Pharmacokinetic interactions of azithromycin and clinical implication
Keywords:
interacciones farmacológicas, azitromicina, farmacocinética, infecciones por coronavirus, COVID-19, SARS-CoV-2.Abstract
Introduction: The severe acute respiratory syndrome (due to COVID-19) is currently the leading cause of death in Peru, so effective and safe drugs are required to mitigate the disease. A bibliographic search was carried out in SciELO and PubMed/Medline; 37 of 58 articles on the topic were selected.Objectives: Review and integrate the information on the pharmacokinetic interactions of azithromycin that are prescribed in the outpatient treatment of COVID-19 in Peru, and evaluate their clinical implication.
Development: Azithromycin is used in COVID-19, due to its anti-inflammatory activity, by inhibiting interleukins (IL1, 6, 8 and TNF-α), and intracellular adhesion molecules 1 (ICAM1); and by inducing the production of type I interferon (IFN-α, IFN-β) and III (IFN-λ) in cells of patients with chronic obstructive pulmonary disease. The three-arm, randomized and open-label studies indicate that azithromycin does not cause changes in the pharmacokinetic parameters of ivermectin, sildenafil, rupatadine, and desloratadine; single-center, open-label, non-fasting, and two-period studies show that azithromycin influences the pharmacokinetic parameters of venetoclax and psychotropics.
Conclusions: Based on the evidence from the reviewed and integrated clinical studies, it is concluded that these are limited and of little clinical relevance, however, it is proposed to use the antibiotic under the scientific criteria of the doctor, to avoid pharmacokinetic interactions and adverse reactions of drugs.
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References
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11. Matzneller P, Krasniqi S, Kinzig M, Sorgel F, Huttner S, Lackner E, et al. Blood, tissue, and intracellular concentrations of azithromycin during and after end of therapy. Antimicrob Agents Chemother. 2013 [acceso: 05/01/2021];57(4): 1736-42. DOI: 10.1128/AAC.02011-12
12. Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol. 2003 [acceso: 10/01/2021]; 188(3): 714-18. DOI: 10.1067/mob.2003.141
13. Zheng Y, Liu SP, Xu BP, Shi ZR, Wang K, Yang JB, et al. Population pharmacokinetics and dosing optimization of azithromycin in children with community-acquired pneumonia. Antimicrob Agents Chemother. 2018 [acceso: 05/01/2021];62(9): e00686-18. DOI: 10.1128/AAC.00686-18
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15. Touret F, Gilles M, Barral K, Nougairède A, van Helden J, Decroly E, et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS‐CoV‐2 replication. Sci Rep. 2020 [acceso: 15/01/2021]; 10:13093. Disponible en: https://doi.org/10.1038/s41598-020-70143-6
16. Arnedo-Pena A, García-Marcos L, Fernández-Espinar JF, Bercedo-Sanz A, Aguinaga-Ontoso I, González- Díaz C, et al. Sunny hours and variations in the preva¬lence of asthma in schoolchildren according to the International Study of Asthma and Allergies (ISAAC) Phase III in Spain. Int J Biometeorol. 2011 [acceso: 15/01/2021]; 55(3): 423-34. Disponible en: https://pubmed.ncbi.nlm.nih.gov/20803035/
17. Menzel M, Akbarshahi H, Bjermer L, Uller L. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients. Sci. Rep. 2016 [acceso: 15/01/2021]; 6: 28698-709. Disponible en: https://pubmed.ncbi.nlm.nih.gov/27350308/
