Pharmacokinetic modeling
From the 24 individuals, there were 400 samples included in the PK analysis. The fraction of samples below the limit of quantification (LOQ) (BLQ) was low (11%), those measured between the LOQ and limit of detection (LOD), Visual inspection of the population data demonstrated a change in the terminal phase occurring after 42 days, with a steeper decline in inter-individual variability (IIV) estimated after this point. Several models with zero-order absorption were assessed with the best model consisting of two absorption paths, one a bolus into the depot compartment and the other a zero-order process into the same depot modeled as the duration (DUR). Absorption from this depot compartment was through a transit compartment with corresponding transit half-life (Structure of the pharmacokinetic model. The best model consisted of two absorption paths, one a bolus into the depot compartment and the other a zero-order process into the same depot modeled as the duration. Absorption from this depot compartment was through a transit compartment with corresponding transit half-life (The IIV was estimated on volume (V/F) as well as separate IIV values for SC administration for DUR, The final model parameter estimates and the bootstrap results are presented (Final population pharmacokinetic estimates and bootstrap results following subcutaneous infusions of benzathine benzylpenicillin GCalculated from bootstrap.RSE, relative standard error; Prediction-corrected visual predictive checks for plasma benzylpenicillin G concentrations (ng/mL on log10 scale). Observed 50th (solid line) and 10th and 90th (dotted lines) percentiles within their simulated 95% CI (gray shaded areas) are shown with overlying data points (ο, The population estimate for RATIO corresponds to 28% of the dose passing through the zero-order absorption pathway; notably, this parameter had the highest IIV (88%). The average duration of this process was around 44 days with the effect of BMI resulting in a range of 38–63 days for the lowest (Simulations demonstrated a longer proportion of time between doses above the threshold of 20 ng/mL for the 13-weekly SCIP 10.8 MIU dose [median 63%, 90% simulation interval (SI) (51%–77%)] compared to standard 4-weekly IM 1.2 MIU doses [median 39% (27%–56%)] (Simulations of the pharmacokinetic model comparing high-dose subcutaneous infusions of benzathine penicillin G (10.8 MIU, dark gray) with intramuscular injection (1.2 MIU, light gray). The shaded region represents median with 90% simulation interval.