Repurposed drugs and safety monitoring

1. REPURPOSED DRUGS
&
SAFETY MONITORING
Dr. Shubhatara Swamy

2. A scanning electron microscope image showing SARS-
CoV-2 (round blue objects) emerging from the surface of
cells cultured in the lab. The virus shown was isolated
from a patient in the U.S. Image captured and colorized
at NIAID's Rocky Mountain Laboratories (RML) in
Hamilton, Montana

3. REPURPOSED DRUGS
&
SAFETY MONITORING
• Global pandemic of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2)
• Critical need to rapidly develop new pharmacologic
interventions
“Necessity
is the mother of invention”

4. Introduction
• COVID-19 with other chronic conditions
• Outpatient basis or during hospitalization
• Potential or proven risk of the co-administration of
drugs
• Patients chronic treatments
• Treatments initiated during the acute phase of the disease

5. Importance during the
Pandemic
Known drugs but used in a different context (not what it was approved for)

6. Drug Repurposing
• Repositioning or Rediscovery
• Serendipitous discovery of pharmacological activity on
new targets
• Suggests a new possible indication of use
Thalidomide
Morning sickness
Multiple myeloma
Sildenafil
Angina & hypertension
Erectile dysfunction
Amantadine
Influenza
Parkinson’s disease

7. Drug Repurposing
• Speeds up the traditional process of drug discovery
• Reduces cost of development (Preclinical, Phase I &
II)
• By identifying a novel clinical use for drugs
• Proven safe and effective in humans
• Approved for other indications

8. Rationale
same molecular pathways
may be involved in
different diseases

9. Why is it relevant?
Risk of Drug–Drug Interaction
(DDI)

10. Pharmacokinetic Interactions
• Drug metabolizing enzymes or transporters (substrate,
inhibitor, inducer)
• Increase or decrease plasma concentrations
• Theoretical variations in exposure, known
concentration-effect relationship, existence of a
narrow therapeutic margin
• Helps in anticipating the risk and its nature

11. Pharmacokinetic Interactions
• Amplitude of the interaction can be determined from
(i) Dedicated interaction studies
(ii) Published retrospective studies or clinical case
reports
(iii) In vitro/in vivo extrapolation using prediction
methods

12. Pharmacokinetic Interactions
• Limitations –
• In healthy volunteers
• Amplitude of the interaction may be different in the target
population
• No evaluation of multiple interactions (polypharmacy)
• Therapeutic drug monitoring (TDM) can help
individually

13. Pharmacokinetic Interactions in Response
to Inflammation
• Alteration of drug transporters mechanisms (P-pg,
BCRP, MRP2, OATP2B1, OATP4A1)
• Alteration of drug metabolizing enzymes activity
(CYPs expression & activity by cytokines)

14. Pharmacodynamic Interactions
• Additive or antagonism of effects
• Knowledge of the mechanisms of action & safety
profiles →
• Anticipation of risk →
• Treatment can be adapted and/or an appropriate
therapeutic alternative is proposed

15. Rationale for drug candidates
selected for repurposing in
COVID-19

16. Sources of Evidence
PRECLINICAL
STUDIES

17. Potential Drugs
Antivirals Lopinavir/ritonavir (LPV/RTV); Remdesivir; Favipiravir
Antimalarials Chloroquine; Hydroxychloroquine
Antihypertensive drug Losartan
Immunosuppressive drugs Tocilizumab; Corticosteroids
Antibiotic Azithromycin
Convalescent plasma

18. Chloroquine(CQ)/ Hydroxychloroquine
(HCQ) in Pandemic
• FDA issued emergency authorization for use of HCQ
& later revoked it
• The National Task Force for COVID, India, also
recommended use of HCQ
• Events during this controversy (hoarding and drug shortage,
deaths due to the self-use, drug-related cardiotoxicity, profit for
Pharmaceuticals)

