A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies

Robert M. Hand, Sam Salman, Nelly Newall, Julie Vine, Madhu Page-Sharp, Asha C. Bowen, Katherine Gray, Amy Baker, Joseph Kado, John Joseph, Julie Marsh, James Ramsay, Dianne Sika-Paotonu, Kevin T. Batty, Laurens Manning, Jonathan Carapetis

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Abstract

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 t1=2. 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.

Original languageEnglish
Pages (from-to)1984-1991
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume74
Issue number7
DOIs
Publication statusPublished - 1 Jul 2019

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Penicillin G Benzathine
Rheumatic Heart Disease
Penicillin G
Pharmacokinetics
Population
Rheumatic Fever
Weights and Measures
Intramuscular Injections
Longitudinal Studies

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Hand, Robert M. ; Salman, Sam ; Newall, Nelly ; Vine, Julie ; Page-Sharp, Madhu ; Bowen, Asha C. ; Gray, Katherine ; Baker, Amy ; Kado, Joseph ; Joseph, John ; Marsh, Julie ; Ramsay, James ; Sika-Paotonu, Dianne ; Batty, Kevin T. ; Manning, Laurens ; Carapetis, Jonathan. / A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease : new insights for improved secondary prophylaxis strategies. In: Journal of Antimicrobial Chemotherapy. 2019 ; Vol. 74, No. 7. pp. 1984-1991.
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title = "A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies",
abstract = "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 t1=2. 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.",
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A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease : new insights for improved secondary prophylaxis strategies. / Hand, Robert M.; Salman, Sam; Newall, Nelly; Vine, Julie; Page-Sharp, Madhu; Bowen, Asha C.; Gray, Katherine; Baker, Amy; Kado, Joseph; Joseph, John; Marsh, Julie; Ramsay, James; Sika-Paotonu, Dianne; Batty, Kevin T.; Manning, Laurens; Carapetis, Jonathan.

In: Journal of Antimicrobial Chemotherapy, Vol. 74, No. 7, 01.07.2019, p. 1984-1991.

Research output: Contribution to journalArticle

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T1 - A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease

T2 - new insights for improved secondary prophylaxis strategies

AU - Hand, Robert M.

AU - Salman, Sam

AU - Newall, Nelly

AU - Vine, Julie

AU - Page-Sharp, Madhu

AU - Bowen, Asha C.

AU - Gray, Katherine

AU - Baker, Amy

AU - Kado, Joseph

AU - Joseph, John

AU - Marsh, Julie

AU - Ramsay, James

AU - Sika-Paotonu, Dianne

AU - Batty, Kevin T.

AU - Manning, Laurens

AU - Carapetis, Jonathan

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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 t1=2. 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.

AB - 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 t1=2. 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.

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JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 7

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