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
Mostly through target-based screening strategy
Combination drug
Modified drug delivery formulation (extended release)
New indication for old drug
New route of administration for old drug
Chronic disease (CNS + metabolic + cardiovascular)
Lethal disease (cancer + infectious)
Common disease
Rare disease
Drug discovery strategies
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
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
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
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
Subcellular content of either S9 (CYP + UGT + SULT + GST) or microsomes (CYP + UGT)
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
Ames test done in-vitro for GENETIC toxicology tests
In-vivo + In-vitro to study reactive metabolites + covalent binding + toxicity
Monoclonal AB
Murine = "o"
Chimeric = "xi"
Humanized = "zu"
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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