18. Dos Santos WG. Natural history of COVID-19 and current knowledge on treatment therapeutic options. Biomed Pharmacother. 2020 [acceso: 15/01/2021]; 129: 110493. Disponible en: https://pubmed.ncbi.nlm.nih.gov/32768971/
19. Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic Contribution to Variable Human CYP3A-Mediated Metabolism. Adv Drug Deliv Rev. 2002 [acceso: 15/01/2021]; 54(10):1271-94. DOI: 10.1016/s0169-409x(02)00066-2
20. Westlind-Johnsson A, Hermann R, Huennemeyer A, Hauns B, Lahu G, Nassr N, et al. Identification and Characterization of CYP3A4*20, a Novel Rare CYP3A4 Allele without Functional Activity. Clin Pharmacol Ther. 2006 [acceso: 15/01/2021]; 79(4): 339-49. DOI: 10.1016/j.clpt.2005.11.015
21. Tanaka E. Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes. J Clin Pharm Ther. 1998 [acceso: 15/01/2021]; 23(6): 403-16. DOI: 10.1046/j.1365-2710.1998.00086.x
22. Snyder B, Polasek T, Doogue MP. Drug interactions: principles and practice. Australian Prescriber. 2012 [acceso: 12/01/2021]; 35(3): 85-8. DOI: 10.18773/austprescr.2012.037
23. Ohno Y, Hisaka A, Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharmacokinet. 2007 [acceso: 12/01/2021]; 46(8):681-96. DOI: 10.2165/00003088-200746080-00005
24. Niemi M, Backman J, Fromm M, Neuvonen P, Kivisto K. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet. 2003 [acceso: 12/01/2021]; 42(9): 819-50. DOI: 10.2165/00003088-200342090-00003
25. Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet.1992 [acceso: 12/01/2021]; 23(2): 106-31. Disponible en: DOI: 10.2165/00003088-199223020-00004
26. von Rosensteil NA, Adam D. Macrolide antibacterials. Drug interactions of clinical significance. Drug Saf .1995 [acceso: 12/01/2021]; 13(2):105-22. DOI: 10.2165/00002018-199513020-00005
27. Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000 [acceso: 12/01/2021]; 50(4): 285-95. Disponible en: DOI: 10.1046/j.1365-2125.2000.00261.x
28. Zhanel GG, Dueck M, Hoban DJ, Vercaigne LM, Embil JM, Gin AS, et al. Review of macrolides and ketolides: focus on respiratory tract infections. Drugs. 2001 [acceso: 23/01/2021]; 61(4):443-98. DOI: 10.2165/00003495-200161040-00003
29. Shakeri-Nejad K, Stahlmann R. Drug interactions during therapy with three major groups of antimicrobial agents. Expert Opin Pharmacother. 2006 [acceso: 23/01/2021]; 7(6):639-51. DOI: 10.1517/14656566.7.6.639
30. Franco D, Henao Y, Monsalve M, Gutiérrez F, Hincapie J, Amariles P. Interacciones medicamentosas de agentes hipolipemiantes: Aproximación para establecer y valorar su relevancia clínica. Revisión estructurada. Farm Hosp. 2013 [acceso: 23/01/2021]; 37(6): 539-57. Disponible en: https://dx.doi.org/10.7399/FH.2013.37.6.1077
31. Machado-Alba JE, Martínez-Pulgarín DF, Gómez-Suta D. Prevalencia de potenciales interacciones farmacológicas de Azitromicina en Colombia, 2012-2013. Rev. salud pública. 2015 [acceso: 23/01/2021]; 17(3): 463-9. Disponible en: https://dx.doi.org/10.15446/rsap.v17n3.44142
32. Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Can Pharm J (Ott). 2016 [acceso: 23/01/2021]; 149(3): 139-52. DOI: 10.1177/1715163516641136
33. John LN, Bjerum C, Martinez PM, Likia R, Silus L, Wali C, et al. Pharmacokinetic and safety study of co-administration of albendazole, diethylcarbamazine, Ivermectin and azithromycin for the integrated treatment of Neglected Tropical Diseases. Clin Infect Dis. 2020 [acceso: 23/01/2021]: ciaa1202. DOI: 10.1093/cid/ciaa1202
