Pharmacokinetic of HCQ and why late use not likely to provide a good clinical outcome in COVID 19 late-stage for any question Profahmaedali@gmail.com

1. Replace with your own text.Understanding HCQ Pharmacology is an
Essential Issue to Optimize its Use in
management of COVID-19
Dr Ahmed S. Ali
Dept. of pharmacology
Faculty of medicine
king Abdulaziz
University
KSA

2. Disclaimer
• This article is intended for education and research
purposes only.
• It is not a substitute nor aimed to change
recommendations provided by national or
international guidelines for the management of COVID-
19.
• Information is provided to illustrate concepts but not
aimed to be used for any kind of intervention in
clinical.
• Authors tried to do their best but do not guarantee,
the accuracy, reliability, completeness of the
information provided in this review

3. Objectives
• Review PK/PD characteristics of
4-aminoquinolenes
• Apply to design optimal dosage regimen
• When to start , dose , frequency , duration
• How to minimize ADE specially cardiac
toxicity
• Concepts and conclusion

4. INTRODUCTION
•
• At the end of 2019, a novel coronavirus was
identified as the cause of a cluster of
pneumonia cases in Wuhan, a city in the
Hubei Province of China.
• It rapidly spread, resulting in an epidemic
throughout China .
• In February 2020, the World Health
Organization designated the disease which
stands for coronavirus disease 2019 (COVID-
19)
• The virus that causes COVID-19 is designated
severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2).

5. VIROLOGY; Origin ? ??
the genomic comparison of
the receptor-binding domain
(RBD) in the spike protein of
SARS-CoV-2 against other
closely related
betacoronaviruses and the
original SARS-CoV virus
revealed that SARS-CoV-2
has significantly higher
binding affinity with
human angiotensin -
converting enzyme 2 (ACE2)
than any of the other viruses

6. CLINICAL FEATURES
• Incubation period — 4-
5 , up to 14 days after
exposure
• ●Mild 81 %.
• ●Severe disease 14 %
• ●Critical disease 5 %.
• ●Fatality rate variable
approx. 2.3 percent
among (severe and
critical Pt
• deaths reported
among noncritical cases
considered very rare .

7. Risk factors for severe illness

8. laboratory features associated with worse outcomes
• These include
• Lymphopenia
• Elevated liver enzymes
• Elevated lactate dehydrogenase (LDH)
• Elevated inflammatory markers (eg, C-reactive protein
[CRP], ferritin)
• Elevated D-dimer (>1 mcg/mL)
• Elevated prothrombin time (PT)
• ●Elevated troponin
• ●Elevated creatine phosphokinase (CPK)
• ●Acute kidney injury

9. Optimal time for the drug is the 1st concept

10. Our hypnosis
Early intervention
 Prevent viral replication (
HCQ/CQ )
 Enhance / protect
immune system
HCQ/CQ accumulate in
microphage ( Rh disease )
NB : SARS-2 invade
microphage
Naturiciticals
ZN , Vit B3 ( niacin )
camel milk )
Figure illustrate early & late phases of COVID-19
SHI, Y., WANG, Y., SHAO, C., HUANG, J., GAN, J., HUANG, X., BUCCI, E., PIACENTINI, M., IPPOLITO, G.
& MELINO, G. 2020. COVID-19 infection: the perspectives on immune responses. Nature Publishing
Group.

11. Ex of Therapies under investigation
Hydroxychloroquine/
Chloroquine
01 03
02 04
Lopinavir-
ritonavir
Remdesivir Interferon beta
05
Favipiravir
1
3

13. Hydroxychloroquine (HCQ) MOA
Figure : Simplified mechanism of Hydroxychloroquine against SARS-CoV-2
1- inhibit entry (interfere with the glycosylation of, ACE2 )
2- inhibit replication ( increasing endosome / lysosome pH )
SARS-CoV-2 life cycle

14. Chemistry of CQ/HCQ
diprotic
lipophilic
weak bases

15. Pharmacokinetics (ADME )

16. Absorption of HCQ
Nearly complete absorption after an oral
dose occurs within 2–4 h .
• Great intersubjective variability in extent of
absorption
• 30–100 %, ( average 70 %
Impact in covid-19
variability in efficacy and toxicity ,
• Serum drug level likely to improve clinical
outcome

17. Distribution
PK of CQ & HCQ are similar differential
sequestration in various tissues of the body
A model with three compartments is considered to
be more accurate
 very large volume of distribution VD
Vc ( central ) 437 L , Vp ( peripheral ) 1390 L
Protein binding: ~40%,
Impact on covid-19 ( access to lung tissues in
therapeutic level

