# Presentation: 904245

## Multiple Inhibitor StudiesWhat, Why, and How

**Kellie Schoolar Reynolds, Pharm.D.**
**Clinical Pharmacology Team Leader**
**OCPB/Division of Pharmaceutical Evaluation 3**

## Multiple Inhibitor Studies

- What?
- What are we talking about?
- Why?
- Why do we need this information?
- How?
- How do we collect the data?

## What are multiple inhibitor studies?

- 	These studies determine the effects of an NME at the maximum exposure likely in patients.

## Why do we need this information?

- Define safety at the top of the exposure-response curve
- Example: assess concentration-response for QT/QTc prolongation

## QT AssessmentICH E14- Clinical Evaluation of QT/QTc Interval Prolongation...Draft

- “If not precluded by considerations of safety or tolerability due to adverse effects, the drug should be tested at **substantial multiples of the anticipated maximum therapeutic exposure**.”
- “Alternatively, if the concentrations of a drug can be increased by drug-drug or drug-food interactions involving metabolizing enzymes (*e.g.*, CYP3A4, CYP2D6) or transporters (*e.g.*, P-glycoprotein), these **studies can be performed under conditions of maximum inhibition**.”
- Preliminary Concept Paper; Draft 4; June 10, 2004

## Why do we need this information?

- Determine the worst case scenario
- There are numerous reasons that patients may be exposed to elevated drug concentrations
- Drug interactions
- Genetic polymorphism (drug metabolizing enzymes)
- Renal impairment
- Multiple factors

## How do we collect the data?

- High dose of NME
- High dose of potent enzyme inhibitor
- Multiple inhibitors (different enzymes)
- if metabolized by several enzymes
- PM genotype
- Multiple impaired conditions
- renal impairment + enzyme inhibitor
- CYP2D6 PM + CYP3A inhibitor

## Considerations for studies

- Safety- animal and human
- safety margin, based on animal data
- human safety and exposure data
- Relevance of high exposure--
- Expected dose (vs doses that have been studied)
- Expected concomitant medications
- Target population

## Evaluation of Multiple FactorsSteps in the Process

- Characterize the effect of individual factors
- Simulate effect of multiple factors
- May need to study lower doses first, to estimate fold-increase in exposure.

## Example: Multiple Inhibitors

- Repaglinide-
- substrate for CYP2C8 and CYP3A4
- Interaction study in 12 subjects (administered with placebo, itraconazole, gemfibrozil, itraconazole + gemfibrozil)
- Repaglinide AUC
****** **41% with itraconazole (CYP3A4 inhibitor)
****** **712% with gemfibrozil (CYP2C8 inhibitor)
****** **1839% with itraconazole + gemfibrozil
- M Niemi, et al, Diabetologia (2003) 46:347-351

## Example: Multiple Impaired Conditions

- Telithromycin
- substrate for CYP3A4
- 13% of dose excreted unchanged in the urine
- May serve as compensatory elimination pathway when metabolic clearance is impaired
- Ketoconazole interaction
****** **AUC 95%
- Several renal impairment (CrCl < 30 mL/min)
**** AUC 90%
- Severe renal impairment + ketoconazole (n = 2)
- AUC 4- to 5-fold **** vs normal renal function, administered alone
- Ketek approved label

## Summary

- Multiple Inhibitor Studies
- What?
- Determine NME effect at maximum exposure
- Why?
- Worst case scenario...define and evaluate
- How?
- Single or multiple factors
- To consider...unanswered questions...
- How practical is this approach?
- When do we need information about multiple factors?
- Do we have enough information about the effect of multiple factors to make a specific recommendation?
- Is a general recommendation acceptable?
- What is the role of population pharmacokinetics?

## Questions

- 	**Is it acceptable** to recommend that under certain conditions (e.g., to estimate QT effects) it is important to determine the maximum exposure of an NME that a patient may experience, by increasing the exposure to the NME in the presence of either
-  a) a single inhibitor,
-  b) multiple inhibitors (when there are more than one pathway responsible for its metabolic clearance) or
- c) under multiple-impaired conditions (e.g., renal impairment and co-administration of a metabolic inhibitor).

## Questions

- What issues should be considered before recommending the type of clinical study be conducted on a NME that is described in the previous question?