19. HCQ
• To prevent or treat malaria
• Disease-modifying antirheumatic drugs (DMARDs)
• WHO Model List of Essential Medicines 2019
• More potent than CQ with less severe side effects
• Retinopathy

20. Mode of action of CQ in malaria and the mechanism of CQ drug resistance
Khuroo MS. Chloroquine and hydroxychloroquine in coronavirus disease 2019 (COVID-19). Facts, fiction and the hype: a critical appraisal. Int J
Antimicrob Agents. 2020 Sep;56(3):106101. doi: 10.1016/j.ijantimicag.2020.106101. Epub 2020 Jul 17. PMID: 32687949; PMCID: PMC7366996.
Basis of HCQ use in rheumatic diseases

21. HCQ in COVID-19
• Antiviral mechanism poorly understood
• Inhibition of pH-dependent entry of virus into host cells or
• Blocking replication of enveloped viruses
• Has anti-inflammatory & immunomodulatory activities
(regulates production of TNFα, interferon & other
cytokines)

22. Proposed sites of action of hydroxychloroquine in SARS-CoV-2
infection.
Khuroo MS. Chloroquine and hydroxychloroquine in coronavirus disease 2019 (COVID-19). Facts, fiction and the hype: a critical appraisal. Int J
Antimicrob Agents. 2020 Sep;56(3):106101. doi: 10.1016/j.ijantimicag.2020.106101. Epub 2020 Jul 17. PMID: 32687949; PMCID: PMC7366996.

23. Major known Drug Interactions of HCQ
• Drugs causing QT prolongation (potentiate
cardiotoxicity)
Macrolides, Quinolones, Antifungals, Antidepressants,
Antiemetics
• Drugs inhibiting CYP450 enzymes (increase drug
levels and toxicity of CQ and HCQ)
Cimetidine, Diltiazem, Verapamil, Fluoxetine, Paroxetine,
Metronidazole

24. Major known Drug Interactions of HCQ
• CQ & HCQ inhibit P-gp (increased levels of drugs
eliminated through P-gp)
Digoxin, Ciclosporin
• Compete with metabolism of other drugs (increase their
bioavailability)
Metoprolol, Tamoxifen, Methotrexate
• Absorption affected by binding in the gut or altering of
stomach pH
Antacids, Kaolin, Proton Pump Inhibitors

25. Verdict on HCQ
• In vitro studies showed promise (Remdesivir)
• Major limitations (small sample size, variable baseline
viral loads, no reported clinical or safety outcomes)
• Paucity of data regarding dosing (safety & efficacy)

26. Verdict on HCQ
• No significant adverse effects reported for CQ at the
doses and durations proposed for COVID-19
• Pharmacodynamic DDI with HCQ
• QTc prolongation (additive cardiotoxicity)
• RECOVERY trial

27. Remdesivir
• Novel investigational antiviral nucleotide prodrug
• FDA approved
• To treat hospitalized COVID-19 adult patients
• To treat pediatric patients with 12 years of age and older
weighing at least 40 kg
• Investigational inhaled formulation (drug-device
combination)

28. Remdesivir
• Broad antiviral activity against RNA viruses (Filoviruses
Coronaviruses, Middle East respiratory syndrome coronavirus)
• Conflicting information on drug efficacy and limited
published clinical pharmacology & drug interaction
studies
• Statistically significant decrease in time to recovery
(return to normal activity or hospital discharge)

29. Remdesivir
• Decreased median time to recovery & increased
survival benefit
• National Institute of Health Adaptive COVID-19
Treatment Trial (ACTT)
• Emergency Use Authorization (EUA) for use of
remdesivir for the treatment of hospitalized patients
with COVID-19 on May 1, 2020
The FDA expanded the EUA for remdesivir following positive results from
the Phase III SIMPLE trial which evaluated remdesivir in hospitalized patients
with moderate COVID-19 pneumonia (NCT04292730), as well as results from
the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Phase
III Adaptive COVID-19 Treatment Trial 1 (ACTT-1; NCT04280705) in
hospitalized patients with a range of disease severity.

