1 / 44

Pharmaceutical aspects of the development of anti-infectives

Pharmaceutical aspects of the development of anti-infectives. Dr Jeffrey R Edwards Infection Therapy Area AstraZeneca. Why develop a new anti-infective agent? The infrastructure required , competition for resources Really ‘new’, another variant or ‘a compound too far’?

lirit
Download Presentation

Pharmaceutical aspects of the development of anti-infectives

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Pharmaceutical aspects of the development of anti-infectives Dr Jeffrey R Edwards Infection Therapy Area AstraZeneca

  2. Why develop a new anti-infective agent? The infrastructure required , competition for resources Really ‘new’, another variant or ‘a compound too far’? Discovery and development.

  3. Why develop a new anti-infective agent? The infrastructure required , competition for resources Really ‘new’, another variant or ‘a compound too far’? Discovery and development.

  4. RESISTANCE

  5. Bacterial resistance is now a high-profile issue for Governments, International bodies and the press • But ....... • there always has been and there always will be bacterial resistance to anti-microbials • we probably don’t really know how to select a dosing regimen and use agents optimally • we don’t help by being imprecise with terminology: we fail to distinguish between ‘mechanisms of resistance’ and therapeutic failure • we rarely identify unusual events or show diminished susceptibility: breakpoints have a lot to answer for! Some observations .........

  6. resistance varies between countries • within hospitals, ITUs have the problems • resistance is seen in the community.

  7. Some highly publicised resistance problems • Enterobacteriaceae • ESBLs, notably in Klebsiella • chromosomal b -lactamases • Enterobacter, Citrobacter etc • Salmonella typhi • Shigella dysenteriae • Pseudomonas aeruginosa • Burkholderia cepacia • Stenotrophomonas maltophilia • multi-resistant staphylococci • penicillin-resistant pneumococci • macrolide-resistant group-A streptococci • VAN-R enterococci • Corynebacterium jeikeium • Mycobacterium tuberculosis

  8. Limited choice of therapy • penicillin- and macrolide-resistant pneumococci • macrolide-resistant Group A streptococci • ESBL bearing Enterobacteriaceae • Enterobacteriaceae over-expressing chromosomal b-lactamases • Pseudomonas aeruginosa • Pseudomonas spp. • Acinetobacter spp. • Burkholderia cepacia • Stenotrophomonas maltophilia

  9. Untreatable bacteria • multi-resistant staphylococci • vancomycin-resistant enterococci • Corynebacterium jeikeium • Mycobacterium tuberculosis

  10. Summary • There are a relatively small number of untreatable bacteria • There is a reduction in the choice of agents to use • There is an unquantified issue relating to undetected diminished susceptibility • Therefore, new agents are needed !

  11. Why develop a new anti-infective agent? The infrastructure required , competition for resources Really ‘new’, another variant or ‘a compound too far’? Discovery and development.

  12. The infrastructure • Therapy areas • GI • Cancer • CNS • CVS • Pain • Respiratory • Infection

  13. The infrastructure • Therapy areas • GI • Cancer • CNS • CVS • Pain • Respiratory • Infection • Commercial activities • Market research • Quantifying opportunities • Preparing for launch • Launching/ selling • Life cycle

  14. The infrastructure • Therapy areas • GI • Cancer • CNS • CVS • Pain • Respiratory • Infection • Commercial activities • Market research • Quantifying opportunities • Preparing for launch • Launching / selling • Life cycle • Development Depts. • Large scale synthesis • Formulation • Manufacture • Safety evaluation • Clinical evaluation • Regulatory • Intellectual Property

  15. The infrastructure Therapy areas Infection • Commercial activities • Market research • Quantifying opportunities • Preparing for launch • Launching and selling • Life cycle • Development Depts • Large scale synthesis • Formulation • Manufacture • Safety evaluation • Clinical evaluation • Regulatory • Intellectual property

  16. Why develop a new anti-infective agent? The infrastructure required , competition for resources Really ‘new’, another variant or ‘a compound too far’? Discovery and development.

