Withdrawn drug and Warnings Flashcards
Safety studies required before
use in humans of an
investigational new drug (IND)
- Safety pharmacology (e.g., vital organ function)
- ADME
- Single dose in two mammalian species
- Repeated dose toxicity
- Genotoxicity
- Immunotoxicity
Phase IV… population
Drug
On the market
Adverse Drug Reactions
Yes
Monitor frequency,
severity, and balance
with effectiveness
Benefit > Cost BBW
Cost > Benefit Withdraw
Overview of major toxicity
types associated with drug
withdrawals
cardiovasc 16%
hematological 11%
hepatic 21%
Drugs usually withdrawn earlier than
later
q
Early toxicity testing
- 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
Withdrawn drugs (examples)
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
Troglitazone Reactive metabolites
Other ‘glitazones’
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 heart failure (withdrawn) (due to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?
So what’s important?
* Dose?
* Metabolism (Reactive metabolites)?
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
Lumiracoxib vs Diclofenac
- 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
Reactive metabolites…probably involved
q
Ibuprofen vs Ibufenac
- 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
So, is metabolism important?
- 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?
Black Box Warning Drugs
- 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
Black Box Warning Drugs
* Clozapine
- 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
clozapine monitoring registry
q
Can we get around it?
- 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
Isoniazid
- 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
Lamotrigine
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.
Tyrosine kinase inhibitors (TKIs)
- 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
Example, dasatinib
Different ring substitutions affected GSH adduct formation!
Ingrifatinib
- Orally active
- TKI
- Low IC50 (nM) for FGFR
- Thought to binds to CYP enzymes
Can we reduce BBW toxicity/risk?
- 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.`
Just because it’s withdrawn here, doesn’t
mean it’s gone…
- 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.
