Pharmacology: Partie 3, Recherche et développement des médicaments Flashcards
Partie 3, Recherche et développement des médicaments
What are the aspects of the pre-clinical development of a drug? (3 main aspects)
- Identification de molécules candidates
- Études in vitro: cellules et animaux
- Études de toxicité aiguë et chronique
Who are études de toxicité aiguë et chronique done on?
Testing medication on at least 2 species of animals of both sexes
What are the aspects of the “étude de toxicité aiguë”?
One administration, first study realized- Étude qualitative: signes toxiques
Étude quantitative: détermination de la dose létale
What is the “dose maximale non létale”?
Highest dose without a toxic effect
What is the “DL50”?
The dose that kills 50% of the test animals after 7 days (very useful for overdoses)
What are the aspects of the “étude de toxicité chronique”?
Effects after repeated administration of the substance
Length of exposition proportional to that expected to be prescribed in humans
Determining the “dose maximale sans effet toxique en prises répétées”
Same method of administration as to be prescribed
Study effets on reproduction
- Impact of medication on fertility - Administer medication a couple weeks before mating and look for latent effects on next generation
Study effects on mutagenesis and carcinogenesis
- Genetic alterations realized in animals and cells, test to see if the medication leads to increased tumour formation and if so… by which mechanisms
Study effects on pharmacokinetics
- Absorption, distribution, metabolism, and elimination
What is tératogénicité?
Capacité de ces médicaments à provoquer de malformations foetales, anomalie des membres (ex: Thalidomide)
What are the 4 stages of development of a medication?
IN HUMANS
- Stage 1: trials on healthy volunteers to see the safety/security of the medication
- Stage 2: trials on small groups of sick individuals
- Stage 3: multi-centric trials
- Stage 4: market testing and followup
What does phase 1 test?
Evolution of the molecule being tested in the human body (cinétique) and the short term toxicity in humans (toxicité)
What are the objectives of phase 1? (5)
- Security of the medication
- Determine tolerated doses (start small… work way up)
- Determine optimal dose
- Determine pharmacokinetic characteristics
- Identify principal metabolites (molecule that has been transformed by enzymes, produced by chemical rxn)
What are the pharmacokinetic characteristics?
Bioavailability, Cmax, Tmax, ASC, T1/2, taux sériques
What is bioavailability?
The relative quantity of active ingredient absorbed that attains systemic circulation expressed in % or fraction from 0-1
- -> IV meds: 100% or 1.. directly into bloodstream
- -> per os meds —> between 0 and 1 (ex: Vancomycine affects the intestines directly and isn’t absorbed into blood therefore has a bioavailability of 0)
What is the Cmax?
Highest plasmatic concentration of medication after its administration
What is the Tmax?
Time where Cmax is reached
What is the ASC (aire sous la courbe)?
expression of plasmatic concentration as a function of time
average plasmatic concentration over duration of time
What is the T1/2 (half-life)?
Time to eliminate 50% of active ingredient from the organism
meds are usually completely eliminated after 5-7 half-lives
Who are the test subjects of phase 1?
20-50 HEALTHY individuals
What is the difference between phase 1a vs 1b?
- 1a: determine safety of medication
- 1b: determine safety and effectiveness of medication
What is the clinical surveillance in phase 1 looking for?
Biochemistry and undesirable effects
What else is evaluated during phase 1? (3)
- Pharmacological effects
- Number of daily doses
- Influence of food on medication
- Foods that slow absorption
- Little or few clinical consequences
- Meds to be taken without food
- Meds to be taken with food
- Foods that slow absorption
What are the objectives of phase 2? (4)
- Establish dose-effect relation
- Determine pharmacokinetic characteristics in actual patients
- Define optimal conditions to take the medication (dose, interval, length of time)
- Establish its safety and tolerability and find out more undesirable side effects
What are biomarkers? (DOSE-EFFECT)
Measurable biological characteristic tied to normal or abnormal processes or the action of a medication
A quantitative measure that allows you to objectify a biological response
What are biomarkers useful for? (DOSE-EFFECT)
Dépistage, réponse à un traitement, rechute, toxicité
Who are the test subjects of phase 2?
Volunteers with the illness BUT patients selected to limit the variability of the response (group as homogeneous as possible)
What is the methodology for phase 2? (4)
Studies on small groups
Studies on bigger groups to determine optimal dose/interval
Comparing multiple doses (3-10 ish)
Determine the “critères d’efficacité”
What are the objectives of phase 3? (3)
- Demonstrate effectiveness and harmlessness (innocuité) of medication in planned clinical conditions
- Prolonged administration of the medication
- Needs to find a significant difference compared to other treatments (p<0.05) according to significant endpoints
Who are the test subjects of phase 3?
Once again patients but this time in different targeted groups according to age, other conditions, etc. —> groups should be representative of future patients (worldwide)
Usually, patients are divided into two groups: one receiving the new medication and the other receiving a reference medication
How is the medication distributed in phase 3?
Repeated doses, sometimes over many years
What is the methodology of phase 3? (4)
- 2 pivot studies that show effectiveness with no doubt
- Comparing to placebo and standard treatment
- Checking tolerance in higher-risk patients
- Checking tolerance with interactions with other medications
What is stage 4?
Surveillance phase
What are the objectives of phase 4? (6)
- Effectiveness and tolerability of medication
- Evaluating the therapeutic benefits of prescription in normal clinical conditions
- Comparing to and with other medications
- Rare side effects
- Finding other uses for the same medication
- Long term studies: mortality, quality of life, pharmacoeconomics
What are the goals of phase 4?
