‫بسم هللا الرحمن الرحيم‬

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PK/PD approach to predict the efficacy of
repurposed antiviral drugs for COVID-19
 Authors
Ahmed S Ali; Shahid Karim; Ibrahim M. Ayoub; AbdulHadi Burzangi Ragia Ghoneim,
Hanin Aljohani; Hmoud Alsamhan; Jehan Barakt

Dept. of pharmacology . Faculty of Medicine King Abdulaziz University

Dept. of Clinical pharmacy , Faculty of Pharmacy King Abdulaziz University

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Objectives
1. Integration of pharmacokinetics (PK)-pharmacodynamics (PD) data to
predict the efficacy of repurposed antiviral drugs against COVID-19 in
clinical setting.
2. Validation of our hypothesis.
Background
o COVID-19 is a complicated viral pneumonia caused by SARS-CoV-2
o Some antiviral drugs were repurposed against the virus
o Preliminary choices were essentially based on their in-vitro efficacy
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 Concepts
1. PK/PD approach allowed optimization of the use of
antibiotics or antifungal drugs in management of lung
infection
This approach, despite its importance, did not receive the
necessary attention early during the pandemic. But
evidence of its importance has begun to accumulate
2. An antiviral drug to be effective in management of viral
pneumonia, it must achieve adequate level in lung
tissues
3. Only protein-unbound drugs are available to traverse cell
membranes and exert a pharmacologic effect
4. We have to consider the viral kinetics (SARS-CoV-2) &
5. Pathophysiological changes associated with COVID-19.

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PK/PD approach
to optimize use
of antibiotics in
bacterial lung
infection is well
known

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 In management of COVID-19??

The drug development process

PD (in-vitro) PK/ADE (animal model) Human

IC50, IC90, selectivity ADME Phase I – Phase III
Protein binding Efficacy
Tissue level Safety
Interaction

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Characteristics
of Covid-19/
SARS-CoV-2
• Covid-19 is an acute complicated viral pneumonia ;
• SARS-CoV-2 : an obligatory intracellular pathogen, which
infects ciliated bronchial epithelial cells, Type 1 pneumocystis,
()
• Huge number of virions produced and released per cell
• Virus production was approximately 3×106 plaque-forming
units per culture,

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https://analyticalscience.wiley.com/do/10.1002/was.00020155
 Methodology

❑ Searching for drug profile of the specified drugs : Lopinavir , Remdesivir,

Favipiravir, Hydroxychloroquine and Arbidol
❑ - Summarizing Relevant Pharmacodynamic, Pharmacokinetic parameters.
❑ The Question is : Predict the achievement of therapeutic drug level at
target site
❑ -- Define efficacy PD parameter : IC 90
❑ We estimate or retrieve free drug level = likely to access lung cells
❑ Draw concentration vs time curve ; total , free , Cmax, Cmin + IC90
❑ Assumption the AUC free > IC 90 actual in vivo efficacy

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 Lopinavir/ritonavir (LPV/r)
• LPV is an antiretroviral protease inhibitor indicated
for the treatment of HIV-1 infection.
• It has been repurposed for management of COVID-
19,
• It is available in fixed combination with Ritonavir, a
potent inhibitor of CYP450 to enhance its oral
bioavailability
• LPV/r good bioavailability after oral administration
about 97%; peak level within 4 hr.
• Variability in drug level

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 PK/PD prediction of efficacy

In vitro In vivo

• LPV is >98% protein-bound in plasma.

