# Presentation: 476267

## THE CLINICAL SIGNIFICANCE OF TRANSPORTER-BASED DRUG INTERACTIONS

- David J. Greenblatt, M.D.
- Department of Pharmacology and Experimental Therapeutics,
- Tufts University School of Medicine and
- Tufts-New England Medical Center
- Boston, MA

## ROLL THE CLOCK BACK TO 1996

- “Clinical significance of drug interactions
- involving the Cytochromes P450”

## 1.  Many recently-approved NCE’s are major 

-      therapeutic advances
- 				   BUT
-      have secondary pharmacologic properties
-      leading to drug interactions
-      Examples:
- 		        -SSRIs
- 		        -Azole antifungals
- 		        -Antiretrovirals (HAART)

## 2.  Many patients with serious disease

-      are doing well, with good quality of
-      life, because of polypharmacy

##  There are too many drug interactions 

-  There are too many drug interactions
-     to memorize
-   Understanding the CYPs provides a
-   first-order structure

## 4. In vitro models MIGHT provide    

-     predictive estimates as to drug
-     interactions that are probable,
-     possible, or unlikely

## RETURNING TO THE PRESENT

##  Bad drug interactions get VERY 

-    bad press

## 2. Drug interactions are unusual

-     Bad drug interactions are rare

## Number		Number of

- of drugs		possible DDI pairs

- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10

- 1
- 2
- 6
- 12
- 15
- 21
- 28
- 36
- 45

## PERSPECTIVE ON DRUG INTERACTIONS

- Outcome

- No interaction

- Clinically unimportant
-   interaction

- Occasional

- Clinically important
-   interaction; monitor
-   and/or adjust dosage

- Unusual

- Common

- Hazardous interaction;
-   combination is contraindicated

- Rare

- Prevalence

## Clin Pharmacol Ther 2004; 76: 85-96

- (9481 Patients)

- a = possible pairs
- b = actual pairs
- c = data available
- d = interaction possible
- e = manageable interaction
- f =  hazardous interaction

## 3.  In vitro systems have major 

-      drawbacks, limitations, and biases

## WHAT YOU HOPE WILL BE TRUE:

-        [I]      AUCI
-            Ki      AUC0

- 1+

- =

## 	CORE QUESTIONS

-   What does Ki or IC50
-    mean?
-   What is [I]?

## AT THE EXTREMES, 

- IT IS EASY

## J AIDS 2000; 24: 129-136

- WITH
- RITONAVIR

- CONTROL

## STATE OF THE ART

-         [I] / Ki		           Interaction probability

- <0.5			Unlikely
- 0.5-5.0		Possible
- > 5.0			Probable or likely

##   4. Focus on clinical interpretation 

-       should be
-     a.  Highly potent inducers/inhibitors
-     b.  Substrate victims with narrow
-          therapeutic ranges

## APPLYING THE CYP LESSON TO

- TRANSPORTERS

## 1.  In vitro models have significant drawbacks, 

-      limitations, and biases
- 	a.  Specificity of cell-based models for
-          individual transporters
-    b.  Specificity of index substrates and
-          inducers/inhibitors
-    c.  Role of passive diffusion

## Drug Metab Disp 2004; 32: 800-804

- _Drug Metab Disp 2004; 32: 800-804_

## Enteric exposure to transport modulators 

- greatly exceeds BBB exposure

## Slide 24

## Slide 25

## HUMAN STUDIES

- Drewe: BrJ Clin Pharmacol 2000; 50: 237-246
- Kharasch: Clin Pharmacol Ther 2003; 74: 543-554

## Slide 27

## How do we isolate the relative importance

- of CYP3A modulation vs. transport modulation
- for dual substrates/inhibitors/inducers?

## Slide 29

## Is there an established exposure-response 

- relationship for the victim?

## Clin Pharmacol Ther 2002; 71: 11-20

- _Clin Pharmacol Ther 2002; 71: 11-20_

## “Excuse me Sir.

- “Have you lived your whole life in
-  New Hampshire?”

## “Not yet”