Transcript PCOL 301.6 Lect.4 (Gen. Principles)

Module 2
#4
Drug development
Plus other points worth remembering
2004-2005
Module 2 #4
• drug development
• drugs in children
• drug regulation
• drugs in the elderly
• drugs in pregnancy
• drug-drug interactions
2004-2005
drug development
patent life 20 years
phase 1
preclinical
phase 3
phase 2
phase 4
clinical
marketing
submission
to regulatory
agency
2004-2005
generic
drug regulation
a “drug” receives a drug identification
number (DIN) - (Federal Govt. - TPD)
• it must be safe and effective for the
indication
• no economic evaluation
• PR drugs need a prescription
• Over-the-counter (OTC) drugs are very
safe (usually)
most provinces have formularies
• the drug must have an advantage over
alternatives.
• economic evaluation (cost/QALY)
• interchangeability
2004-2005
Health Canada
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_e.html
• Therapeutic Products Directorate (TPD)
• Health Canada's Therapeutic Products Directorate is the
Canadian federal authority that regulates pharmaceutical
drugs and medical devices for human use. Prior to being
given market authorization, a manufacturer must present
substantive scientific evidence of a product's safety,
efficacy and quality as required by the Food and Drugs
Act and Regulations.
2004-2005
LET YOUR COMPUTER DO THE SEARCHING!
• ... Need to know how to market a new drug in
Canada?
• ... Want information on the drug regulatory process?
• ... Need to know what the newest drugs on the
Canadian market are?
• ... Want direct access to forms and policies?
• ... Need to know the requirements for labeling drugs?
• All this and more is available on the
• Therapeutic Products Directorate / Biologics and
Genetic Therapies Directorate / Marketed Health
Products Directorate Website (s)
at
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/
http://www.hc-sc.gc.ca/hpfb-dgpsa/bgtd-dpbtg/
2004-2005
ICH
http://www.ich.org/UrlGrpServer.jser?%40_ID=2
76&%40_TEMPLATE=254
• The International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) is a unique
project that brings together the regulatory
authorities of Europe, Japan, the United States and
Canada and experts from the pharmaceutical
industry in the these regions to discuss scientific
and technical aspects of product registration.
2004-2005
Clinical Trials Guidelines
• The ICH guideline: "General Considerations for
Clinical Trials" has been developed by an ICH
Expert Working Group ………. regulatory parties
which include Canada.
• The guideline provides an overview of drug
development during the clinical phases.
• The Therapeutic Products Directorate of Health
Canada has adopted this international guideline.
2004-2005
Clinical trials
• Overhead
2004-2005
What is a QALY?
A quality-adjusted life year (QALY) takes into account
both quantity and the quality of life generated by
Healthcare interventions. It is the arithmetic product of
life expectancy and a measure of the quality
of the remaining life years.
• quality adjusted life year
• quality of life rated by the public
• varies from 0 (dead) to 1.0 (robust health)
• cost/QALY $20,000 is good
• cost/QALY $100,000 is too expensive
2004-2005
• cost/QALY $20,000- $100,000 is debatable.
interchangeability
compare Cp/time curves in >17 normal volunteers:
each receives one oral dose of both drugs 2 weeks apart
plasma conc. (mg/L)
innovator
copycat
15
AUCc = 80-125%
AUCi
12
9
Tmax and Cmax
(same 80-125%)
6
3
0
0
10
time (hr)
2004-2005
20
30
drugs in pregnancy
US FDA Classification
www.perinatology.com/druglist.htm
?