34. Muirhead GJ, Faulkner S, Harness JA, Taubel J. The effects of steady-state erythromycin and azithromycin on the pharmacokinetics of sildenafil in healthy volunteers. Br J Clin Pharmacol. 2002 [acceso: 23/01/2021]; 53: 37S-43S. DOI: 10.1046/j.0306-5251.2001.00031.x
35. Solans A, Izquierdo I, Donado E, Antonijoan R, Peña J, Nadal T, et al. Pharmacokinetic and safety profile of rupatadine when coadministered with azithromycin at steady-state levels: a randomized, open-label, two-way, crossover, Phase I study. Clin Ther. 2008 [acceso: 23/01/2021]; 30(9): 1639-50. Disponible en: https://doi.org/10.1016/j.clinthera.2008.09.002
36. Agarwal SK, Tong B, Bueno OF, Menon RM, Salem AH. Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Adv Ther. 2018 [acceso: 23/01/2021]; 35(11): 2015-23. Disponible en: https://doi.org/10.1007/s12325-018-0793-y
37. Bilbul M, Paparone P, Kim AM, Mutalik S, Ernst CL. Psychopharmacology of COVID-19. Psychosomatics. 2020 [acceso: 23/01/2021]; 61(5): 411-27. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232075/pdf/main.pdf
2. Alvarado AT, Muñoz AM, Loja B, Miyasato JM, García JA, Cerro R, et al. Estudio de las variantes alélicas CYP2C9*2 y CYP2C9*3 en muestras de población mestiza peruana. Biomedica. 2019 [acceso: 15/12/2020]; 39(3): 601-10. DOI: 10.7705/biomedica.4636
3. Moreno I, Quiñones L, Catalán J, Miranda C, Roco A, Sasso J, et al. Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study. Biomedica. 2012 [acceso: 15/12/2020]; 32(4): 570-7. DOI: 10.1590/S0120-41572012000400012
4. Kong FYS, Rupasinghe TW, Simpson JA, Vodstrcil LA, Fairley CK, McConville MJ, et al. Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men. PLoS ONE. 2017 [acceso: 24/05/2021]; 12(3): e0174372. DOI: 10.1371/journal.pone.0174372
5. Pino-Marín D, Madrigal-Cadavid J, Amariles P. Relevancia clínica de interacciones de antibióticos relacionadas con cambios en la absorción: revisión estructurada. Rev CES Med. 2018 [acceso: 20/12/2020]; 32(3): 235-49. Disponible en: https://www.scielo.org.co/pdf/cesm/v32n3/0120-8705-cesm-32-03-235.pdf
6. Fohner AE, Sparreboom A, Altman RB, Klein TE. PharmGKB summary. Macrolide antibiotic pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet Genomics. 2017 [acceso: 20/12/2021]; 27(4):164-7. DOI: 10.1097/FPC.0000000000000270
7. López JM. Azitromicina: síntesis química, mecanismo de acción, farmacocinética. Info-Farmacia.Com. [acceso: 20/10/2020]. Disponible en: https://docs.google.com/viewer?a=v&pid=sites&srcid=aW5mby1mYXJtYWNpYS-5jb218aW5mby1mYXJtY-WNpYXxneDo1ZTQwMDQ1MDFhYWRjMTZl
8. Peters DH, Friedel HA, McTavish D. Azithromycin; A Review of Antimicrobial Activity, Pharmacokinetic Properties and Clinical Efficacy. Drugs. 1992 [acceso: 05/01/2021]; 44 (5): 750-99. DOI: 10.2165/00003495-199244050-00007
9. McMullan BJ, Mostaghim M: Prescribing azithromycin. Aust Prescr. 2015 [acceso: 05/01/2021];38(3): 87-9. Disponible en: https://www.nps.org.au/assets/bfcb06798716fdf9-d3971d4b774f-Prescribing-azithromycin.pdf
10. Lode H. The pharmacokinetics of azithromycin and their clinical significance. Eur. J. Clin. Microbiol. Infectar. Dis. 1991 [acceso: 05/01/2021]; 10 (10): 807-12. DOI: 10.1007/BF01975832
