Challenges in Antimicrobial Clinical Development Axel Dalhoff & - - PowerPoint PPT Presentation

Challenges in Antimicrobial Clinical Development

Axel Dalhoff & Heino Staß Institut für Klinische Pharmakologie Bayer AG, Wuppertal, D

5 10 15 20 1983- 1987 1988- 1992 1993- 1997 1998- 2002

New antibacterial agents approved in the United States 1983 - 2002

• No. of New Antibacterial Agents

56 %

Spellberg, CID May 01,2004; 38

Challenges for Antibiotic R & D in Pharma Research

High failure rate in Research Lack of pipeline compounds Difficulty to discover new agents even for experienced people

• if not shifted to different research targets

Highly promising approach to genomic based new agents has failed to date Research focus in favour of chronic treatments

e.g. chronic viral diseases as HIV, HCV vs. acute treatments

Based on cumulated experience in animal models, high safety margins have to be achieved preclinically

Exploratory Research Exploratory Research Strategic Project Strategic Project DP0 DP0 DP1 DP1

Molecular Molecular Target Target

Screen Screen Strategic Strategic Project Project Development Development Candidate Candidate

Success Rates

60% 20 - 25 %

Time Course

50% 15 Months 15 Months

I) Research Phase

From DP1 to Market: 6 Years, 800 mio Euro II) Development Phase

DP0= decision point 0: Decision about novel strategic project DP1= decision point 1: Decision about start of development

From Target to Drug / Patent life time

• > ~ 50% of patent shelf life used for development

Challenges in the Development of Anti-infectives

Regulatory

Pharmacokinetics and Pharmacodynamics in the development

• f antibacterial medicinal products

CPMP/EWP/2655/99

R&D

Discovery of and proof of concept for „Improved Candidates‘“ „Patents“

Strategic

„Superiority Claims“ „Time to Market“ in a very competitive environment

Role of Clinical Pharmacology in tackling the Challenges in the Development of Antimicrobials

• Classical safety and PK

(frequent and less frequent AEs)

• PK/PD Defining the dose for clinical studies
• > ‘mechanistic’ PK/PD approaches
• Sources and of PK variability (e.g. interactions) and

their impact on antimicrobial activity

• > population (‘probabilistic’) PK/PD approaches
• Justify the dosing regimen for the patient population

based on PK/PD -> population PK/PD approaches

• Dosing recommendations for clinically relevant

drug drug interactions drug drug interactions and patients at risk patients at risk

General Strategy to Define and Validate the Clinical Dose by PK/PD

Scientific knowledge Scientific knowledge regulatory guidelines regulatory guidelines Development Development Candidate Candidate Proof of Proof of Concept Concept Approvable Approvable Drug Drug ~ 3 years

‚ ‚Mechanistic Mechanistic‘ ‘ approach approach ‚ ‚Probabilistic Probabilistic‘ ‘ approach approach

PK: non-compartmental compartmental Physiology Based PK (PBPK) PK/PD: In vitro/ in vivo/in silico based on lead organisms PK: Population methods in patients Modeling and Simulation PK/PD: statitistical tools based on epidemiological data, e.g. Monte Carlo Simulations

PK/PD Tools I

Mechanistic:

Physiology Based PK Interspecies scaling of PK Target tissue concentrations Tests of antibacterial effects: static in vitro models -> MIC Determination of the dominant PK/PD index driving the effect: animal models, dynamic in vitro models (-> time to kill; change in viable counts; maximum re- duction in viable counts; IE; AUBC, AABC AUC/MIC, Cmax/MIC, t>MIC, AUBKCnorm Determination of the magnitude

• f the PK/PD Index
• > PK/PD cut off points,

Target Concentration Strategy / Phase I-II

Deterministic PK/PD in early Phase I

Decision on target dose for MFX based on PK/PD from single dose escalation

M oxifloxacin / AU IC as a function of M IC for a O D dose regim en

M IC [m g/L]

0.2 0.4 0.6 0.8 0.0 1.0

AUIC

1 10 100 1000 10000 G ram negative Threshold G ram Positive Threshold

susceptible (M IC < 0.125 m g/L) borderline susceptible (M IC < 0.5 m g/L)

50 m g 100 m g 200 m g 400 m g

Use:

• Early dose

estimation based

• n good knowledge
• f PK and PD

properties of MFX

• Predicted dose:

400 mg once daily

Target Concentration Strategy / Phase II - III

Deterministic PK/PD mapping to characterize the effect

• f PK variability on the bactericidal effect of MFX

0.01 0.1 1 10 100 1000 0.0 0.2 0.4 0.6 0.8 1.0 200 300 400 500 600 700 800

AUBC24, norm MIC Dose [mg]

Gati (0.25) Gati (0.50) Gati (1.00) Moxi (0.12) Moxi (0.25) Moxi (0.50) Moxi (1.00)

Use:

• Decision on clinical

dose

• Predicted dose:

400 mg once daily

• Decision on

necessity of dose adjustments (interactions, special populations)

ICC, 2001

PK/PD Tools II

Probabilistic PK/PD methods

Principle: Determination of the likelihood of clinical success by implementing information on PK variability and PD variability into PK/PD analysis Requirements: Models describing the pharmaco kinetic variability in the target population using population PK methods Epidemiological distribution pattern of the target pathogens PK/PD indices identified and quantified by mechanistic methods based on epedimiologic data on the targeted micororganisms e.g. AUIC cut off, microbiological breakpoint