• Pharmacodynamics • The Vd (central) 17 L.
• The elimination half-life 6.9 ± 2.2 h
• In vero 6 cells • The median plasma LPV peak (4 hr. post-dose) and
• (IC50) of Lopinavir trough (before next dose) concentration in Q12
regimen were about 18 ug/mL; ( total drug )
16.7 ug/ml. ✓ Many drug-drug interactions
✓ Side effects
✓ Predication : Very POOR access to lung tissues??
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 LPV 400 mg+ ret 100 BD in human

EC 50 ug/ml
30
total ug/ml
20 unbound ug/ ml

LPV Ug/ ml
EC 90
10
0.5
0.4
0.3
0.2
0.1
0.0
0 5 10 15
Time h

Fig. Total and free LPV median peak and trough levels in COVID-19 patients,
ritonavir-boosted Lopinavir 400/100 mg twice daily
Data adapted from [59]
High protein binding restricts the achievement of therapeutic level at target site

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 Clinical Trials

• Conflicting results were reported,

• Lack of efficacy?? (Cao et al., 2020)
• Faster viral clearance in a triple regimen
with inhaled ribavirin or interferon beta-1b
patients most have mild symptoms.
• Another study reported higher progression
to severe illness occurred in patients
received LPV/r arm (18%) versus those
received standard of care in USA (12%).
• A meta-analysis suggested a lake of efficacy
[56]

14 Viral clearance LPV/ Control

 Conclusion
• Alone, the combination of LPV/r had little therapeutic benefit
in patients with COVID-19
• May be beneficial when used in combination with other drugs,
including ribavirin and interferon beta-1b143,144.
• The Randomized Evaluation of COVID-19 therapy (RECOVERY)
trial, a national clinical trial program in the UK, has stopped
treatment with LPV/r as no significant beneficial effect was
observed in a randomized trial established in March 2020 with
a total of 1,596 patients145

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Remdesivir (RDV) (GS-5734) “The molecule of hope“ ???????
• A pro-drug, originally developed for hepatitis C. Later FDA
approval for COVID-19???
• Mechanism:
• It is categorized as RdRp (RNA polymerase) inhibitor
- Possible delayed chain termination (similar to entecavir)

• Dose (Intravenous): Per Study Protocol

- 200 mg on day 1, followed by 100 mg daily for various time
courses

• Adverse Events:
- Elevated LFTs (typically 2-3x normal), unclear significance
- GI symptoms (nausea, vomiting, gastroparesis, rectal bleeding)

RdRp: RNA-dependent RNA polymerase

 • Figure 1 RdRp Structure
Modeling of RDV onto the SARS-CoV-2

Cell Reports 2020 32DOI: (10.1016/j.celrep.2020.107940)

Copyright © 2020 The Authors Terms and Conditions
 The Lancet
Volume 396 Issue 10256 Pages 953-954 (October 2020)
DOI: 10.1016/S0140-6736(20)32019-5

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 Remdesivir IC50 and SARS-CoV-2

Activity Against SARS-CoV-2 (2019-CoV): Vero E6 Cells)

120 IC50=0.77 120

CC >100
IC50 = 0.770 nM 90 90
IC90 = 1,760 nM,

% Cytotoxicity
% Inhibition
cytotoxic concentration 60 60
>100 mM
30 30

0 0

-30 -30

0.1 1 10 100

Remdesivir [µM]

Source: Wang TP, et al. Cell Res. 2020;30:269-71.

 PK of Remdesivir and GS-441524
Remdesivir GS-441524

Parameter Day 1 Day 5 Day 1 Day 5

Cmax 5.44 µg/mL 2.61 µg/mL 0.15 µg/mL 0.14 µg/mL

9.03 µMb 4.33 µMb 0.52 µMb 0.48 µMb
2.92 h* µg/mL 1.56 h* µg/mL 2.24 h* µg/mL 2.23 h* µg/mL
AUC a
4.85 µMb 2.59 µMb 7.69 µMb 7.66 µMb
t½
0.98 (0.82–1.03)c h 0.89 (0.82–1.09)c h N/A 25.30 (24.10–30.32)c h

Free fraction 12.1% 85–127%

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• Zou H et al. Front.
Pharmaco 2020

