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 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.

Figure 1.

Structure of the final pharmacokinetic model. k_el, elimination rate constant.

Figure 2.

Diagnostic plots of the population pharmacokinetic model. (a) Observed versus population-predicted plasma concentrations. (b) Observed versus individual-predicted plasma concentrations. (c) Weighted residuals versus time. (d) Weighted residuals versus population-predicted concentrations. The continuous lines are lines of identity. BLQ data are included in each plot.

Figure 3.

Prediction-corrected VPCs for plasma benzylpenicillin concentrations (mg/L on log₁₀ scale) for children with a lower BMI (<25 mg/kg²; a) and a higher BMI (≥25 mg/kg²; b). Observed 50th (continuous line) and 10th and 90th (dotted lines) percentiles within their simulated 95% CI (dark grey shading represents the 95% CI for the observed; light grey areas represent the 95% CI for the 10%–90% percentiles) are shown; data points are indicated by circles. Fraction BLQ (triangles with dashed black line) is also demonstrated with the simulated median (light grey line) and 95% CI (darker grey lines).

Figure 4.

Summary of simulations of 1000 children with a lower BMI [<25 mg/kg²; continuous black line (median) and dotted black lines (90% prediction intervals)] and a higher BMI [≥25 mg/kg²; dashed grey line (median) and dotted grey lines (90% prediction intervals)] with equal numbers of gender. (a) Percentage of time >0.02 mg/L. (b) Peak concentrations. (c) Trough concentrations.