Bioavailability comparison study of two benzathine benzylpenicillin 1,200,000 IU intramuscular formulations in healthy male participants under fast state
DOI:
https://doi.org/10.5327/DST-2177-8264-2024361373Keywords:
Benzathine benzylpenicillin, Penicillin G, Bioavailability, Biological availability, PharmacokineticsAbstract
Introduction: Benzathine benzylpenicillin G is a drug present in the list of essential medicines of the World Health Organization and largely used in Brazil, where this antibiotic is used for treating pneumonias, pharyngitis, syphilis, and other infections caused by Gram-positive bacteria, being one of the most prescribed antibiotics of the public healthcare system. Objective: The objective of this study was to evaluate the relative bioavailability of two formulations of benzathine
benzylpenicillin (Benzetacil®) 1,200,000 IU, both manufactured by Eurofarma Laboratórios S/A, by comparison of plasma levels of both drugs administered intramuscularly, evaluating the pharmacokinetic parameters: Cmax and AUC0-t, being t=672 h. Methods: A randomized, parallel, open-label study with one treatment and one period in 168 healthy male volunteers. Subjects received the test or reference formulations by intramuscular injection. A total of 20 blood samples were
collected after administration for plasmatic quantification of the drug by LC-MS/MS along 672 h. Results: Both formulations were considered well tolerated, and no serious adverse event was reported during the trial. Cmax and AUC0-t were compared: the rate between test and reference formulations for Cmax was 97.75% with confidence interval (CI) (86.34–110.67%) and power 90.55%. The rate between test and reference formulations for AUC0-t was 91.15% CI (85.29–97.42%)
and power of 99.99%. The rate between test and reference formulations for AUC0-inf was 87.98% with CI (81.29–95.23%) and power of 99.85%. Conclusion: Reference and test formulations were shown to be statistically bioequivalents according to their rate and extension of absorption, based on ANVISA criteria.
Downloads
References
World Health Organization. WHO model list of essencial medicines.
Geneva: World Health Organization; 2021.
World Health Organization. WHO guidelines for the treatment of
treponema pallidum (syphilis). Geneva: World Health Organization; 2016.
Braail. Ministério da Saúde. Secretaria de Ciência, Tecnologia, Inovação
e Insumos Estratégicos em Saúde. Departamento de Assistência
Farmacêutica e Insumos Estratégicos. Relação nacional de medicamentos
essenciais: reaname 2022. Brasília: Ministério da Saúde; 2022.
Katzung BG. Basic and clinical pharmacology. New York: McGraw-Hill
Education; 2017.
Brasil. Ministério da Saúde, Secretaria de Vigilância em Saúde e
Ambiente Departamento de HIV/AIDS Tuberculose Hepatites Virais e
Infecções Sexualmente Transmissíveis. Boletim Epidemiológico. Sifilis
Brasilia: Ministério da Saúde; 2023.
Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved
Tool supplement detection and treatment of syphilis in pregnancy to
reduce syphilis related stillbirths and neonatal mortality. BMC Public
Health. 2011;11 Suppl 3(Suppl 3):S9. https://doi.org/10.1186/1471-
-11-S3-S9
Wyber R, Taubert K, Marko S, Kaplan EL. Benzathine Penicillin G for the
management of RHD: concerns about quality and access, and opportunities
for intervention and improvement. Glob Heart. 2013;8(3):227-34. https://
doi.org/10.1016/j.gheart.2013.08.011
Gomez GB, Kamb ML, Newman LM, Mark J, Broutet N, Hawkes
SJ. Untreated maternal syphilis and adverse outcomes of pregnancy:
a systematic review and meta-analysis. Bull World Health Organ.
;91(3):217-26. https://doi.org/10.2471/BLT.12.107623
King Pharmaceuticals I. Bicillin® L-A (penicillin G benzathine injectable
suspension) Drug Label: Food And Drug Administration – USA; 2012
[cited on June 03, 2022]. Available from: https://www.accessdata.fda.gov/
drugsatfda_docs/label/2012/050141s231lbl.pdf
BICILLIN L-A- penicillin g benzathine injection, suspension. New
York: Pfizer Laboratories Div Pfizer Inc; 2021. [cited on June 03, 2022].