http://www.fda.gov/womens/registries/default.htm
•A
Safe; lots of data
•B
Likely safe: animals OK
•C
Uncertain; risk vs. benefit
•D
Likely unsafe: risk vs. benefit
•X
Unsafe, do not use
•(see overhead)
2004-2005
drugs in pregnancy
the placenta is
a lipid barrier
unsafe
safe
2004-2005
www.motherisk.org
www.orpheus.ucsd.edu/ctis/
www.perinatology.com
ACE inhibitors
anticholinergics
anticancer drugs
hypoglycemic drugs
phenytoin
warfarin
renal tubular dygenesis
meconium ileus
CNS malformations
neonatal hypoglycemia
growth retardation
skeletal and CNS defects
hypertension
depression
diabetes
headache
nausea
thrombosis
methyldopa, beta blockers
tricyclics. fluoxetine
insulin, gluburide, metformin
acataminophen
Diclectin
heparin
Drugs in breast milk
• http://www.who.int/child-adolescenthealth/New_Publications/NUTRITION/BF_Maternal_Medi
cation.pdf
• http://www.ukmicentral.nhs.uk/drugpreg/qrg_p1.htm
• It contains a summary of the significance of the excretion of
the commonly used drugs via breast milk, and their
absorption by the infant.
• In the interests of clarity and easy reference this guide is
limited to those drugs which are more commonly prescribed
for breast-feeding mothers. It is not intended that it should
include
all
drugs
and
non-inclusion
does
not
imply
safety.
2004-2005
Drugs in breast milk
These drugs are unsuitable for administration to breast-feeding
mothers because;
Serious adverse effects have been described.
Serious adverse effects may be anticipated on theoretical
grounds.
These drugs can be administered to breast-feeding mothers only
where the mother and infant can be monitored.
Minor adverse effects have been described.
Insufficient information relating to breast-feeding available to
allow classification as a safe drug.
These drugs may be administered to breast-feeding mothers.
They either:
Are not excreted in breast milk. Are not absorbed by the infant.
Give very low levels in infant with no apparent effects
see overhead
2004-2005
• few studies done in kids
• some changes in
clearance
Changes in
clearance with
age:
Developmental
patterns of
CYP1A2 isoform
– caffeine as a
substrate
2004-2005
drugs in children
drugs in the elderly
those >65- 14% of population, 33% of prescription drugs, 25% of DAEs
average of 5 drugs per patient
physiologic changes
• reduced gastric acidity, gi motility decreased absorption?
• increased body fat
increase Vd (lipid sol)
• reduced GFR (0.5%/year)
decreased clearance
(water sol drugs)
CCr= (140-age)*Wt(kg)/ 0.81.SeCr (for females multiply by 0.85)
• reduced hepatic blood flow
2004-2005
decreased clearance
(not phase 2)
drug interactions
www.medletter.com
pharmacodynamic
2 drugs affecting the same
system: e.g. sedatives
pharmacokinetic
1 drug changes the ADME of
another
absorption
distribution
tetracycline/antacids, thyroxine/Ca
competition for albumin by
phenylbutazone and warfarin
probenecid/penicillin
CYP3A4 drugs
2004-2005
excretion
metabolism
Advisories and Warnings
The Marketed Health Products Directorate (MHPD),
Therapeutic Products Directorate (TPD) and the Biologic
and Genetic Therapies Directorate (BGTD) posts safety
alerts, public health advisories, press releases and other
notices from industry as a service to health professionals,
consumers, and other interested parties.
To receive the Newsletter and Advisories free by email, join Health Canada's Health_Prod_Info
mailing list
2004-2005
Advisories and warnings
• Important drug safety information for Paroxetine:
warning for SSRIs and other newer antidepressants regarding the potential for behavioural
and emotional changes, including risk of self-harm
- GlaxoSmithKline Inc.
Date: 2004-06-02
• Health Canada advises of potential adverse effects
of SSRIs and other anti-depressants on newborns
Date: 2004-08-09
2004-2005
summary
• the feds decide what drugs get on the market
• the provinces decide which ones to pay for
• drugs in pregnancy are problematic:
teratogenicity
• pediatric dosing is problematic, clearance
may be increased.
• geriatric dosing is problematic
2004-2005