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

New antibacterial agents approved in the United States 1983 - 2002 20 No. of New Antibacterial Agents 15 10 5 56 % 0 1983- 1988- 1993- 1998- 1987 1992 1997 2002 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

From Target to Drug / Patent life time I) Research Phase -> ~ 50% of patent shelf life used for development Exploratory Research Strategic Project Exploratory Research Strategic Project DP0 DP0 DP1 DP1 Molecular Molecular Strategic Development Strategic Development Screen Screen Project Project Candidate Candidate Target Target Success 60% 20 - 25 % 50% Rates Time Course 15 Months 15 Months II) Development Phase From DP1 to Market: 6 Years, 800 mio Euro DP0= decision point 0: Decision about novel strategic project DP1= decision point 1: Decision about start of development

Challenges in the Development of Anti-infectives Regulatory Pharmacokinetics and Pharmacodynamics in the development of antibacterial medicinal products CPMP/EWP/2655/99 R&D Strategic „Superiority Claims“ Discovery of and „Time to Market“ proof of concept for in a very „Improved Candidates‘“ competitive environment „Patents“

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 and patients at risk patients at risk drug drug interactions

General Strategy to Define and Validate the Clinical Dose by PK/PD Scientific knowledge regulatory guidelines regulatory guidelines Scientific knowledge Development Development Proof of Approvable Proof of Approvable Concept Drug Concept Drug Candidate Candidate ~ 3 years ‚Mechanistic Mechanistic‘ ‘ approach approach ‚Probabilistic Probabilistic‘ ‘ approach approach ‚ ‚ PK: PK: non-compartmental Population methods in patients compartmental Modeling and Simulation Physiology Based PK (PBPK) PK/PD: PK/PD: statitistical tools based on In vitro/ in vivo/in silico epidemiological data, based on lead organisms 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; I E ; AUBC, AABC AUC/MIC, Cmax/MIC, t>MIC, AUBKC norm Determination of the magnitude of 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 Use: for a O D dose regim en • Early dose 10000 borderline susceptible susceptible (M IC < 0.5 m g/L) estimation based (M IC < 0.125 m g/L) on good knowledge 1000 of PK and PD AUIC G ram negative Threshold properties of MFX 100 G ram Positive Threshold • Predicted dose: 10 400 m g 400 mg once daily 50 m g 100 m g 200 m g 1 0.0 0.2 0.4 0.6 0.8 1.0 M IC [m g/L]

Target Concentration Strategy / Phase II - III Deterministic PK/PD mapping to characterize the effect of PK variability on the bactericidal effect of MFX 1000 Gati (0.25) Use: Gati (0.50) 100 Gati (1.00) Moxi (0.12) • Decision on clinical Moxi (0.25) Moxi (0.50) dose Moxi (1.00) AUBC 24, norm 10 • Predicted dose: 400 mg once daily • Decision on 1 necessity of dose adjustments (interactions, 0.1 special populations) 1.0 0.8 0.6 MIC 0.01 0.4 200 300 400 0.2 500 600 700 0.0 800 ICC, 2001 Dose [mg]

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

90 1600 PK PD PK/PD Tools II 400mg p.o . 80 1400 70 1200 60 1000 Dalhoff, 2000 50 800 n = 374 n 40 600 30 400 20 200 10 0 0 <0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 15-20 20-25 30-35 35-40 40-45 45-50 50-55 55-60 60-65 65-70 70-75 75-80 10-15 25-30 MIC (mg/L) AUC - Range [mg*h/L] AUIC<30 PD- Monte Carlo Simulation 70>AUIC>30 Index 125>AUIC>70 1.63% AUIC>125 0.99% 3.79% PK/PD 93.60% \PHSTS\PKPD MFX Mod elmaker3 sts 0 5030 3.ppt

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 Sensitivity analysis of target hit rates for a drug candidate using population PK/PD methods for a given PK, dose regimen and PD distribution 120 Use: * 100 Target Hit Rate [%] • translate THR at MIC 0.5 preclinical PK/PD 80 THR at MIC1 results into clinical 60 dosing regimen 40 • plan and optimize 20 study designs 0 0 25 50 75 100 125 150 AUIC cut off [h] * each THR was obtained from a Monte Carlo simulation

Probabilistic PBPK/PD Approaches in Phase I Planning of study designs using Modelling & Simulation based on literature data Comparison between predictions and population PK results obtained from patients receiving a single 1000 mg dose of Prostate concentration [mg/kg] Cipro XR prior to prostate biopsy 12 9 6 3 0 0 1 2 4 5 Time [h]

PK/PD - where are we? PK/PD methodology is a very powerful instrument to plan development and validate clinical findings and beyond ... 1.E+05 In vitro PK/PD MFX 400 experiments GFX 400 1.E+04 suggest that LFX 500 compounds from LFX 750 1.E+03 one class (FQs) Ref. AUBKCnorm [h] behave similar 1.E+02 (vs S. aureus), 1.E+01 but... 1.E+00 1.E-01 0.01 0.10 1.00 10.00 MIC [mg/L] Bauernfeind et al., ECCMID 2005

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 3 years 0 1 2 Preclin. Dev. Phase I PhaseII Phase III • Definition of clinical Approval dose regimen in Phase I Market • 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