Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.
Adult
Antiviral Agents
/ administration & dosage
COVID-19
/ blood
Computer Simulation
Drug Dosage Calculations
Drug Repositioning
Female
Humans
Lung
/ metabolism
Male
Middle Aged
Models, Biological
Nitro Compounds
/ administration & dosage
Reproducibility of Results
Thiazoles
/ administration & dosage
Tissue Distribution
Young Adult
COVID-19 Drug Treatment
COVID-19
SARS-CoV-2
coronavirus
lung
pharmacokinetics
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
10
09
2020
received:
12
05
2020
accepted:
09
10
2020
pubmed:
22
10
2020
medline:
1
4
2021
entrez:
21
10
2020
Statut:
ppublish
Résumé
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.
Sections du résumé
BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC
METHODS
A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC
RESULTS
The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated.
CONCLUSION
The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.
Identifiants
pubmed: 33085781
doi: 10.1111/bcp.14619
pmc: PMC8056737
doi:
Substances chimiques
Antiviral Agents
0
Nitro Compounds
0
Thiazoles
0
nitazoxanide
SOA12P041N
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Validation Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
2078-2088Subventions
Organisme : Medical Research Council
ID : MR/S00467X/1
Pays : United Kingdom
Organisme : NIH HHS
ID : R24AI118397
Pays : United States
Organisme : Medical Research Council
ID : MR/V028391/1
Pays : United Kingdom
Organisme : NIH HHS
ID : R01AI134091
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_17167
Pays : United Kingdom
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Int J Clin Pharmacol Ther. 2002 May;40(5):213-20
pubmed: 12051573
Antiviral Res. 2020 Sep;181:104866
pubmed: 32659293
Lancet Infect Dis. 2014 Jul;14(7):609-18
pubmed: 24852376
Annu Rev Pathol. 2008;3:499-522
pubmed: 18039138
Pharm Res. 2002 Oct;19(10):1400-16
pubmed: 12425456
Int J Clin Pharmacol Ther. 2000 Aug;38(8):387-94
pubmed: 10984012
Natl Health Stat Report. 2018 Dec;(122):1-16
pubmed: 30707668
Aliment Pharmacol Ther. 2006 Nov 15;24(10):1423-30
pubmed: 17081163
J Neuroimmune Pharmacol. 2020 Sep;15(3):359-386
pubmed: 32696264
Antiviral Res. 2015 Feb;114:1-10
pubmed: 25451075
Front Immunol. 2019 Mar 19;10:531
pubmed: 30941148
J Pharm Sci. 2006 Jun;95(6):1238-57
pubmed: 16639716
J Cancer Sci Ther. 2012 Jul 21;4(7):ix-xi
pubmed: 22984635
Clin Pharmacokinet. 2008;47(4):261-75
pubmed: 18336055
Adv Parasitol. 2010;73:197-230
pubmed: 20627144
Drug Metab Dispos. 2010 Jul;38(7):1147-58
pubmed: 20368326
J Pharm Sci. 2005 Jun;94(6):1259-76
pubmed: 15858854
Expert Opin Drug Metab Toxicol. 2015 Jun;11(6):893-905
pubmed: 25797064
Bioanalysis. 2012 May;4(8):909-17
pubmed: 22533565
N Engl J Med. 2020 Feb 20;382(8):727-733
pubmed: 31978945
Clin Pharmacol Ther. 2020 Oct;108(4):775-790
pubmed: 32438446
Open Forum Infect Dis. 2020 Mar 23;7(4):ofaa105
pubmed: 32284951
Cell Res. 2020 Mar;30(3):269-271
pubmed: 32020029
J Virus Erad. 2020 Apr 30;6(2):52-60
pubmed: 32405422
Clin Infect Dis. 2020 Jul 28;71(15):732-739
pubmed: 32150618
Int J Clin Pharmacol Ther. 2002 May;40(5):221-7
pubmed: 12051574
J Infect Dis. 2010 Nov 1;202 Suppl 3:S351-5
pubmed: 20887223
Lancet. 2020 Mar 28;395(10229):1054-1062
pubmed: 32171076
J Adv Res. 2020 Mar 16;24:91-98
pubmed: 32257431
Antimicrob Agents Chemother. 2015 Feb;59(2):1061-9
pubmed: 25451059
Cell. 2020 Apr 16;181(2):281-292.e6
pubmed: 32155444
Antimicrob Agents Chemother. 2008 Nov;52(11):4069-71
pubmed: 18710916
Lancet. 2020 Jul 4;396(10243):27-38
pubmed: 32479829
Br J Pharmacol. 2020 Nov;177(21):4942-4966
pubmed: 32358833
Influenza Other Respir Viruses. 2017 May;11(3):240-246
pubmed: 28146320
Front Pharmacol. 2019 Feb 14;10:51
pubmed: 30837866
Br J Clin Pharmacol. 2015 Jan;79(1):6-17
pubmed: 24548174
Biomed Pharmacother. 2019 Feb;110:700-716
pubmed: 30553197
Clin Pharmacol Ther. 2021 Jul;110(1):64-68
pubmed: 33113246
iScience. 2019 Dec 20;22:299-313
pubmed: 31805434
Clin Pharmacokinet. 2014 Jul;53(7):611-24
pubmed: 24859035
Antiviral Res. 2008 Jan;77(1):56-63
pubmed: 17888524
ACS Chem Neurosci. 2020 Apr 15;11(8):1192-1194
pubmed: 32233443
Int J Pharm. 1999 Sep 20;186(2):119-25
pubmed: 10486429
Infect Dis Poverty. 2020 Mar 17;9(1):29
pubmed: 32183901
Clin Pharmacokinet. 2015 Jun;54(6):639-50
pubmed: 25523214
Crit Rev Toxicol. 2012 Oct;42(9):751-67
pubmed: 22954170
Antiviral Res. 2014 Oct;110:94-103
pubmed: 25108173
Mod Pathol. 2020 Nov;33(11):2104-2114
pubmed: 32561849
JAMA. 2020 May 12;323(18):1824-1836
pubmed: 32282022
Antimicrob Agents Chemother. 2018 Oct 24;62(11):
pubmed: 30104275
Antiviral Res. 2017 Nov;147:142-148
pubmed: 28986103
Parasitology. 2018 Feb;145(2):219-236
pubmed: 28805165
Trop Med Int Health. 2008 Dec;13(12):1470-8
pubmed: 19000156
J Pharmacokinet Pharmacodyn. 2008 Dec;35(6):635-59
pubmed: 19130188
Int J Oral Sci. 2020 Feb 24;12(1):8
pubmed: 32094336
Mol Ther. 2021 Feb 3;29(2):873-885
pubmed: 33333292
Clin Immunol. 2020 May;214:108393
pubmed: 32222466
J Infect Dis. 2019 May 5;219(11):1735-1742
pubmed: 30566691
Br J Clin Pharmacol. 2021 Apr;87(4):2078-2088
pubmed: 33085781