2 Flashcards
(17 cards)
Cerivastatin NW
Cholesterol treatment
Linked to 40 deaths - Rhabdomyolyse/Schädigung Skelettmuskulatur !!
Vioxx NW
nonsteroidal anti-inflammatory drug (NSAID)
Withdrawn from the market - erhöhtes Risiko für Schlaganfall!!!
Mibefradil (Posicor)
Calcium T- and L-channel blocker - Roche for use in hypertension
starke Interaktionen mit anderen Medis via P-gp und 3A4!!!
Inhibitor of both CYP3A4 and P-glycoprotein
Severe drug-drug interactions with:
- other Ca2+ blockers
- beta blockers
- digoxin
- cyclosporine
- simvastatin
- tacrolimus
Medikament an sich praktisch keine Nebenwirkungen, aber sehr viele Interaktionen mit anderen Medikamenten(
TGN1412
Potential to treat autoimmune and inflammatory diseases
Cytokine storm with multi-organ failure → Species differences !
Cytokinsturm mit Multiorganversagen → Speziesunterschiede
BIA 10-2472
Development of fatty acid amide hydrolase (FAAH) inhibitors to treat neuropathic pain
128 participants: 1 brain dead / brain damage in others
Investigations non-conclusive (inhibition of off-target cerebral receptors?).
The toxicology program carried out in 4 preclinical species (mouse, rat, dog, and monkey) did not demonstrate significant neurotoxicity - Species differences !
what consequences have been drawn from failed drug trials?
Safety first
Fail cheap and early:
(Discovery and non-clinical development phase: US$ 50 million average ‘only’, 1 to 3 years)
Before you start with clinical development the potential issues/interactions have to be known (Posicor)
Risk management:
- Balance risk and benefit (e.g. above examples and use of teratogenic Thalidomide (Contergan) in leprosy and ulceration as immunomodulator !!) (just don’t give to pregnant women, otherwise is good drug)
Important role of pre-clinical toxicology !
Klinische Entwicklung Phase I
- Subjects: Mainly healthy volunteers (cancer: patients) → No avoidable risk and highest ethical standards
Design: Often SAD, MAD (Dosis langsam erhöhen)
- Goal: Characterization of pharmacokinetics
- Goal: Safety
- Goal: If possible PK/PD readout
- Goal: Preparation of phase II trials
Welche Ethischen Richtlinien gibt es und welche Themen sind wichtig fur Phase I?
Nuremberg Code (1947) and the Declaration of Helsinki (1964 - present)
Ethical questions and issues:
- Drugs for children, clinical trials with children? Schwierig, weil Kinder nicht selbst entscheiden können, aber im Moment keine Medikamente für Kinder, fast nur off-label use
- Financial compensation for participation in clinical trials? Geld ist auch Druckmittel (leverage)
- Participation of women in clinical trials?
Toxicological Tasks for clinical studies phase I
Eliminate’ all risks for (healthy) volunteers
- Safety in vitro
- Safety in vivo in at least two animal species (1 rodent and 1 non-rodent, e.g. rat and dog)
- Estimation of the starting dose
- Estimation of the maximum tolerated dose (MTD) in humans
- Identification of potential issues to guide design of clinical trials
- Prepare for regulatory as well as independent ethical review
Examples of drug testing prior to EIH (entry into human)
- Identification of drug-drug interactions (DDI) with the drug transporter P-glycoprotein
- DDI with cytochrome P450
P-Glykoprotein
Species differences.
- Human: MDR1
- Rodents: mdr1a (or mdr3) and mdr1b (or mdr1)
Polymorphism and induction of P-gp
Transportiert Stoffe aus Zelle raus, wichtig für Blut-Hirn-Schranke
Consequences for P-gp substrates: Vergleich von wild-type und knock out
Bi-directional transport (functional) assay
- Recombinant cell lines on Transwell filters:
- Transport assay (Kontrolle mit Inhibitoren)
- Analytics
Asymetry of transport is an indication for a directed and active transport process
ZNS gängige Substanzen sind Substrate von P-gp
Richtig/Falsch?
Falsch: Marketed (im Verkauf) CNS compounds are not P-gp substrates!
Mit welcher Vorgehensweise (approach) sollte man P-gp/CYP betrachten?
IDENTIFY P-gp substrates early
FLAG: A transport ratio of > 3 is a finding which needs to be followed up for ZNS
or in vitro finding for CYP
DE-RISK by showing that:
- Efficacy in animal model (i.e. high activity / low variability despite P-gp)
- Safety: High safety margin of drug candidate
- Transport ratio human > ratio animal model
- Early proof-of-concept in humans (i.e. PET study or pharmacological effect)
- DDI in animals
CYPs kind of
- CYP3A4: Most important, up to 60% liver P450 content (after induction), broad substrate specificity (small and lipophilic molecules,
- CYP1A1: Mostly extrahepatic (lung), highly inducible by smoking
- CYP1A2: Caffeine, inducible by diet, role in chemical carcinogenesis substrates: planar molecules of moderate volume and basicity
- CYP2D6: Genetic polymorphism (poor metabolizers: 7% caucasian; 50% asian), Not inducible substrates: hydrophilic with a basic atom (nitrogen)
- CYP2C19: Genetic polymorphism (poor metabolizers: 3% caucasian; 20% asian), substrates: neutral or weakly basic, moderate lipophilicity
- CYP2E1: substrates: small, neutral, lipophilic (e.g. ethanol, halogenated hydrocarbons)
CYP-dependent metabolism of drugs Identifying
Human liver microsomes (pool of 20 donors) used to identify substrates as well as inhibitors of CYP’s
Identification of Inhibitors:
- Specific test probes using substrates 1/isoform except 3A4: 3/
- LC-MS/MS quantification, derived parameter: IC50s