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 Suggested PK Limitations
❖ its rapid transformation (within 2 hr.) to a slightly polar nucleoside with expected
lower ability to transport across cell membrane compared to Remdesivir.
❖ level of the nucleoside ( 0.14 ug/ ml ) is very low compared to EC50 or EC90 (FIG 1)
❖ The bio activation of nucleoside into monophosphate is a rate-limiting step
❖ lung tissues have a lower ability to metabolize GS-441524 to the triphosphate form
compared to liver cells,
• Yan and Muller concluded that GS-441524 is superior to Remdesivir for COVID-19
treatment. GS-441524 has more simple synthesis and documented in vivo efficacy in
animals.[45].
• Other investigators suggested using both IV and inhalation route to achieve optimal
efficacy in the management of COVID-19 [46]

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Fig 4: Total and free Remdesivir level, Nucleoside total level
Data adapted from[35]
It demonstrates the peak level of the pro drug is misleading, due to its short
half-life

RSV at steady state

C t ug/ ml

EC90 Free level ug/ml

Level ug/ml

1.0

EC50 ug/ml
0.5

Nuc ug/m
0.0
0 10 20 30
Time h

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Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19:
Results, Clinical Improvement Rates

Remdesivir Placebo
80
Clinical Improvement Rates (%)

65
60 58

40
27
23
20

3 3
0
Day 7 Day 14 Day 28
Days after Study Inclusion

Source: Wang Y, et al. Lancet. April 29, 2020 [Epub ahead of print]
 Remdesivir
Placebo
20

15
15
13
Remdesivir Randomized
Deaths (%)

10
10
9
Controlled Trial in Adults
with Severe COVID-19:
6
5 Results, Mortality
5
Source: Wang Y, et al. Lancet. April
29, 2020 [Epub ahead of print]

0
Day 7 Day 14 Day 28
Days after Study Inclusion
WHO

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 Conclusion

• Integration of PK/PD data of the repurposed drug is an effective tool to predict their
efficacy
• clinical finding more or less agreed with the predication of PK limitation of most
antiviral drugs.
• The following parameters are suggested to extend our novel approach for other drugs.
1- Time of free drug level > IC90
(variables, peak & trough levels; EC90, protein binding and half-life )
2- AUC0-24/IC90
(variables, peak & trough levels; EC90, protein binding and half-life)
3- Extent of lung access; (free drug level, Vd)
(variables protein binding, Vt, Ion trapping)

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 • VENISSE, N., PEYTAVIN, G., BOUCHET, S., GAGNIEU, M.-C., GARRAFFO, R.,
GUILHAUMOU, R., SOLAS, C., ANRS-AC43 CLINICAL PHARMACOLOGY
COMMITTEE, S. T. D. M. & TREATMENT PERSONALIZATION, G. 2020.
Concerns about pharmacokinetic (PK) and pharmacokinetic-
pharmacodynamics (PK-PD) studies in the new therapeutic area of
COVID-19 infection. Antiviral research, 181, 104866-104866.
• ZOU, H., BANERJEE, P., LEUNG, S. S. Y. & YAN, X. 2020. Application of
Pharmacokinetic-Pharmacodynamics Modeling in Drug Delivery:
Development and Challenges. Frontiers in Pharmacology, 11.

Key • WALSH, T. J., GOUTELLE, S., JELLIFFE, R. W., GOLDEN, J. A., LITTLE, E. A.,
DEVOE, C., MICKIENE, D., HAYES, M. & CONTE, J. E. 2010. Intrapulmonary
pharmacokinetics and pharmacodynamics of micafungin in adult lung
transplant patients. Antimicrobial agents and chemotherapy, 54, 3451-

References •
3459.
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 • Cao, B. et al. A trial of lopinavir-ritonavir in adults
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• PubMed Article Google Scholar
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poor efficacy Lopinavir-Ritonavir. No clinical benefit from use of

lopinavir-ritonavir in hospitalized COVID-19 patients
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