11. Matzneller P, Krasniqi S, Kinzig M, Sorgel F, Huttner S, Lackner E, et al. Blood, tissue, and intracellular concentrations of azithromycin during and after end of therapy. Antimicrob Agents Chemother. 2013 [acceso: 05/01/2021];57(4): 1736-42. DOI: 10.1128/AAC.02011-12
12. Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol. 2003 [acceso: 10/01/2021]; 188(3): 714-18. DOI: 10.1067/mob.2003.141
13. Zheng Y, Liu SP, Xu BP, Shi ZR, Wang K, Yang JB, et al. Population pharmacokinetics and dosing optimization of azithromycin in children with community-acquired pneumonia. Antimicrob Agents Chemother. 2018 [acceso: 05/01/2021];62(9): e00686-18. DOI: 10.1128/AAC.00686-18
14. Alfonso I, Calvo DM, Jiménez G, Lara C, Broche L. Azitromicina y efectos cardiovasculares notificados al Sistema Cubano de Farmacovigilancia, 2003-2012. Rev Cubana Farm. 2014 [acceso: 15/01/2021]; 48(2):519-28. Disponible en: https://www.medigraphic.com/pdfs/revcubfar/rcf-2014/rcf143q.pdf
15. Touret F, Gilles M, Barral K, Nougairède A, van Helden J, Decroly E, et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS‐CoV‐2 replication. Sci Rep. 2020 [acceso: 15/01/2021]; 10:13093. Disponible en: https://doi.org/10.1038/s41598-020-70143-6
16. Arnedo-Pena A, García-Marcos L, Fernández-Espinar JF, Bercedo-Sanz A, Aguinaga-Ontoso I, González- Díaz C, et al. Sunny hours and variations in the preva¬lence of asthma in schoolchildren according to the International Study of Asthma and Allergies (ISAAC) Phase III in Spain. Int J Biometeorol. 2011 [acceso: 15/01/2021]; 55(3): 423-34. Disponible en: https://pubmed.ncbi.nlm.nih.gov/20803035/
17. Menzel M, Akbarshahi H, Bjermer L, Uller L. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients. Sci. Rep. 2016 [acceso: 15/01/2021]; 6: 28698-709. Disponible en: https://pubmed.ncbi.nlm.nih.gov/27350308/
18. Dos Santos WG. Natural history of COVID-19 and current knowledge on treatment therapeutic options. Biomed Pharmacother. 2020 [acceso: 15/01/2021]; 129: 110493. Disponible en: https://pubmed.ncbi.nlm.nih.gov/32768971/
19. Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic Contribution to Variable Human CYP3A-Mediated Metabolism. Adv Drug Deliv Rev. 2002 [acceso: 15/01/2021]; 54(10):1271-94. DOI: 10.1016/s0169-409x(02)00066-2
20. Westlind-Johnsson A, Hermann R, Huennemeyer A, Hauns B, Lahu G, Nassr N, et al. Identification and Characterization of CYP3A4*20, a Novel Rare CYP3A4 Allele without Functional Activity. Clin Pharmacol Ther. 2006 [acceso: 15/01/2021]; 79(4): 339-49. DOI: 10.1016/j.clpt.2005.11.015
21. Tanaka E. Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes. J Clin Pharm Ther. 1998 [acceso: 15/01/2021]; 23(6): 403-16. DOI: 10.1046/j.1365-2710.1998.00086.x
22. Snyder B, Polasek T, Doogue MP. Drug interactions: principles and practice. Australian Prescriber. 2012 [acceso: 12/01/2021]; 35(3): 85-8. DOI: 10.18773/austprescr.2012.037
23. Ohno Y, Hisaka A, Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharmacokinet. 2007 [acceso: 12/01/2021]; 46(8):681-96. DOI: 10.2165/00003088-200746080-00005
24. Niemi M, Backman J, Fromm M, Neuvonen P, Kivisto K. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet. 2003 [acceso: 12/01/2021]; 42(9): 819-50. DOI: 10.2165/00003088-200342090-00003
25. Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet.1992 [acceso: 12/01/2021]; 23(2): 106-31. Disponible en: DOI: 10.2165/00003088-199223020-00004