Available from: https://labeling.pfizer.com/ShowLabeling.aspx?id=691
Allergic reactions to long-term benzathine penicillin prophylaxis for
rheumatic fever. International Rheumatic Fever Study Group. Lancet.
;337(8753):1308-10. PMID: 1674296.
Kaplan EL, Berrios X, Speth J, Siefferman T, Guzman B, Quesny F.
Pharmacokinetics of benzathine penicillin G: serum levels during the
days after intramuscular injection of 1,200,000 units. J Pediatr.
;115(1):146-50. https://doi.org/10.1016/s0022-3476(89)80352-x
Currie B. Benzathine penicillin–down but not out. Northern Territory Dis
Control Bull. 2006:13:1-3.
Araujo RS, Souza ASS, Braga JU. Who was affected by the shortage of
penicillin for syphilis in Rio de Janeiro, 2013-2017? Rev Saude Publica.
;54:109. https://doi.org/10.11606/s1518-8787.2020054002196
Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes 3rd
NAM, et al. 2011 ACCF/AHA/HRS focused update on the management of
patients with atrial fibrillation (updating the 2006 guideline): a report of the
American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Circulation. 2011;123(1):104-23.
https://doi.org/10.1161/CIR.0b013e3181fa3cf4
Carapetis JR, Beaton A, Cunningham MW, Guilherme L, Karthikeyan G,
Mayosi BM, et al. Acute rheumatic fever and rheumatic heart disease. Nat
Rev Dis Primers. 2016;2:15084. https://doi.org/10.1038/nrdp.2015.84
Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ,
Gorbach SL, et al. Practice guidelines for the diagnosis and management
of skin and soft tissue infections: 2014 update by the Infectious Diseases
Society of America. Clin Infect Dis. 2014;59(2):e10-52. https://doi.
org/10.1093/cid/ciu444
Shahbazi MA, Azimi K, Hamidi M. Benzathine penicillin G: a model
for long-term pharmacokinetic comparison of parenteral long-acting
formulations. J Clin Pharm Ther. 2013;38(2):131-5. https://doi.
org/10.1111/jcpt.12014
Brasil. Ministério da Saúde. Agência Nacional de Vigilância Sanitária.
Resolução –RE 1.170, de 19 de abril de 2006.
Brasil. Ministério da Saúde. Conselho Nacional de Saúde. Resolução no
, de 12 de dezembro de 2012.
International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use. Guideline for good clinical practice
E6(R1). Geneva: ICH; 1996.
Brasil. Agência Nacional de Vigilância Sanitária. Benzetacil. Bula para
profissional de saúde. Anvisa; 2020 [cited on May 25, 2022]. Available from:
https://consultas.anvisa.gov.br/#/bulario/q/?nomeProduto=benzetacil
Garcia JFB, Aun MV, Motta AA, Castells M, Kalil J, Giavina-Bianchi
P. Algorithm to guide re-exposure to penicillin in allergic pregnant
women with syphilis: efficacy and safety. World Allergy Organ J.
;14(6):100549. https://doi.org/10.1016/j.waojou.2021.100549
Kaya A, Erkoçoğlu M, Senkon OG, Ekici FK, Toyran M, Çetin II,
et al. Confirmed penicillin allergy among patients receiving benzathine
penicillin prophylaxis for acute rheumatic fever. Allergol Immunopathol
(Madr). 2014;42(4):289-92. https://doi.org/10.1016/j.aller.2012.12.007
Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman and Gilman’s:
the pharmacological basis of therapeutics. 13th ed. New York: McGraw-
Hill Education; 2017.
Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haidar SH, Patel DT,
et al. Comparing generic and innovator drugs: a review of 12 years of
bioequivalence data from the United States Food and Drug Administration.
Ann Pharmacother. 2009;43(10):1583-97. https://doi.org/10.1345/
aph.1M141
European Medicines Agency. Committee for Medicinal Products for
Human Use. Guideline on the investigation of bioequivalence. 2010
[cited on June 04, 2022]. Available from: https://www.ema.europa.eu/en/
documents/scientific-guideline/guideline-investigation-bioequivalencerev1_
en.pdf
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Brazilian Journal of Sexually Transmitted Diseases
This work is licensed under a Creative Commons Attribution 4.0 International License.
