Pharmacology 4350A/B Lecture Notes - Lecture 8: Rifabutin, Bosentan, Muromonab-Cd3

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Types of new drugs
FDA sped up process in 1990 + Biopharmaceutical in 1980
-
Small molecules + peptides + proteins
Comes in different form
-
First-in-class drug
1.
2.
Mostly through target-based screening strategy
-
Combination drug
3.
Modified drug delivery formulation (extended release)
4.
New indication for old drug
5.
New route of administration for old drug
6.
Diseases
Chronic disease (CNS + metabolic + cardiovascular)
1.
Lethal disease (cancer + infectious)
2.
Common disease
3.
Rare disease
4.
Drug discovery strategies
Target-based
1.
Automated system in conducting chemical, genetic, pharmacological tests and allow
identification of active compounds + AB + genes involved in a biomolecular pathway
Universities use this to make money and allow academia teaching
High throughput screening assays best serves this strategy
-
Easy rapid chemical optimization of developmental drug
-
Sometimes the target is not actually related to pathogenesis
-
First-in-class + BCR-AB1 tyrosine kinase inhibitor
Target AB1 tyrosine kinase 3D structure allowed binding pocket structure
Discovery pre-clinical development took many years but clinical development took only 3
years to be registered on market
First rational drug design: Imatinib
-
Phenotype-based
2.
Low throughput testing
-
Hard to optimize chemical
-
Drug approved without knowing what the mechanism/target was
Later found to target NPC1L1 (cholesterol transporter) + metabolite Ezetimibe Glucuronide
is more effective
Ex: Ezetimibe (prevents cholesterol absorption from diet)
-
Strategy more successful for infectious disease + CNS diseases
-
Biologic
3.
When target is identified and related to pathogenesis
-
Successful strategy for immune diseases
-
Muronomab-CD3 (OKT3) (immunosuppressant)
Ex: Monoclonal Antibodies (first mAB = OKT3)
-
increase LDL-receptors + lower blood cholesterol
Successful in phase 2 trials + AB cannot be oral administered (IV only)
Ex: Mono AB for PCSK9 (proprotein covertase substillin/kexin 9)
-
Modification of a natural substance
4.
Usually small chemicals
-
Our advanced knowledge in ADME properties reduce failure rate due to PK issues
Determine ADME proeprties using In-vivo + in-vitro + in-sillico testing before human trials
-
Validate early stages of hit agents + optimization of chemical properties
Vivo studies require 4 different animal models (mouse/rat/monkey/dog)
Murine used due to easy genetic manipulation
Determine AUC + CL + T1/2 + what order kinetics + major metabolites formed
Drug and metabolites tested for toxicity using vivo
In-vivo
-
Subcellular content of either S9 (CYP + UGT + SULT + GST) or microsomes (CYP + UGT)
In-vitro
-
Drugs that may be administered once a day move on
In-vitro studies can predict hepatic + non-hepatic clearance which predicts in-vivo clearance
-
Drugs that can be metabolized by many CYP + metabolized by non-popular CYP +
metabolized by CYP with limited polymorphisms (move on)
Determine which CYP is metabolically active
Determine IC50 + Ki
[NCE]/Ki > 1 = interaction //// > 1.5 = dramatically increase AUC
Level of activation is drug-concentration dependent
PXR activated by diverse ligands (most common = HIV protease inhibitors)
Determine EC50 + Emax from drugs of interest to determine PXR activation
Statin drugs (shown in-vitro to activate PXR)
False positives are common as the therapeutic plasma concentration is lower
than concentration needed for PXR activation
Cmax predicts drug levels in intestine + liver because drug levels in organs are
hard to measure
Still on market for HIV treatment
Tipranavir (HIV protease inhibitor) is the first non-peptidic HIV protease
inhibitor and is PXR activator
PXR activation is commonly used to predict induction-type drug interaction
Determine drug-drug interactions
In-vitro use of recombinant enzymes to phenotype CYP activity
-
Covalent binding - microsomes + tissues + in-vivo rodent
Detect GSH conjugates
Drugs administered in >100mg are more likely for IADR and <10mg is least likely
Determine if drug is mutagenic using Salmonella strain (his-) + S9 fraction
(bioactivation)
Ames test done in-vitro for GENETIC toxicology tests
1.
In-vivo + In-vitro to study reactive metabolites + covalent binding + toxicity
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Monoclonal AB
Murine = "o"
-
Chimeric = "xi"
-
Humanized = "zu"
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Human = "u"
-
Idiosyncratic toxicity - must be < 1/1000 + unpredictable
Lecture 8 - Drug Discovery
April -21-12
8:35 PM
clinical pharm Page 1
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