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Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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Page 1: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

Overview of Use of PK-PD in Streamlining Drug

Development

William A. Craig

Professor of Medicine

University of Wisconsin

Page 2: 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

Page 3: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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

Page 4: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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

Page 5: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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

Page 6: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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

Page 7: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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

Page 8: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

Relationship Between 24-Hr AUC/MIC and Efficacy of Ciprofloxacin in 64 Patients

with Serious Bacterial Infections

0

20

40

60

80

100

0-62.5 62.5-125 125-250 250-500 >500

Eff

icac

y

Clinical

Microbiologic

Forrest et al. AAC 37:1073, 1993

Page 9: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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

Page 10: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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

Page 11: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

Correlation of Serum Concentrations with Sites of Infection

Serum

Interstitial fluidFluid Collections (sinusitis, AOM)AbscessELF ( macrolides; vanco, dapto)CSFIntracellular fluidUrine

Good

Poor

Page 12: Overview of Use of PK-PD in Streamlining Drug Development William A. Craig Professor of Medicine University of Wisconsin

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