Pharmacology 4350A/B Lecture Notes - Lecture 10: Torcetrapib, Pioglitazone, Atorvastatin

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Strongest design
Systemic review of well conducted RCT
1.
Individual RCT
2.
Systemic review of cohort studies (observation)
3.
Individual cohort study
4.
Case control study
5.
Case series
6.
7.
RCT
Randomization
1.
Concealed allocation
2.
Blind
3.
Minimal loss to follow-up
4.
Intention to treat
5.
Strong components
-
EXAMPLE: Perindopril (treat cardiovascular events) (ACE inhibitor)
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Class vs agents
Lipophilicity or hydrophilicity
1.
T1/2
2.
Dose-response
3.
Toxicity
4.
Metabolism
5.
Drug interactions
6.
Differences in
-
Rosiglitazone increase vascular events + pioglitazone may decrease
1.
Rosuvastatin no effect on heart failure + atorvastatin helps heart failure
2.
Examples of class effects different from agent
-
Toxicity Detection
Only young healthy volunteers while most drug toxicity occur to senior/renal/hepatic failure
RCT endpoints are efficacy endpoints, usually not safety efficacy
RCTS are poor at detecting
-
Confounding factors + selection bias
Pharmacoepidemeology showed increase death from hyperkalemia
Example: spironolactone shown in 1 RCT to help with heart failure + no hyperkalemia
Phase 4-post marketing pharmacoepidemeology (observation)
1.
Only applicable to healthy volunteers
No CV endpoints but meta-analysis show increase risk for CV events (rosiglitazone pulled)
Example: Rosiglitazone lowers blood glucose for diabetes
Meta-analysis of all RCTs
2.
Composite endpoints
Increase statistical precision + require fewer volunteers
1.
Helpful if low number of trials
2.
Allow similar endpoints equally relevant to be grouped
3.
Limit separate statistical analysis
4.
Better understanding on Overall therapy on a particular disease
5.
Some endpoints may be related and in a composite preserves intent-to-treat
6.
Why is it used?
-
Sample size + variables + power + subgroups are all geared towards primary endpoint
Clinical trials are designed for a primary hypothesis with primary endpoints
Example: Pioglitazone (treating diabetes 2), changed primary endpoints to all -cause mortality
-
Are the endpoints similarly important to patient
1.
Are there endpoints that occur in different frequency
2.
Are all endpoints have similar effects/findings?
3.
Criteria of composite endpoints
-
Surrogate endpoints
Intermediate biomarkers DIFFERENT from clinical endpoint
-
FDA does not require clinically relevant endpoints (death) to approve drugs based on surrogate
endpoints
-
Screen clipping taken: 22/04/2012, 5:40 PM
Lecture 10 - Appraise drug literature
April -22-12
5:08 PM
clinical pharm Page 1
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