Exam 2 lecture 13

Question 1

preclinical & phase 0

Answer 1

• 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)

Question 2

Phase 1

Answer 2

PK/PD in healthy volunteers or pts: drug metabolizing enzymes (phase I & II), transporter, molecular targets

Question 3

phase II/III

Answer 3

• 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)

Question 4

key components of clinical pharmacology

Answer 4

• optimal use of existing meds

- evaluation of new drugs

Question 5

what phase do most drugs fail?

Answer 5

phase 2

Question 6

discovery phase

Answer 6

• 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

Question 7

development phase

Answer 7

• clinical PK/PD studies (phase 0-III)
• population PK
• dose-response modeling/simulation
• PG trial
• phase IV

Question 8

preclinical pharmacology PK & bioavailability

Answer 8

• protocol
• analytical methods
• PK analysis
• statistical methods
• justification for bioavailability study
• discussion

Question 9

clinical pharmacology PK & bioavailability

Answer 9

• protocol (ADME)
• analytical methods
• PK analysis
• statistical methods
• bioavailability study (blood level)
• individual study report

Question 10

types of clinical trials

Answer 10

treatment
prevention
screening/early detection
diagnostic
genetics
QOL/supportive care

Question 11

phase I primary objectives

Answer 11

15-30 people

• what dosage is safe
• how should treatment be given
• how does treatment affect the body

Question 12

phase II primary obectives

Answer 12

<100 people

• dose treatment do what it is supposed to
• how does treatment affect the body

Question 13

phase III

Answer 13

100-thousands

- compare new treatment with current standard

Question 14

phase IV

Answer 14

hundreds- thousands

• usually takes place after drug is approved
• used to further evaluate long-term safety & efficacy

Question 15

conclusion of phase I trial

Answer 15

toxicity- acute/ delayed
response- target for phase II
max tolerated dose

Question 16

phase 0

Answer 16

• proof of concept in clinic setting

- target development

Question 17

phase 0 trials need a

Answer 17

exploratory IND

Question 18

microdose studies

Answer 18

PK or imaging as endpoints

Question 19

pharmacologically relevant doses

Answer 19

doses higher than microdose; more safety data needed; PD enpoints

Question 20

pharmacodynamic endpoint studies

Answer 20

PD biomarker endpoints

Question 21

PD assay criteria

Answer 21

accuracy
dynamic range
precision
sensitivity
reproducibility
robustness

Question 22

PD assay is required for

Answer 22

phase 0 trial

Question 23

potential benefits of phase 0 trial

Answer 23

• 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

Question 24

Phase 0 trial limitaions

Answer 24

• 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