30. Role in Covid-19
• Halts viral replication
• By inhibiting the essential replicating enzymes RNA
dependent RNA Polymerase

31. Drug Interactions with Remdesivir
• Substrate of multiple cytochrome P450 enzymes
(CYP2C8, CYP2D6, CYP3A4)
• Impact of inhibitor/inducer significantly attenuated
[high to moderate extraction ratio (0.6–0.8)]
• Low potential for drug-drug interactions with the
administered drug

32. Drug Interactions with Remdesivir
• In view of available data on the inducing and/or
inhibiting potential of its metabolites, no
pharmacokinetic interaction is expected
• Remdesivir is very rapidly metabolized, its plasma
exposure is low
• Few significant interactions are therefore expected

33. Adverse Drug Events in VigiBase®
• 1004
• Elevation of liver enzymes and those arising from
kidney injury
1. Remdesivir-induced Symptomatic Bradycardia in the treatment of COVID-19 Disease. [published
online ahead of print, 2021 May 15]. HeartRhythm Case Rep. 2021;10.1016/j.hrcr.2021.05.004.
doi:10.1016/j.hrcr.2021.05.004 https://doi.org/10.1016/j.hrcr.2021.05.004
2. Probable Interaction Between Warfarin and the Combination of Remdesivir With Dexamethasone
for Coronavirus Disease 2019 (COVID-19) Treatment: A 2 Case Report. First Published April 15,
2021 https://doi.org/10.1177/08971900211008623
3. Remdesivir-Warfarin Interaction: A Case Report. HCA Healthcare Journal of Medicine (2020)
1:COVID-19 https://doi.org/10.36518/2689-0216.116

34. How did Remdesivir fare?

35. Verdict on Remdesivir
• Low certainty of evidence on beneficial effects of
remdesivir on important patient outcomes
• WHO recommended against remdesivir administration
• In hospitalized COVID-19 patients regardless of
disease severity (November 20th, 2020)
• Updated data shows little or no effect on hospitalized
patients with COVID-19 (indicated by overall mortality,
initiation of ventilation, hospital stay duration)

36. Verdict on Remdesivir
• Low certainty of evidence on beneficial effects of
remdesivir on important patient outcomes
• WHO recommended against remdesivir administration
• In hospitalized COVID-19 patients regardless of
disease severity (November 20th, 2020)

37. Verdict on Remdesivir
• Results of the 2 largest trials (ACTT-1 and Solidarity)
• Patients with all severities of COVID-19 (including
severe and critical)
• Vary slightly in their point estimate on the effect of
remdesivir on mortality
• Neither trial showed a statistically significant lower
mortality rate with remdesivir
In hospitalized adults with COVID-19, remdesivir
probably results in little to no difference in mortality
and no more than a small reduction in the need for
ventilation, but it probably improves the percentage
recovered and reduces serious adverse events. For
patients not receiving ventilation, a 5-day course
may provide greater benefits and fewer harms, with
lower drug costs, than a 10-day course

38. Corticosteroids
• Reviews of outcomes in other viral pneumonias
• No associations with improved survival
• High rates of complications including hyperglycemia,
psychosis, avascular necrosis
• Benefit in bacterial rather than viral infections

39. Corticosteroids
• Rationale for the use is to decrease the host
inflammatory responses
• Leading to acute lung injury & acute respiratory
distress syndrome(ARDS)
• Benefit outweighed by adverse effects (delayed viral
clearance & increased risk of secondary infection)

40. Corticosteroids in COVID-19
• Clinical evidence does not recommend the use of
corticosteroids
• Associated with increase in the viral load
• A clinical trial proved that dexamethasone saved the life of
seriously ill COVID-19 infected patients in UK
• Approved as an immediate treatment option for
hospitalized patients who were seriously ill & on ventilator

