DRUG DEVELOPMENT AND CONTROL Chapter 2 Dr. Dipa Brahmbhatt VMD MpH Ms [e-mail]

1
DRUG DEVELOPMENT AND CONTROLChapter 2 Dr. Dipa
Brahmbhatt VMD MpH Msdbrahmbh_at_yahoo.com
2
The development of drugs is both lengthy and
expensive average of 7 years of testing
usually costs millions of dollars
Many steps are involved (youll need
time AND money)
3
(No Transcript)
4
(No Transcript)
5
DRUG DEVELOPMENT

• Stage 1) The ___________or synthesis of a new
  drug with the potential for therapeutic value
• __________________________
• Series of tests run on computer models
• Testing in lab media,____________, or fungi
• to see if the drug produces the desired effect
• Observed side effects

6
DRUG DEVELOPMENT

• STAGE 2 - If the results are satisfactory,
• ______________________________________
• Drugs safety and effectiveness
• Laboratory animals / _____________ species
• Short-term and long-term tests
• Check for immediate drug reactions, organ
• damage, reproductive effects, carcinogenicity,
  and _________________________
• Submit _______________________ (INAD) application
  for the drug to the FDA
• Clinical trials begin once application is
  approved

7
(No Transcript)
8
Scientists are looking for signs of

• - Short-term toxicity reactions occurring
  _______________ after dosing such as convulsions
  or paralysis
• - Long-term toxicity ______________ months of
  regular dosing to check for organ damage. Animal
  is euthanized to examine the effects on tissues.
• - Systems-oriented screening tests the drugs
  effect on the body systems specifics on how it
  affects the_____________________ , nervous
  systems, etc.
• - Reproductive effects does it effect
  ovulation, conception, or _____________________
• -Carcinogenicity do large doses for a prolonged
  time cause tumors?
• -Teratogenicity are __________________ caused
  by administering the drug to pregnant animals?

9
Examples of teratogenicity
10
DRUG DEVELOPMENT

• Stage 2 If the preclinical trials are OK
• Application for an INAD (Investigational New
  Animal Drug) is filed with the FDA
• NOTE Pesticide ?EPA (Environmental Protection
  Agency), biologic (vaccines) ? USDA
• The FDA responds within ____________ days for
  approval

11
DRUG DEVELOPMENT

• Stage 2 Phase I Dose finding
• Limited clinical trials
• __________________ species
• Drug safety and effectiveness
• Short-term and long-term toxicity and
  effectiveness studies
• Toxicity, SE, tissue residue, withdrawal time
• _______________________________
• Pharmacokinetics

12
DRUG DEVELOPMENT

• Stage 2 Phase II Efficacy/Activity
• Target species with ___________ or condition
• Large scale clinical trials
• Different locations
• Submit ______________________________________(NAD
  A) to FDA (USDA/EPA)

13
DRUG DEVELOPMENT

• Stage III
• Phase III Comparative
• Target species
• Monitor drug efficacy and adverse reactions
• _____________________________ new drugs to
  existing treatments
• Approval and license are granted for successful
  drugs

14
DRUG DEVELOPMENT

• Stage IV Postmarketing surveillance stage
• The drug company and the government monitor
  (active versus passive) the product as long as
  the drug is manufactured
• This monitoring ensures product safety and
  efficacy

15

• Figure 2-1

16
ADVERSE REACTIONS Pre-approval clinical
trials Following treatment with REVOLUTION,
transient localized alopecia with or without
inflammation at or near the site of application
was observed in approximately 1 of 691 treated
cats. Other signs observed rarely (0.5 of 1743
treated cats and dogs) included vomiting, loose
stool or diarrhea with or without blood,
anorexia, lethargy, salivation, tachypnea, and
muscle tremors. Post-approval experience In
addition to the aforementioned clinical signs
that were reported in pre-approval clinical
trials, there have been reports of pruritis,
urticaria, erythema, ataxia, fever, and rare
reports of death. There have also been rare
reports of seizures in dogs (see WARNINGS)
17
http//www.revolution4cats.com/display.asp?country
USlangENdrugRVspeciesFLsec010
SAFETY REVOLUTION has been tested safe in over
100 different pure and mixed breeds of healthy
dogs and over 15 different pure and mixed breeds
of healthy cats, including pregnant and lactating
females, breeding males and females, puppies six
weeks of age and older, kittens eight weeks of
age and older, and avermectin-sensitive collies.
A kitten, estimated to be 56 weeks old (0.3 kg),
died 8 1/2 hours after receiving a single
treatment of REVOLUTION at the recommended
dosage. The kitten displayed clinical signs which
included muscle spasms, salivation and
neurological signs. The kitten was a stray with
an unknown history and was malnourished and
underweight (see PRECAUTIONS).
18

