Withdrawn drug and Warnings

Question 1

Safety studies required before
use in humans of an
investigational new drug (IND)

Answer 1

• Safety pharmacology (e.g., vital organ function)
• ADME
• Single dose in two mammalian species
• Repeated dose toxicity
• Genotoxicity
• Immunotoxicity

Question 2

Phase IV… population

Answer 2

Drug
On the market
Adverse Drug Reactions

Yes
Monitor frequency,
severity, and balance
with effectiveness

Benefit > Cost BBW

Cost > Benefit Withdraw

Question 3

Overview of major toxicity
types associated with drug
withdrawals

Answer 3

cardiovasc 16%
hematological 11%
hepatic 21%

Question 4

Drugs usually withdrawn earlier than
later

Answer 4

q

Question 5

Early toxicity testing

Answer 5

• Why do this early?
• Toxicity is the primary cause of drug attrition
• R&D costs have increased 100x from 1950-2010 and
  drugs are most likely to fail today than in the 1970s

Question 6

Withdrawn drugs (examples)

Answer 6

rezulin (troglitazone)
heapatotoxicity

Troglitazone
* Part of the “glitazone” family (thiazolidinedione), including pioglitazone
and rosiglitazone.
* PPAR𝜸 agonist, it was the only drug in its class at the time.
* These drugs were used for type II diabetes
* Why was it removed?
* Idiosyncratic liver toxicity (Type B ADR)
* Mar 2000, product was recalled (FDA)

Note the dose

Question 7

Troglitazone Reactive metabolites

Other ‘glitazones’

Answer 7

rosiglitazone
pioglitazone
less hepatotoxic, but…
Rosi -> heart failure (withdrawn) (due to
fluid retention)
Pioglitazone still available in Canada
What is this molecule ?
Does it look like the above?

Question 8

So what’s important?
* Dose?
* Metabolism (Reactive metabolites)?

Answer 8

Dose appears important…

Metabolism is important…usually.

What is this molecule ?
Does it look like the above?
The metabolism of troglitazone to reactive
metabolites can be rationalized here

Question 9

Lumiracoxib vs Diclofenac

Answer 9

• Reactive metabolites = yes
• Approved = no
• Reason : hepatotoxicity
• Dose: 400 mg
• Reactive metabolites = yes
• Approved = yes
• Dose: 100 mg
• Rare hepatotox: 1 -5 / 10 000
  users

Question 10

Reactive metabolites…probably involved

Answer 10

q

Question 11

Ibuprofen vs Ibufenac

Answer 11

• Both have ~ same dose
• Ibufenac is considered to have a
  more reactive acyl glucuronide
• BUT, ibuprofen still has protein
  adducts, but they don’t seem to
  matter much
• Ibufenac: hepatotox»RA benefit

Question 12

So, is metabolism important?

Answer 12

• Should be wary of metabolism, but it doesn’t have to be a show
  stopper.
• If it were, do you think acetaminophen would be approved
  today?

Question 13

Black Box Warning Drugs

Answer 13

• Drugs that we need to fulfil a certain therapy, but come at some
  acceptable risk.
• Clozapine (Clozaril®)
• Antipsychotic (used for treatment-resistant schizophrenia)
• Dose: 300 – 900 mg
• Major risk: agranulocytosis
• Isoniazid - anti-tuberculosis
• antibacterial
• Dose: 300 mg
• Major risk: hepatotoxicity
• Lamotrigine
• Anticonvulsant
• Dose: 600 mg
• Major risk: cutaneous ADRs

Question 14

Black Box Warning Drugs
* Clozapine

Answer 14

• Reactive metabolites
• History:
• Mid 1970s, Finland:
  17/100
  agranulocytosis
• 8/17 – died
• Withdrawn in 1975
  (Canada)
• Re-introduced in US in
  1989, 1991 in Canada
• Special authorization

Lots of clozapine reactive metabolites

Question 15

clozapine monitoring registry

Answer 15

q

Question 16

Can we get around it?

Answer 16

• Eli Lilly  let’s change the structure
• Not a complete replacement of clozapine
• Has caused weight gain, law suits
• Dose: 5 – 20 mg
• Rare agranulocytosis reports
  Olanzapine
  Fewer side-effects
  (but lower dose too!)

Point of care - WBC

Question 17

Isoniazid

Answer 17

• Liver toxicity
• A transient increase in ALT/AST is observed in 25% of patients, but
  most recover. 1% of the 25% may experience hepatototoxicity (INH
  hepatitis).
• Peripheral neuropathy – treatment must be terminated.
• Reactive metabolites: yes

Question 18

Lamotrigine

Answer 18

Usually well-tolerated antiepileptic.
* Fairly high incidence of cutaneous ADRs (> 10%); blood
dyscrasias and hepatotoxicity are rare.
* HLA associations – can be used for screening. This has been
successfully been applied for abacavir.

Question 19

Tyrosine kinase inhibitors (TKIs)

Answer 19

• TKIs are small heterocyclic compounds
• Used in oncology
• Imatinib (first in class, 2001)
• Many subsequent drugs have been developed to targets TKIs
  associated with receptors
• However, 22/33 of these drugs have liver injury risks

Question 20

Example, dasatinib

Answer 20

Different ring substitutions affected GSH adduct formation!

Question 21

Ingrifatinib

Answer 21

• Orally active
• TKI
• Low IC50 (nM) for FGFR
• Thought to binds to CYP enzymes

Question 22

Can we reduce BBW toxicity/risk?

Answer 22

• Combination therapy (research needed)
• Screening for human leukocyte antigen genotype
• Bousman et al., 2021. Review and Consensus on Pharmacogenomic
  Testing in Psychiatry. Pharmacopsychiatry. 54(1), pp. 5-17
• This review, like many before it, and cautious; they recommend using
  PGx for care during therapy, and hope to get to screening.`

Question 23

Just because it’s withdrawn here, doesn’t
mean it’s gone…

Answer 23

• Dipyrone or metamizole
• Approved in 1921 (USA, UK)
• Withdrawn in 1975
• In Canada – ok for veterinary use
• Reports indicate it can cause many side effects, especially
  agranulocytosis. In fact, anti-drug antibodies are likely formed
  (classic study of Wagner and Moeschlin, 1952 – blood from
  agran patient to naïve patient resulted in agran!)
• However, there is some geographic variability has been observed.