A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies.
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
received:
06
11
2018
revised:
27
01
2019
accepted:
29
01
2019
pubmed:
17
4
2019
medline:
12
8
2020
entrez:
17
4
2019
Statut:
ppublish
Résumé
Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD. We conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data. Eighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½. Few children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes.
Sections du résumé
BACKGROUND
Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD.
METHODS
We conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data.
RESULTS
Eighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½.
CONCLUSIONS
Few children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes.
Identifiants
pubmed: 30989171
pii: 5464313
doi: 10.1093/jac/dkz076
pmc: PMC6587412
doi:
Substances chimiques
Anti-Bacterial Agents
0
Biomarkers
0
Penicillin G Benzathine
RIT82F58GK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1984-1991Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
Références
Clin Pharmacol Ther. 1972 Jul-Aug;13(4):516-9
pubmed: 5042368
Eur J Radiol. 2006 Jun;58(3):480-4
pubmed: 16495027
Curr Opin Pediatr. 2015 Feb;27(1):116-23
pubmed: 25490689
Pharmacol Toxicol. 1995 Apr;76(4):259-62
pubmed: 7617556
Pediatr Infect Dis J. 2017 Jul;36(7):692-694
pubmed: 28121967
Antimicrob Agents Chemother. 2014 Nov;58(11):6735-41
pubmed: 25182635
Patient Prefer Adherence. 2015 Jul 02;9:923-42
pubmed: 26170642
Pediatrics. 1996 Jun;97(6 Pt 2):984-8
pubmed: 8637787
JAMA. 1968 Oct 14;206(3):565-8
pubmed: 5695575
Arthritis Rheum. 1990 Jan;33(1):91-4
pubmed: 2302272
Am J Clin Nutr. 1979 Nov;32(11):2233-6
pubmed: 495540
Drug Metab Pharmacokinet. 2009;24(1):25-36
pubmed: 19252334
J Am Med Assoc. 1952 Dec 20;150(16):1571-5
pubmed: 12990472
Drug Deliv Transl Res. 2016 Oct;6(5):572-8
pubmed: 27465618
Lancet. 2005 Jul 9-15;366(9480):155-68
pubmed: 16005340
N Engl J Med. 2017 Aug 24;377(8):713-722
pubmed: 28834488
Antimicrob Agents Chemother. 2017 Jul 25;61(8):
pubmed: 28559267
Vet Res Commun. 2002 Aug;26(6):459-65
pubmed: 12241099
Malar J. 2008 Aug 02;7:149
pubmed: 18673575
Antimicrob Agents Chemother. 2018 Sep 24;62(10):
pubmed: 30012775
Antimicrob Agents Chemother. 1994 May;38(5):1203-4
pubmed: 8067767
J Am Med Assoc. 1950 May 13;143(2):151-3
pubmed: 15415234
N Engl J Med. 1982 Aug 5;307(6):356-8
pubmed: 7088101
Curr Opin Infect Dis. 2012 Apr;25(2):145-53
pubmed: 22327467
J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504
pubmed: 11768292
N Engl J Med. 1959 Apr 2;260(14):697-702
pubmed: 13644570
Med J Aust. 2015 Sep 7;203(5):221.e1-7
pubmed: 26852054
Br J Clin Pract. 1957 Dec;11(12):936-9
pubmed: 13489129
South Med J. 1978 Mar;71(3):296-7
pubmed: 628854