Pharmacology 4350A/B Lecture Notes - Lecture 8: Theralizumab, Mibefradil, Torcetrapib

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Drug development
11% successfully make it to registration stage
Drug safety + side effects + therapeutic window + market (life long preventive or treatment)
Purpose of clinical trial
Challenges: ethics board approval + develop network of clinical investigators/patients
Determine common ADR
Determine dose without high incidence of side effects
Determine pharmacokinetic ADME
Intrinsic Effect on special population (renal/hepatic failure + preg + age +sex/race)
Extrinsic effect (drug/drug interaction + drug/food interaction)
Objective: On Healthy individuals + special population
Uncontrolled clinical trials (esclating single doses + recurrent doses)
Descriptive observation (measured drug CONC) + prediction (mathematical model) +
Mechanistic theory (molecular biology)
PK determines if development continues + determine financial info (route of intake +
frequency of intake)
Determine pharmacokinetics
6 healthy volunteers +2 placebo
Developed intense systemic inflammatory that led to organ failure + critical ill
Phase 1 trial contracted to Paraxel
Paraxel dosed 6 subjects simultaneously when they should've dosed 1 before dosing
all 6
TGN1412 = monoclonal antibody CD28 (treat autoimmune disease)
50% of volunteers are not provided with free health care from clinical trial
Phase 1
Challenges: Ethics approval + develop network of clinical investigators/patients
Determine therapeutic efficacy in PATIENTS of interest
Determine experimental protocols for phase 3 (dose + duration + right endpoints to
Objective: Patients
Very narrow range of selection
On patients with disease of interest usually excluding special populations
No active control (no standard of care)
Failure to treat does not cause a serious event
Inactive placebo is appropriate if
Placebo (account non-drug effect) + randomization (selection bias) + blind format
( interpretation bias)
Placebo-controlled trial
Parallel group = Costly + more subjects required +randomized or control
Dose escalates for cross-over study
Cross-over patients have effects carryover so limit confounding factors
Parallel group (gold standard) or cross-over study
Therapeutic window + toxic window
Biochemical changes
Symptoms (pain + headache)
Clinical signs (BP + HR)
Clinical end points (hospitalization + dialysis time)
Level of response determined by endpoints
Determine exposure-response relationship (PK/PD)
Phase 2 trial found torcetrapid to raise HDL, raise more HDL with atorvastatin (lipitor),
double raise HDL when double dosed (HDL endpoint)
Another phase2/3 trial on torcetrapid comparing torcetrapid + atorvastatin and
atorvastatin only (clinical endpoints) found increase in BP
Drug discontinued
Torcetrapib - raise HDL cholesterol
Phase 2
More effective?
Determine quantitative info on efficacy of drug compared to current gold standard therapy
Provide necessary information regulators request + any additional safety data
Data for marketing
Provide several phase 3 trials to achieve regulatory approval
Randomized controlled
Several trials in different locations (multicentre)
300-5000 people
Duration of trial determined by disease of interest
1 study found mibefradil + beta-blocker improved angina/ischemia prevention
Adverse effect from drug interactions
2nd study found mibefradil + betablocker and Dihydropyridine (calcium channel
3rd study found mibefradil + Diltiazem increased the plasma level of
methylprednisolone (adrenal-suppressant) from co-administration because mibefradil
(CYP3A inhibitor)
4th study found mibefradil administered orally decreased clearance but IV mibefradil
did not + zero-order kinetics
Mibefradil (calcium channel blocker)
Phase 3
Acquire more safety data
Acquire marketing data
Determine off-label use
Extend phase 3
Phase 4
Unless it is a treatment for life-threatening diseases
1/50,000 risk for adverse event will cause withrawal
Size of study must be at least n=16,667 in order to reach 95% confidence
Studies to rule out ADE
Clinical investigators have financial gain
Oxycontin - falsely promotion of drug with unproven findings
Several factors that ruin the clinical results
Phase 2 - broad end points to look at everything
Phase 3 - narrow end points and more clinical end points
Problems with endpoint assessment
Some illness heal on its own + illness comes in waves
Condition of patient (old age leads to MI/stroke more than anything)
Unpredictable factors
Endpoint assessment may be subjective
Lecture 8 - Drug Development
9:46 AM
clinical pharm Page 1
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