26. von Rosensteil NA, Adam D. Macrolide antibacterials. Drug interactions of clinical significance. Drug Saf .1995 [acceso: 12/01/2021]; 13(2):105-22. DOI: 10.2165/00002018-199513020-00005
27. Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000 [acceso: 12/01/2021]; 50(4): 285-95. Disponible en: DOI: 10.1046/j.1365-2125.2000.00261.x
28. Zhanel GG, Dueck M, Hoban DJ, Vercaigne LM, Embil JM, Gin AS, et al. Review of macrolides and ketolides: focus on respiratory tract infections. Drugs. 2001 [acceso: 23/01/2021]; 61(4):443-98. DOI: 10.2165/00003495-200161040-00003
29. Shakeri-Nejad K, Stahlmann R. Drug interactions during therapy with three major groups of antimicrobial agents. Expert Opin Pharmacother. 2006 [acceso: 23/01/2021]; 7(6):639-51. DOI: 10.1517/14656566.7.6.639
30. Franco D, Henao Y, Monsalve M, Gutiérrez F, Hincapie J, Amariles P. Interacciones medicamentosas de agentes hipolipemiantes: Aproximación para establecer y valorar su relevancia clínica. Revisión estructurada. Farm Hosp. 2013 [acceso: 23/01/2021]; 37(6): 539-57. Disponible en: https://dx.doi.org/10.7399/FH.2013.37.6.1077
31. Machado-Alba JE, Martínez-Pulgarín DF, Gómez-Suta D. Prevalencia de potenciales interacciones farmacológicas de Azitromicina en Colombia, 2012-2013. Rev. salud pública. 2015 [acceso: 23/01/2021]; 17(3): 463-9. Disponible en: https://dx.doi.org/10.15446/rsap.v17n3.44142
32. Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Can Pharm J (Ott). 2016 [acceso: 23/01/2021]; 149(3): 139-52. DOI: 10.1177/1715163516641136
33. John LN, Bjerum C, Martinez PM, Likia R, Silus L, Wali C, et al. Pharmacokinetic and safety study of co-administration of albendazole, diethylcarbamazine, Ivermectin and azithromycin for the integrated treatment of Neglected Tropical Diseases. Clin Infect Dis. 2020 [acceso: 23/01/2021]: ciaa1202. DOI: 10.1093/cid/ciaa1202
34. Muirhead GJ, Faulkner S, Harness JA, Taubel J. The effects of steady-state erythromycin and azithromycin on the pharmacokinetics of sildenafil in healthy volunteers. Br J Clin Pharmacol. 2002 [acceso: 23/01/2021]; 53: 37S-43S. DOI: 10.1046/j.0306-5251.2001.00031.x
35. Solans A, Izquierdo I, Donado E, Antonijoan R, Peña J, Nadal T, et al. Pharmacokinetic and safety profile of rupatadine when coadministered with azithromycin at steady-state levels: a randomized, open-label, two-way, crossover, Phase I study. Clin Ther. 2008 [acceso: 23/01/2021]; 30(9): 1639-50. Disponible en: https://doi.org/10.1016/j.clinthera.2008.09.002
36. Agarwal SK, Tong B, Bueno OF, Menon RM, Salem AH. Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Adv Ther. 2018 [acceso: 23/01/2021]; 35(11): 2015-23. Disponible en: https://doi.org/10.1007/s12325-018-0793-y
37. Bilbul M, Paparone P, Kim AM, Mutalik S, Ernst CL. Psychopharmacology of COVID-19. Psychosomatics. 2020 [acceso: 23/01/2021]; 61(5): 411-27. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232075/pdf/main.pdf
Published
2021-07-01
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Saravia Bartra M, Losno García R, Valderrama-Wong M, Muñoz Jáuregui AM, Bendezú Acevedo M, García Ceccarelli J, et al. Pharmacokinetic interactions of azithromycin and clinical implication. Rev Cubana Med Milit [Internet]. 2021 Jul. 1 [cited 2025 Apr. 4];50(3):e02101284. Available from: https://revmedmilitar.sld.cu/index.php/mil/article/view/1284
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