PK/PD Tools II

\PHSTS\PKPD MFX Mod elmaker3 sts 0 5030 3.ppt

PK/PD

93.60% 3.79% 1.63% 0.99% AUIC<30 70>AUIC>30 125>AUIC>70 AUIC>125

400mg p.o. AUC - Range [mg*h/L]

10-15 15-20 20-25 25-30 30-35 35-40 40-45 45-50 50-55 55-60 60-65 65-70 70-75 75-80

n

10 20 30 40 50 60 70 80 90

n = 374

MIC (mg/L)

PK PD

200 400 600 800 1000 1200 1400 1600

<0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4

Dalhoff, 2000

PD- Index

Monte Carlo Simulation

Probabilistic PK/PD Approaches in Phase III

Target hit rates based for 3 FQs based on unbound concentrations for 5000 simulated patients with S. aureus infection

Use:

• confirm microbiological

breakpoints

• validate dose regimen

for safe clinical use

Ambrose et al., AAC 2004

Probabilistic PK/PD Approaches in Phase I

20 40 60 80 100 120 25 50 75 100 125 150 AUIC cut off [h] Target Hit Rate [%]

THR at MIC 0.5 THR at MIC1

Sensitivity analysis of target hit rates for a drug candidate using population PK/PD methods for a given PK, dose regimen and PD distribution * Use:

• translate

preclinical PK/PD results into clinical dosing regimen

• plan and optimize

study designs

* each THR was obtained from a Monte Carlo simulation

Probabilistic PBPK/PD Approaches in Phase I

1 2 4 5 Time [h] 3 6 9 12 Prostate concentration [mg/kg]

Planning of study designs using Modelling & Simulation based on literature data

Comparison between predictions and population PK results

• btained from patients receiving a single 1000 mg dose of

Cipro XR prior to prostate biopsy

PK/PD - where are we?

PK/PD methodology is a very powerful instrument to plan development and validate clinical findings and beyond ...

In vitro PK/PD experiments suggest that compounds from

• ne class (FQs)

behave similar (vs S. aureus),

but...

Bauernfeind et al., ECCMID 2005

1.E-01 1.E+00 1.E+01 1.E+02 1.E+03 1.E+04 1.E+05 0.01 0.10 1.00 10.00 MIC [mg/L] AUBKCnorm [h]

MFX 400 GFX 400 LFX 500 LFX 750 Ref.

PK/PD - where are we?

AUIC FQ Indication Ref. cut off ______________________________________________________ > 125 Cipro Gram - severe RTI, Schentag et al. elderly patients > 75 Grepa Gram+ community acquired Pickerill et al. RTI, elderly patients > 30 Gati Gram+ community acquired Ambrose et al. RTI, elderly patients > 12* Levo Gram+ community acquired Preston et al. RTI, cSSSI, Gram - UTI ______________________________________________________

* peak/MIC cut off, (AUIC~100)

PK/PD - where are we?

• Open questions remain
• individual PK/PD indices or per compound

class/disease/patient population.... ?

• applicability to various patient groups given

?

• plasma or target tissue concentrations

?

• ...
• for polymicrobial infections no clinically useful models

exist to date

• However, wealth of different PK/PD methods

available

• PK/PD indispensable to achieve ‘lean’ and smart

development -> ...

PK/PD in Clinical Development of Moxifloxacin

1 2 3 years

Preclin. Dev.

Phase I

PhaseII

Phase III

Approval

Market

• Definition of clinical

dose regimen in Phase I

• Merged Phase IIa and b
• Confirmation of dose

decision in Phase II

• PK/PD validation in Phase III

PK/PD in Clinical Development of Moxifloxacin

Case study Moxifloxacin: development cost benefit

Consequences for development: Cost [T€]

Phase I: 2 Phase I MD bracketing studies saved

• 250

Phase II: Condensed program (without separate 2B)

• 300

Phase III: Population PK/PD evaluations + 50 Total:

• 500 (< 1%°*)

*compared to total development cost

Advantages a) direct cost savings, but marginal compared to total development costs b) expenses for development are postponed to later phases c) -> financial risk reduction

PK/PD in Clinical Development of Moxifloxacin

Case study Moxifloxacin: strategic benefit

Consequences for development: Time savings

Phase I: 2 Phase I MD bracketing studies saved 3 months Phase II: Condensed program (without separate 2B) 9-12 months Phase III: Population PK/PD evaluations + 0

Overall, development time reduced by ~ 1 year

PK/PD in Clinical Development of Moxifloxacin

Case study Moxifloxacin: economic benefit Advantages

a) Market entry approximately 12 - 15 months earlier b) Total savings of 10-50 Mio € (after discounting and risk adjustment) c) Launch ahead of (potential) competitors, thus stronger competitive positioning d) One additional year of patent exclusivity -> additional sales at peak sales level

Change of paradigms in drug development

Yesterday Today Future

Primary science animal experiment Secondary science modeling simulations Learning science in silico simulations Confirmatory science animal experiment Primary science animal experiment Secondary science modeling simulations

modified from Pharma 2005, PricewaterhouseCoopers

Conclusion

Clinical Development of Antiinfectives is a challenging business, but ...

• In a competitive climate for clinical development modern PK/PD

methods have evolved as a versatile tool to steer clinical development and to cope with these challenges

• While direct cost savings by use of PK/PD concepts are small

in view of the total development costs, ...

• ... the strategic advances make the PK/PD tools a mandatory

instrument of clinical development

• Scientifically, application of PK/PD concepts remains a

fascinating field of research and development

• Few areas remain where application of PK/PD concepts is less

supportive