Where do Drugs and Medicines come from? 2

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  • Created by: Louise
  • Created on: 28-12-14 15:36

Discovery of Anticancer Drugs

More than one in three of us will get cancer, just over one in four of us will die of cancer...

Therefore development of anticancer drugs is very important, therefore "fast track" development is needed

Problems with discovering new anti-cancer drugs

  • Very difficult to model the time course of most cancers
  • Most cancers are heterogeneous
  • Most animal models have very low predictability

Discovery

  • Rational design (biological target, medicinal chemistry)
  • In silico screening
  • Random screening (cell panels, chemical libraries, combinatorial chemistry)
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Preclinical Evaulation

Characterization of primary PD:

  • In vitro studies - cell types, sensitivity/resistant. Activity profile, mechanism of action/resistance. Cell cycle depenency
  • In vivo studies - therapeutic indec, schedule dependency, xenografts

Evaulation of toxicity - estabilish maximum tolerated dose (MTD) and target organ toxicity:

  • Saftey pharmacology
  • PK/TK studies 
  • Single dose tox 
  • Local tolerance 

 

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Phase I Trials - Anticancer

  • Usually first studies in man
  • Primary objectives - Determine MTD (dose for phase II). Adverse event profile, target organ, reversibility, PK/PD parameters 
  • Secondary objectives - tumour response, symptomatic therapy
  • Eligibility of Patients - confirmed cancer, adults no radiotherapy last 4 weeks and no chemotherapy last 4-6 weeks, life expectancy of > 8-12 weeks, normal marrow function and no major organ impairments, informed consent. 
  • Why would terminal patients take part? clinical benefit (although unlikely) allutrism
  • Starting dose based on preclin tox. Dose escalation
  • No other treatment ro be concomitantly administrated
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Phase I Trials - Anticancer

  • Each patient should have at least 2 cycles, discontinue treatment if disease progresses, if patient requests or incase of non-accceptable side effect/ADR. Continue treatment if tumour response seen.
  • Min 3 Patients at each dose (when no toxicity) Min 6 patients when toxicity - 
  • Termination of study - MTD reached and side effects assesed (reversibility and severity)
  • Conclusions of study - MTD, recommended dose for phase II, tests to evaulate toxicity, PK data, observations of any clinical benefits 
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Phase II Trials - Anticancer

  • Objectives - randomised or non randomised trials, determine if significant response can be seen in target tumours, further characterise PK profile, further characterise dose and schedule dependency, determine best route of administration, further characterise toxicity
  • Patiets - have confirmed cancer, ultilize patients to meet study objectives
  • Treatment - dose clearly indicated, dose modifications outlined, other concomitant treatment defined
  • Evaulation of toxicity as in Phase I
  • Evaulation of response - Independent review, time to progression, survival, assessment of symptoms
  • Termination of study - an observation of severe side effect not observed in Phase I, evidence of unacceptable cumulative toxicity
  • Conclusions (efficacy and toxicity) - significant activity or inactivity in target tumour. adequacy of the study, acute and sub-acute toxicity, reasons for early termination
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Phase III Trials - Anticancer

  • Objectives - to confirm antineoplastic activity, to provide comprehenisve data to enable risk/benefit assessment of new agent, to study the ffects of new agent - progression free survival, overall survival, response rate, symptoms (QOL)
  • Types of treatment investigated - single agent, combination treatment, new use for an established agent
  • Design of trials - eligibility criteria well defined, evaulation of efficacy (survival, response rates, symptoms), randomised trial - compare to established therapy, statistics well worked out.
  • Termination - Independent DSM - efficacy and toxicity, experimental plan fufilled
  • Conclusions - Efficacy of new agent, safety of new agent, relative efficacy 
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