Pharmacovigilance et pharmacoéconomie
Who are the test subjects of phase 4?
Large, varied population including those excluded in phase 3 (ex: kids, very old people)
Who can declare the side effects of medications in stage 4?
ANYONE!
What is the first step for the approval of a drug (in Canada) ?
The pharmaceutical company submits a presentation for a new drug which is then evaluated by Health Canada
What does Health Canada look at? (5 main things)
- Safety, effectiveness and quality of the medication
- Study results of preclinical and clinical trials in Canada or elsewhere
- Details relating to production, packaging and labelling of medication
- Study information concerning therapeutic properties and side effects of medication
- Big question: DO THE BENEFITS OUTWEIGH THE RISKS??
Indications of a medication: (reasons for use)
For a specific population with solid data on security and effectiveness
APPROVAL IS FOR THE INDICATIONS, NOT THE MEDICATION AS A WHOLE
What happens once a medication is approved?
Given “avis de conformité”, a DIN, and put out on the market
Facts about clinical trials in Canada:
Currently > 500 new products being developed here
BUT Canada only receives 1% of global funding for drug development
What is the Canadian center for coordination of clinical trials?
9 recommendations for better coordination and to increase participation in Canadian clinical trials
Want to simplify procedures followed by companies and researchers
What are the rules concerning the development of a new drug?
GXP:
- GLP: good laboratory practices
- GCP: good clinical practices
- GMP: good manufacturing practices
ICH: International Conference on Harmonization
… What are the objectives of these rules?
- Protect rights and security of patients
- Assure integrity of products
What laws do Canadian companies/Quebec companies need to follow in terms of Ethics?
Nuremberg Code (1947)
Helsinki Declaration (1964)
Free and informed consent
Quebec civil code
Sometimes companies will pull their drugs off the market… why?
Proven acquired risk associated with taken these medications
What are the 5 Bs of pharmacotherapy?
Bon medicament, bon patient, bon dose, bonne voie et bon moment
What are you looking for when studying pharmacotherapies?
The link between the dose and the effect
What are the 4 steps of pharmacokinetics?
- Absorption: irreversible transfer of the active ingredient from the administration site to the systemic circulation
- Distribution: active ingredient can bind to plasmatic proteins (not always) and diffuse through tissues and organs… The medication then is distributed throughout the organism through the blood
- Metabolism: active ingredient is eliminated from the organism as metabolites either extra hepatic or hepatic (2 phases: Phase 1: “cytochrome” and Phase 2: “conjugaison”)
- Elimination: renal, intestinal elimination
What is pharmacodynamics?
Action of the medication on the organism
What is pharmacokinetics?
Action of the organism on the medication
What are the parameters used to measure each step of pharmacokinetics?
- Absorption —> bioavailability
- Distribution —> distribution volume, % fixed to plasmatic proteins
- Metabolism —> clearance
- Excretion/elimination —> clearance and half-life
How are medications metabolized? (liposoluble vs hydrosoluble)
Liposoluble molecules: absorbed, cross cellular membranes and then transformed into hydrosoluble molecules to then be eliminated
Hydrosoluble molecules: not really absorbed, not toxic, renal elimination
What is the effect of the first pass effect?
Renal elimination of medication before it reaches the bloodstream which lowers the bioavailability of the drug
What is the effect of grapefruit on medication?
Contains furanocoumarines that can interfere with how the body transforms certain medications
Are NHPs typically declared to doctors?
7/10 people will have taken NHPs in the past year but >70% will not declare that information
What are the categories of NHPs?
Vitamin/mineral supplements, plants, traditional remedies, homeopathic medicine, probiotics, enzymes, etc.
Who regulates NHPs?
Règlement sur les produits de santé naturel
All places that fabricate, export, package, label and import these products must have a license in order to legally distribute products in Canada
When can generic medications be produced?
After expiration of the patent “brevet” —> 20 years
What is the same between generic and brand name?
Active ingredients
Same strict federal production and quality control laws
Needs to respond to Health Canada’s bioequivalence laws
What is bioequivalence?
A strong similarity between 2 pharmaceutical products with the same active ingredient and dose
Absorbed similarly
Not likely to produce clinical differences concerning therapeutic and side effects
2 products are considered bioequivalent if?
studies show the same amount of active ingredient present in the blood of healthy patients as with the name brand product
What is a “proof of bioequivalence”?
Required element in the “dossier de demande d’inscription d’un médicament générique”
According to Health Canada, products are bioequivalent if what?
Same galenic formulation (ex: par os, IV) and contains the same dose of and types of active ingredients
What is different between generic and brand name?
Inactive ingredients (watch out for allergies)
Colour, shape and inscriptions on capsules
Price… usually cheaper
What is the intervalle de confiance (testing for bioequivalence)?
(90%) de 80-125%
CERTAIN medications have very narrow “intervalles de confiance” therefore the 80-125% rule do not apply
What does (90%) de 80-125% rule mean?
90% confidence interval of the ratio of a log-transformed exposure measure (ASC and/or Cmax) falls completely within the range 80-125% and the results must show that certain parameters are similar to those of the original medication
ASC of generic must not be < 80% or > 125% of the brand name
Cmax (average) must be between 80-125%
What are the roles of pharmaceutical companies in the transmission of information?
Since 2000, there has been a decrease in the development of new products
In recent years, the cost to develop new medications has increased SIGNIFICANTLY (billions $$$)
In recent years, the focus has shifted to publishing negative and neutral results of studies alongside positive ones to further increase clinical trial transparency