• Dogs
• In safety studies, REVOLUTION was administered
  at 1, 3, 5, and 10 times the recommended dose to
  six-week-old puppies, and no adverse reactions
  were observed. The safety of REVOLUTION
  administered orally also was tested in case of
  accidental oral ingestion. Oral administration of
  REVOLUTION at the recommended topical dose in 5-
  to 8-month-old beagles did not cause any adverse
  reactions. In a pre-clinical study selamectin was
  dosed orally to ivermectin-sensitive collies.
  Oral administration of 2.5, 10, and 15 mg/kg in
  this dose escalating study did not cause any
  adverse reactions however, eight hours after
  receiving 5 mg/kg orally, one avermectin-sensitive
  collie became ataxic for several hours, but did
  not show any other adverse reactions after
  receiving subsequent doses of 10 and 15 mg/kg
  orally. In a topical safety study conducted with
  avermectin-sensitive collies at 1, 3 and 5 times
  the recommended dose of REVOLUTION, salivation
  was observed in all treatment groups, including
  the vehicle control. REVOLUTION also was
  administered at 3 times the recommended dose to
  heartworm infected dogs, and no adverse effects
  were observed.
• Cats
• In safety studies, REVOLUTION was applied at 1,
  3, 5, and 10 times the recommended dose to
  six-week-old kittens. No adverse reactions were
  observed. The safety of REVOLUTION administered
  orally also was tested in case of accidental oral
  ingestion. Oral administration of the recommended
  topical dose of REVOLUTION to cats caused
  salivation and intermittent vomiting. REVOLUTION
  also was applied at 4 times the recommended dose
  to patent heartworm infected cats, and no adverse
  reactions were observed.
• In well-controlled clinical studies, REVOLUTION
  was used safely in animals receiving other
  frequently used veterinary products such as
  vaccines, anthelmintics, antiparasitics,
  antibiotics, steroids, collars, shampoos and dips.

19
Safety and Effectiveness Evaluation

• Short-term tests
• hours following a test dose
• check the animal for obvious _____________
• reactions
• Long-term tests
• typically run for 3 to 24 months of repeated
• dosing
• check the animals various __________ systems for
  
• toxicity damage

20
Safety and Effectiveness Evaluation

• Special tests (Short/ Long term tests)
• Reproductive affects
• Conception, fertilization, pregnancy
• Carcinogenicity
• _________________ causing
• Teratogenicity
• Fetal defects in pregnant animals

21
Toxicity Evaluation

• Conducted on mice
• ________________ dose that results in tissue and
  organ damage
• Highest dose that results in permanent injury or
  ________________

22
Effective and Lethal Dose

• Effective dose the amount of the test drug
  (dose) that causes a __________________ in 50 of
  the animals that receive it
• ED50
• _______________________ the amount of the test
  drug that kills 50 of the animals that receive
  it
• LD50

23
LD 50
24
Therapeutic Index

• Therapeutic index is the drug dosage
• or dose that produces the__________________
• with _________________ or no signs of toxicity
• Also called the margin of safety
• Determined by comparing the lethal dose and
  effective dose of the drug
• LD50 ED50
• A wide therapeutic index means that the drug can
  produce its desired effect without approaching
  __________________

25
Therapeutic Index Which Drug is Safer?

• Drug A is designed to lower heart rate (n100)
• It causes 50 of the mice to have a lower heart
  rate at a dosage of 2 mg/lb.
• Effective dose ED50 ________mg/lb
• Drug A is then given at 100 mg/lb and 50 of the
  mice die
• Lethal dose LD50 ______________ mg/lb
• TI LD50/ED50 100 mg/lb 2 mg/lb ______
• Since the Therapeutic Index is 50, one would have
  to ingest ___________ times the effective dose to
  ingest the ______________ dose

.
26
Therapeutic Index Which Drug is Safer?

• Drug B is also used to lower heart rate. It is
  given to 100 mice and produces a lower heart rate
  in 50 mice at 10 mg per pound (effective dose)
• When Drug B is given at a dose of 20 mg per
  pound, 50 mice die (lethal dose)
• TI LD50/ED50 20 mg per lb/10 mg per lb 2
• For Drug B, the TI is 2, which means that one
  would have to ingest _________________ the
  effective dose to ingest the lethal dose

27
Therapeutic Index Which Drug is Safer?

• DRUG A TI 50
• DRUG B TI 2
• DRUG A has the higher ______________ INDEX or
  ___________________________________

28
Additional Testing

• Systems-oriented screening
• After toxicity studies
• Specific _______________________ / body system
• Evaluation of long-term effects (Chronic studies)
• 3 months 2 yrs
• Histopathology
• Evaluation of reproductive effects,
  carcinogenicity, and teratogenicity

29
CHARLEY

• http//www.youtube.com/watch?vdJQG6V1MOVY
• an example of teratogenicity- cerebellar
  hypoplasia (most likely due to vaccination of the
  queen during gestation)

30
MEDICAL CALCULATION 2

• How many mg of drug should be given to a patient
  who weighs 22 lbs. if the dosage is 0.2 mg/kg
  body weight?
• 50 dextrose mg/ml?