# Presentation: 332747

## Overview of Use of PK-PD in Streamlining Drug Development

- William A. Craig
- Professor of Medicine
- University of Wisconsin

## Why Interest in Pharmacodynamics?

- Always occurs when there is narrow difference between MICs and obtainable drug concentrations
- 		- early days of penicillin in 1940s (low doses 			used)
- 		- appearance of Pseudomonas infections in 			1960s and 1970s (high MICs)			- appearance of resistant *Streptococcus **	**	**	**	**pneumoniae* and other bacteria in 				1990s

## Applications of PK-PD

- Optimize dosage regimens
- 	- once-daily dosing of aminoglycosides
- 	- prolonged or continuous infusion of beta-lactams
- Establish susceptibility breakpoints
- 	- new NCCLS breakpoints with oral beta-lactams 	and with ceftriaxone/cefotaxime for 	pneumococci
- Preventing the emergence of resistance
- 	- with fluoroquinolones and gram-negative bacilli

## PK/PD Parameters versus Emergence of Resistance for Fluoroquinolones

**	****	****	****	****	****Resistance Developed**
_**24-Hr AUC/MIC**_**	****      **_***P. aeruginosa***_**   **_**Other GNB**_**   **
**<100 - Monotherapy****	****      80%****	****	****  100%**
**>100 – Monotherapy****	****      33%****	****	****    10%**
**   ****Combinations****	****	****      **_**11%**_**	****	****    **_**  0%**_**	****	****	****	****                25%****	****	****    12%**
**Thomas et al.  AAC 42:521, 1998**

## Applications of PK-PD

- Guideline development
- 	- CDC guidelines for pneumonia and otitis media
- 	- Sinus and Allergy Health Partnership guidelines 	for sinusitis
- Formulary decisions
- 	- based on local or regional susceptibility data

## Application  of PK-PD for New Drug Development

- Dose Selection for Phase 2/3 Studies
- 	- in vitro and animal studies to identify PK-PD 	target for efficacy
- 	- phase 1 studies to determine which doses reach 	target with high probability
- 	- mostly with antibacterials; rarely with antifungals
- Susceptibility Breakpoint Selection
- 	- required by NCCLS by M23 (1 of 4 parameters 	used for breakpoint selection)
- 	- FDA – variable use

## Application of PK-PD for New Drug Development

- PK-PD studies in phase 2/3 clinical trials
- 	- optimal sampling techniques
- 	- interest in including “time to events”
- 	- statistical strategies to model both clinical 	and microbiological outcomes
- 	- bacteriologic cure usually harder to obtain 	than clinical cure

## Relationship Between 24-Hr AUC/MIC and Efficacy of Ciprofloxacin in 64 Patients with Serious Bacterial Infections

- Forrest et al.  AAC 37:1073, 1993

## PK-PD Studies in Phase 2/3 Clinical Trials

- Increases complexity of study
- Increases cost
- No established benefit with regulatory agencies
- Can such studies reduce the number of patients needed for efficacy trials ?
- 	- used for a fluoroquinolone to reduce number of cases for inclusion of penicillin-resistant pneumococci in label

## Dose Selection

- What is the PK-PD indice that best determines efficacy?  Requires in vitro or animal models
- What is the magnitude of the PK-PD indice required for efficacy? Should be based on free drug levels and linked to survival in animal models
- How do neutrophils effect the magnitude of the
- 	PK-PD indice?
- Does the magnitude vary with different organisms especially resistant strains?
- Does the magnitude vary with different sites of infection

## Correlation of Serum Concentrations with Sites of Infection

- Serum

- Interstitial fluid
- Fluid Collections
-    (sinusitis, AOM)
- Abscess
- ELF
-    (   macrolides;
-        vanco, dapto)
- CSF
- Intracellular fluid
- Urine

- Good

- Poor

## Dose Selection

- What is the magnitude of the PK-PD indice required to prevent the emergence of resistance?
- Can nontoxic doses of the drug in humans reach the magnitude of the PK-PD indice required for efficacy and for prevention of resistance with a high probability? Should be based on free drug concentrations