducer**

- *Population PK studies

**Yes/**
**unknown**

**Yes/**
**unknown**

- Step 1

## Drug B with      	     AUC	      Cmax

**Midazolam  ****	****	****	****6x****	****	****3x**

**NME - CYP3A inhibitor **

**Simvastatin****	****	****	****8x****	****	****5x**

**Cisapride****	****	****	****3x****	****	****2x**

**Theophylline****	****	****	****1x****	****	****1x**

**Warfarin****	****	****	****1x****	****	****1x**

- Step 1

## 

Ketoconazole
Itraconazole
Clarithromycin
Saquinavir
Erythromycin
Diltiazem
Fluconazole
Verapamil
Grapefruit juice
Cimetidine
Ranitidine
Azithromycin

**Ketoconazole**
**Itraconazole**
**Clarithromycin**
**Saquinavir**
**Erythromycin**
**Diltiazem**
**Fluconazole**
**Verapamil**
**Grapefruit juice**
**Cimetidine**
**Ranitidine**
**Azithromycin**

**% AUC vs. baseline**

_**Mild**_

_**Moderate**_

_**Potent**_

***Oral Midazolam****** as probe substrate***

**500**
**200**

_**Potent**_

## Sensitive substrates or substrates with “narrow” therapeutic range:

**Labeling language **
**(e.g., contraindication) **
**with the “strong inhibitors”**

**midazolam, triazolam**
**simvastatin, lovastatin, atorvastatin**
_**terfenadine, cisapride, astemizole,**_
_**pimozide**_

- Step 2

## Potential Labeling Language

**The use of Drug B,**** ****a **_**strong **_**CYP3A inhibitor, is *****contraindicated***** with *****cisapride*****, p*****imozide, simvastain******....*****...**

- Step 3

** ****	****	****	****monitored****..**_***midazolam***_***...others, such as ***_***sildenafil, budesonide***_***...(those carrying ketoconazole labeling..)***

**Classification system-potential use **

** ****Used to guide *****in vivo***** studies**

** ****Used in labeling inhibitors/substrates**

** ****Concerns**

** ****Potent inhibitors may affect other enzymes/transporters**
**  ****(UGT, P-gp)**

**  ****Substrates are also substrates of other enzymes/transporters**

** ****Multiple drugs are prescribed**

** ****Varied data from various study designs**

** ****others**

** **

_**Potent inhibitors may affect other **_
_**enzymes/transporters (UGT, P-gp)**_

##  P-gp based interactions

## CYP3A and P-gp inhibitors 

**IC 50 ratios (CYP3A/P-gp)**

**verapamil**

**cyclosporine**

**quinidine**

**PSC833**

**<Wandel C et al, Cancer Res 1999 >**

## 			      	     AUC	      Cmax

**Ketoconazole ****	****	****	****2.7x****	****	****2.4x**

**P-gp substrates- fexofenadine **

**Itraconazole****	****	****	****2.4-2.8x   2.4-2.5x**

**Rifampin****	****	****	****0.3x****	****	****0.5x****	**** **

***< PDR for fexofenadine; Hamman MA, et al,  Clin Pharmacol Ther 2001;  Dresser GK, et al, Clin Pharmacolg Ther 2003; Dresser G, et al, Shon J, et al,  Lemma GL, et al, ASCPT 2003; ***
**** compared to water or acute dosing; ** possible OATP involvement>***

**Grapefruit juice******	****	****0.5x****	****	****0.5x**

**St John’s Wort*****	****	****0.5x****	****	****0.6-0.7 **

**Erythromycin****	****	****2.1x****	****	****1.8x**

**Verapamil****	****	****	****---****	****       1.5,1.3,1x **

**	****	****	****	****	****	****	****(C at days 1,10,38)**

## 			      	     AUC	         Cmax

**Quinidine****	****	****	**** ---****	****   2.4x (Css,7)**

**P-gp substrates- **_**digoxin**_

**Verapamil****	****	****        ---****	****  1.4-1.7x(Css,-)**

***< Belz GC, et al; Clin Pharmacol Ther 1982; Klein HO, et al, Circulation 1982; ; Lee Y, et al, ASCPT 2003; Durr, Clin Pharmacol Ther, 2000; Greiner B J Clin Invest 1999 > < Huang SM et al, JCP, 1999; Marroum PJ et al, CPT, 2000>***

** ****surveys indicated that cimetidine and digoxin most often**
**  ****studied in submissions reviewed in 1996 and 1987-1997**

**  ****digoxin continued to be studied, if likely to be co-administered**

**Rifampin****	****	****	****0.7x****	****	****0.5x****	**** **

**St John’s Wort****	****	****0.8x****	****	****--- **

**Aprepitant****	****	****0.93-0.99x****	****---**

**Grapefruit juice******	****	****1.09x****	****---**

**Notes:**
Indiana study showed days 1, 10, 38 

##  Next Steps

##  Guidance revision

** ****Guidance for Industry**
**In Vivo Drug Metabolism/Drug**
**Interaction Studies —**
**Study Design, Data Analysis, and**
**Recommendations for**
**Dosing and Labeling**

** ****Draft Cross Labeling MAPP**

** ****Draft In Vitro Metabolism/Transport MAPP**

##  Questions for the Panel

** ****1. What other factors to consider in**
**      ****implementing the classification **
**      ****system for CYP3A inhibitors in **
**      ****the labeling?**
**      ****- definition of sensitive substrates?**

##  Questions for the Panel (2)

** ****3. What about transporter-based **
**     ****interactions? - should we recommend**
**     ****routine evaluation?**

** ****2. Should we consider application of**
**     ****Classification systems to inhibitors**
**     ****of other CYP enzymes? Inducers?**

## Acknowledgement

**Acknowledgement**
**In vitro (in vivo) Metabolism/transport**
**interaction working group and others**
**involved in CDER rounds discussions**
**Sophia Abraham ****	****Sayed Al Habet ****	****Debra Birnkrant**
**Sang Chung ****	****	****Phil Colangelo ****	****Jerry Collins**
**Barbara Davit ****	****John Duan ****	****	****Shiew-Mei Huang**
**Russell Katz ****	****	****Ronald Kavanagh ****	****Lawrence J Lesko**
**Atiqur Rahman ****	****Kellie Reynolds ****	****Solomon Sobel**
**John M Strong ****	****Robert Temple ****	****Wei Qiu**
**Ramana Uppoor****	****Jim Xiaoxiong Wei ****	****Lei K Zhang**
**Jenny H Zheng ****	****Jenny J Zheng**

## Slide 36