18. Tissue level of HCQ in rats 40 mg/kg/day

19. CQ relative distribution , high level in
lung & Leukocytes

20. Effect of viral infection on distribution ??
• Background
• Chloroquine has two basic groups with Pka 1 =
8.1 , Pka2 = 10.2,
• At a physiologic pH of 7.4, 18 % of chloroquine
is monoprotonated CQ+ but still fat soluble and
able to traverse cell membranes.
• Ion trapping ( accumulation in lysosome )
• , chloroquine, is biprotonated ( CQ ++ ) in
lysosome (pH = 4–5 ),
• It is sequestered and prevented from traversing
back out to the cytoplasm )

21. Ion trapping , ( intracellular accumulation )
depend on PH difference

22. Effect of pH on % ionized, will impact access to lung
tissues and target site ( lysosome )

23. Illustration of complex relationship between blood level & target site level
Important issue is pH , gradient
Remember the drug is Basic , Viral infection in general lower pH ( Acidosis )
How about in acidosis ???

24. Figure 1. Pharmacokinetic data in critically ill patients and simulation ( 2020 )
Red dots represent HCQ blood levels for a dosing regimen of 200 mg three
times daily,
triangles represent HCQ blood levels after discontinuation of treatment,
circles represent HCQ blood levels for a dosing regimen of 200 mg twice daily.
The green shaded zone represents the 90% simulation interval obtained with
the model of Carmichael et al for HCQ 200 mg three times daily [2].

25. Figure 2. Hydroxychloroquine pharmacokinetic simulation
The brown A: 400 mg once daily for 5 days (
The blue B: 400 mg twice daily for 7 days (NCT04316377).
The pink C: 800 mg loading dose followed by 600 mg 8 hours later
and then 600 mg once daily for 4 days (NCT04308668).
The red line represents treatment D: 200 mg three times daily for 7 days [9].
The green line represents the recommended treatment E: 800 mg loading dose
followed by 200 mg twice daily for 6 days;
the green shaded zone represents its 90% simulation interval.
We recommended LD 600 mg to be divided into 3 doses also ( early use of HCQ )

27. CQ/HCQ cardiotoxicity
• Cardiotoxicity may be
seen with serum levels
of 1 mg/L (1000 ng/mL);
• serum levels reported in
life threating cases have
ranged from 1 to 210
mg/L (average, 60 mg/L).
• Suggestion
• Use multiple low dose /
day Infusion or SR
Formulation will be ideal
co-prescription of azithromycin in
Covid-19 could amplify this risk
with HCQ
(. Cardiology, 2020
? Severe illness , hypokalaemia,
cytokines
High risk of CV ADE of drugs

28. Conclusion
Fact : 2-3 days my be needed to attain effective level in lung
tissues & cells
Impact : Use HCQ as early as possible to insure efficacy ( before
acidosis & viral replication )
Fact : high peak level may increase cardiac toxicity
Impact : Divided LD into 3 or 4 doses / day to reduce peak/
trough fluctuation
Fact : Acidosis , , impair distribution and hence efficacy ( late
phase of Covid-19 )
Impact : Using HCQ in late phase of COVID-19 , efficacy is
questionable , higher risk of cardiac toxicity

29. Other issues to consider
HCQ, accumulation into leukocytes
HCQ : if used early it may , protect the immune system
HCQ act as anti inflammatory & prevent lung thrombosis
Additional unique favorable effects
Easley synthesized , low coast,
Effective orally , convenient
Well known pharmacology
Therapeutics drug monitoring . PK modeling l
Improving delivery to lung , Nano technology , inhalation

30. SMS
Pharmacologists are
essential members in
clinical trials team

31. Acknowledgment
Huda Alkerathy1 , Mahran S AbdulRahman 2;; Riyadh S.
Almalikil3 Abir S. Mohamed4; -Khalid A. Alfaifi5
Abdelbabgi El fadil6, Fatmah A. Alsubhi7 Nagla A
EL-Shitany7&8 $
1. Dept. of pharmacology faculty of medicine, King AbdulAziz University, KSA.
2. Dept. of Pharmacology, Faculty of Medicine, Assiut University, Egypt
3. Dept. of Pharmacology Faculty of Pharmacy, Umm Alqura University, KSA
4. Dept. of Internal Medicine , Faculty of Public health and tropical medicine, Jazan University
5. Department of Pharmacy, Medical Services Directorate, Taif, KSA.
6. Department of Medical Microbiology and Parasitology Faculty of Medicine, King Abdul-Aziz
University, KSA.
7. Dept. of Pharmacology and toxicology , Faculty of Pharmacy , King Abdul-Aziz University, KSA
8. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
Most Ph D & Master students , Voluntary helped in collecting data and presention
Specially ; Dr, Mohamed Zahir , Hamad Alharbi , Abdullah Almalki & Eman Hamed

32. 70 Most are 2020
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