  17. A compound too far .............. ??

  18. b-lactam antibiotics

  19. NH NH S NH S CH 3 CH N N N 3 O O O COOH penicillin cephalosporin carbacephem H H H H S N N O O COOH carbapenem penem Nucleus COOH COOH COOH

  20. Outer membrane b-Lactamase Periplasmic space Peptidoglycan Cytoplasmic membrane

  21. Penicillins benzylpenicillin / methicillin or oxacillin ampicillin / amoxycillin amoxycillin + clavulanate piperacillin piperacillin + tazobactam Continuing problem of instability to b-lactamases

  22. Cephalosporins cefotaxime ceftriaxone ceftazidime cefepime / cefpirome Problems of emergence of resistance, commonly b-lactamases

  23. Carbapenems

  24. Structures of meropenem and imipenem + cilastatin CH3 OH CH3 H CON H CH3 CH3 S NH N O COOH Meropenem N H 2 OH S H H C OOH + CH3 CH NH NH S N O N H O COOH COOH Imipenem Cilastatin

  25. Gaps in the spectrum of carbapenems • methicillin-resistant staphylococci • some enterococci • some pseudomonads • ? B. cepacia • S. maltophilia • Newer molecules have exhibited toxicities • not normally associated with b-lactams !!

  26. Quinolones

  27. Quinolones • what has been ‘added’ since ciprofloxacin? • what will be added in the future? • toxicity seen in • temafloxacin • trovafloxacin • grepafloxacin • moxifloxacin • clinafloxicin • others struggling?

  28. Really new ........... genome-based target discovery

  29. Filters Antifungal Antibacterial essential for viability selectivity spectrum technical feasibility literature review knowledge/experience literature review knowledge/experience literature review knowledge/experience TARGETS Model Genomes E. coli or S. cerevisiae

  30. Genome-based target discovery • new targets do not guarantee new drugs • new targets have no ‘history’ • how will they be viewed by Regulatory agencies ? • how will you, the user, feel about a series of agents • about which you know nothing ? • will you reserve them as drugs to use last ? • diversity in the compound-collection is very important • when screening.

  31. Why develop a new anti-infective agent? The infrastructure required , competition for resources Really ‘new’, another variant or ‘a compound too far’? Discovery and development.

  32. World market for anti-infectives is ~$US 37 billion

  33. World market for anti-infectives is ~$US 37 billion • anti-bacterials is ~$ 24 bn • hospital anti-bacterials is $ 8.5 bn • serious hospital anti-bacterials is $ 2.5 bn • s/h respiratory is $ 0.7 - 1 bn.

  34. The cost of developing a multi-indication anti-bacterial is ~ $US 400 - 600 million

  35. No company can do everything, so ....... • Focus research in • selected areas • against drug-profiles which are based on • medical need and • commercial attractiveness.

  36. New agents will come from genome-based programmes • The process • Select and validate a target • design a 500,000 HTS • identify hits and ‘sanitise’ • progress chemistry • select lead series • optimise leads • select candidate(s) for development. • With attrition at every stage, you’r lucky to do this in 5 years.

  37. Evaluating candidates for development • (assume you have in vitro and in vivo activity) • perform extensive laboratory studies on short-list • pre-screen for toxicity • assess pK in animals and model for human kinetics • can it be manufactured? • select candidate • After these several years, is it still competitive? • If this is a new target and a new chemical series there • will be no precedent upon which to make judgements.

  38. Developing a new agent (1) • be sure of • toxicological support for the compound • a secure route of manufacture • patent protection of the molecule and its • route of synthesis • secure resources for • the pre-clinical phase • the ‘proof of concept testing’ • the complete clinical package to support both • Regulatory and launch requirements.

  39. Developing a new agent (2) • decide upon which indications to trial, globally • narrow-spectrum does not mean narrow indications • select and access suitable clinical trial centers • many are not acceptable to major Agencies • co-ordinate microbiology, kinetics, clinical programme • and all other components of a regulatory dossier • plan launches in anticipation of acceptable licenses • file your dossier(s) and be prepared to interact with • and respond rapidly to questions • hopefully, launch in first territories and prepare for others.

  40. BUT ................................. • you can be well through the process when things change! • IDSA guidelines • new problems with an established class may result • in changes in Regulatory requirements • ESBLs had not been documented when cefepime was • discovered.

  41. Why develop a new anti-infective agent? The infrastructure required , competition for resources Really ‘new’, another variant or ‘a compound too far’? Discovery and development.

  42. Summary • the process is increasingly complex and expensive • we all agree that new anti-infective agents are required • conversely, the difficulty in discovering and • developing new molecules in not appreciated fully • some of the ‘problems’ and ‘needs’ require precise definition • new agents will emerge only with the co-operation of • providers, users and Regulators.

More Related