41. Mucormycosis (Zygomycosis)
• Rare but serious angio-invasive infection
• Caused by mucormycetes
• Infects lungs, sinuses and extends into the brain &
eyes
• Systemic corticosteroids/other immunomodulating
drugs in mild or moderate patients with COVID-19 to
be avoided

42. Interferons
• Type I interferon (interferon beta-1b)
• Monotherapy or in combination (lopinavir/ritonavir &
ribavirin)
• Decreased the time to nasopharyngeal swab
negativation (from 12 to 7 days)
• Low potential for pK DDIs (limited interactions with
CYPs)

43. Interferons in COVID-19
• Inhibits viral replication [via toll-like receptors (TLR)]
• IFNα & β displayed activity against the SARS-CoV in-
vitro
• Latest study revealed that IFN had slightly or no effect
on hospitalized patients with COVID-19 (overall
mortality, initiation of ventilation)

44. Interleukins
• Expression & activity of the hepatic isoenzymes
CYP1A2, CYP2C9, CYP2C19, CYP3A4 reduced by
cytokines (IL)
• IL-1, 6 (inflammatory cytokine)
• Anakinra (IL-1 alpha & beta competitive inhibitors on
IL-1 type I receptors)

45. Interleukins in COVID-19
• Proposed as symptomatic treatment for COVID-19
• Downregulates CYP expression
• Restores the CYP-mediated metabolism of drugs
• Previously reduced during the inflammatory process

46. Anticytokines or Immunomodulatory Agents
• Monoclonal antibodies against inflammatory cytokines
• Significant organ damage is caused by an amplified
immune response & cytokine release (cytokine storm)
• Tocilizumab & Sarilumab (IL-6 receptor antagonist, for
RA)
• Bevacizumab, Fingolimod, Eculizumab

47. Immunomodulatory Agents in COVID-19
• FDA approved for cytokine release syndrome
• Improved respiratory function, rapid defervescence,
successful discharge with one dose
• Lack of comparator group limits interpretation of the
drug specific effect
• Warrants caution until more data are available

48. Azithromycin
• Macrolide antibiotic
• Inhibits protein synthesis by binding to the 50S
ribosomal subunit
• Known P-gp inhibitor (CYP3A4, OATP1A2, OATP2B1)
• Active in vitro against Ebola

49. Azithromycin in COVID-19
• Immunomodulatory activity (increases expression of
interferon b & k during viral respiratory infections
• Moderately reduces production of TNFa
• To cover the risk of secondary bacterial infection

50. Azithromycin in COVID-19
• Weak inhibitor of CYP3A4 (few or no clinically
significant interactions)
• Combination with HCQ showed reduction in COVID-
19 associated mortality
• Co-prescription (QTc prolongation)
• Not pharmacokinetic but pharmacodynamic

51. To summarise…

52. Viral Induced Host Immune Response

53. Symptoms and grades of cytokine release syndrome (cytokine storm)
& its impact on drug exposure

54. Summary
• Potential DDIs or disease-drug interaction important
consideration in optimal treatment regimens
• Inflammatory response enforces changes in the
expression & activity of transporters
• Treatment of COVID-19 infection involves CYPs
enzymes & transporters (ABC, SLC )

55. Regulatory Perspective
• Accelerated approvals with minimal evidence
• Remdesivir (Ebola) during the pandemic
• Japan (Exceptional Approval Pathway), USA
(Emergency Use Authorization), United Kingdom
(Early Access to Medicine Scheme)
• At the cost of drug safety and effectiveness data

56. Take Home Message
• Assumption that benefits (in vitro/clinical evidence)
outweigh associated risks (adverse drug reactions)
• Propensity to cause acute toxicity
• Augmented toxicity with combination therapy
• Paucity of evidence demonstrating a clear benefit may
not justify the risk of the repurposed agent(s)

57. THANK YOU