preclinical & phase 0
- preparation for human studies: gene ID, SNPs, linked to PK (ADME) & PD (targeting); gene (SNP) linked to disease progression
- data collection & exploratory studies: GWAS (untreated & treated pts), RNA microarray (disease & treatment response)
Phase 1
PK/PD in healthy volunteers or pts: drug metabolizing enzymes (phase I & II), transporter, molecular targets
phase II/III
- PK in pts
- PK/PD modeling & simulation
- PD studies in pts response to therapy (targeted genes, SNPs, disease associated genes & SNPs, genes or SNPs previously linked to similar drugs)
- exploratory studies & biomarkers: GWAS (treated pts), RNA microarray (Disease & treated response)
key components of clinical pharmacology
- optimal use of existing meds
- evaluation of new drugs
what phase do most drugs fail?
phase 2
discovery phase
- consultation on selection of lead compounds
- assistance in preclinical pharm/tox studies
- consultation on SAR study
- participating in GO/NO GO decision
- assistance in formulation/pharmaceuticals
- participating in GLP/GMP/quality evaluation
- participating in pre-IND meeting & IND filing
development phase
- clinical PK/PD studies (phase 0-III)
- population PK
- dose-response modeling/simulation
- PG trial
- phase IV
preclinical pharmacology PK & bioavailability
- protocol
- analytical methods
- PK analysis
- statistical methods
- justification for bioavailability study
- discussion
clinical pharmacology PK & bioavailability
- protocol (ADME)
- analytical methods
- PK analysis
- statistical methods
- bioavailability study (blood level)
- individual study report
types of clinical trials
treatment prevention screening/early detection diagnostic genetics QOL/supportive care
phase I primary objectives
15-30 people
- what dosage is safe
- how should treatment be given
- how does treatment affect the body
phase II primary obectives
<100 people
- dose treatment do what it is supposed to
- how does treatment affect the body
phase III
100-thousands
- compare new treatment with current standard
phase IV
hundreds- thousands
- usually takes place after drug is approved
- used to further evaluate long-term safety & efficacy
conclusion of phase I trial
toxicity- acute/ delayed
response- target for phase II
max tolerated dose
phase 0
- proof of concept in clinic setting
- target development
phase 0 trials need a
exploratory IND
microdose studies
PK or imaging as endpoints
pharmacologically relevant doses
doses higher than microdose; more safety data needed; PD enpoints
pharmacodynamic endpoint studies
PD biomarker endpoints
PD assay criteria
accuracy dynamic range precision sensitivity reproducibility robustness
PD assay is required for
phase 0 trial
potential benefits of phase 0 trial
- early human trial w/ reduced pharm/tox data
- small # of patients
- relatively low cost
- facilitate rational drug discovery/lead selection
- streamline phase I trial & reduce development time
Phase 0 trial limitaions
- no data on efficacy or safety
- no intent to replace phase I
- not ideal for candidates w.out a defined target
- increased costs in PD assay development
- if the target is incorrectly ID, an effective drug may be eliminated
- PD effects are not necessarily shown in low doses & dose-dependent
- not for all agents
